WO2023149978A1

WO2023149978A1 - Cancer biomarkers and cancer treatments

Info

Publication number: WO2023149978A1
Application number: PCT/US2022/080569
Authority: WO
Inventors: John Lewicki; Ann KAPOUN; Ghanashyam SARIKONDA; Cedric WIESNER
Original assignee: Mereo Biopharma 5, Inc.
Priority date: 2022-02-04
Filing date: 2022-11-29
Publication date: 2023-08-10

Abstract

The present invention provides methods for identifying cancer patients for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody.

Description

CANCER BIOMARKERS AND CANCER TREATMENTS

TECHNICAL FIELD

[0001] The present invention relates to methods for identifying cancer patients for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, and in particular identifying patients with ovarian cancer, cervical cancer or uveal melanoma. The present invention also relates to methods of treating cancer comprising administering an anti-TIGIT antibody and an anti-PD-1 antibody.

BACKGROUND TO THE INVENTION

[0002] Cancer immunotherapy is a therapy used to treat cancer patients that involves or uses components of the immune system. Some cancer immunotherapies consist of antibodies that bind to, and inhibit the function of, proteins expressed by cancer cells. Other cancer immunotherapies include vaccines and T cell infusions. The immune system is a highly complex system made up of a great number of cell types, including but not limited to, T-cells, B-cells, natural killer cells, antigen-presenting cells, dendritic cells, monocytes, and macrophages. These cells possess complex and subtle systems for controlling their interactions and responses. The cells utilize both activating and inhibitory mechanisms and feedback loops to keep responses in check and not allow negative consequences of an uncontrolled immune response (e.g., autoimmune diseases).

[0003] Several evolutionarily conserved negative regulators of T cell activation act as ‘checkpoint molecules’ to fine-tune the immune response and regulate hyperactivation. Cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed cell death 1 (PD1) are examples of T cell immune checkpoint molecules.

[0004] Another example of an immune checkpoint inhibitor is T-cell immunoreceptor with Ig and ITIM domains (TIGIT), which is a type I transmembrane glycoprotein that contains an immunoglobulin variable (IgV) domain. TIGIT belongs to the poliovirus receptor (PVR) family and binds to the poliovirus receptor (PVR; CD155) with high affinity and to PVRL-2 (CD112) and PVRL-3 (CD113) with a lower affinity. TIGIT is expressed on T-cells, including regulatory T-cells (Tregs) and memory T-cells, as well as on NK cells and is upregulated following activation of naive CD4+ T-cells.

[0005] The immune system and response to immuno-therapy are complex. The effectiveness of anti-cancer agents can change based on the unique patient characteristics. Accordingly, there is a need for targeted therapeutic strategies that identify patients who are more likely to respond to a particular anti-cancer agent and, thus, improve the clinical outcome for patients diagnosed with cancer.

SUMMARY OF THE INVENTION

[0006] The inventors have shown that a combination of an anti-TIGIT antibody and an anti-PD-1 antibody is effective at treating PVR positive cancers, such as PVR positive (+) and PD-L1 negative (-) or PD-L1 positive (+) cancers. Therefore, in some aspects the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the method comprises (a) obtaining a tissue sample of the cancer from the patient; (b) determining that the cancer is PVR positive (+) and PD-L1 negative (-) or PD-L1 positive (+); and optionally (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+) and PD-L1 negative (-) or PD-L1 positive (+) cancer in the patient. In some embodiments, the method further comprises in step (b) determining that the cancer is TIGIT positive (+) and in step (c) optionally administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+) and TIGIT positive (+) cancer in the patient. In some embodiments, the method further comprises in step (b) determining that the cancer is CD226 positive and optionally in step (c) administering the anti-TIGIT antibody and the anti- PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) cancer in the patient. In some embodiments, the method further comprises in step (b) determining that the cancer is CD226 positive (+) and CD8 positive (+) and optionally in step (c) administering the anti-TIGIT antibody and the anti-PD- 1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) and CD8 positive (+) cancer in the patient.

[0007] In another aspect, the invention provides a method of treating cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody to the patient, wherein the cancer is PVR positive (+) and PD-L1 negative (-) or PD-L1 positive (+). In some embodiments, the cancer is PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+) and TIGIT positive (+). In some embodiments, the cancer is CD226 positive (+) and optionally CD8 positive (+).

[0008] The inventors have identified that a combination of an anti-TIGIT antibody and an anti-PD-1 antibody is effective at treating cervical cancers that are PVR positive (+) and PD-L1 positive (+). Therefore, in some aspects the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is cervical cancer, wherein the method comprises (a) obtaining a tissue sample of the cervical cancer from the patient; (b) determining that the cervical cancer is PVR positive (+) and PD-L1 positive (+); and optionally (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+) and PD-L1 positive (+) cervical cancer in the patient. In some embodiments, the method further comprises in step (b) determining that the cervical cancer is TIGIT positive (+) and in step (c) optionally administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 positive (+) and TIGIT positive (+) cervical cancer in the patient. In some embodiments, the method further comprises in step (b) determining that the cervical cancer is CD226 positive and optionally in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) cervical cancer in the patient. In some embodiments, the method further comprises in step (b) determining that the cervical cancer is CD226 positive (+) and CD8 positive (+) and optionally in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) and CD8 positive (+) cervical cancer in the patient.

[0009] In another aspect, the invention provides a method of treating cervical cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody to the patient, wherein the cervical cancer is PVR positive (+) and PD-L1 positive (+). In some embodiments, the cervical cancer is PVR positive (+), PD-L1 positive (+) and TIGIT positive (+). In some embodiments, the cervical cancer is CD226 positive (+) and optionally CD8 positive (+).

[0010] The inventors have identified that a combination of an anti-TIGIT antibody and an anti-PD-1 antibody is effective at treating ovarian cancers that are PVR positive (+) and PD- L1 negative (-). Therefore, in some aspects the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is ovarian cancer, wherein the method comprises (a) obtaining a tissue sample of the ovarian cancer from the patient; (b) determining that the ovarian cancer is PVR positive (+) and PD-L1 negative (-); and optionally (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+) and PD-L1 negative (-) ovarian cancer in the patient. In some embodiments, the method further comprises in step (b) determining that the ovarian cancer is TIGIT positive (+) and in step (c) optionally administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) and TIGIT positive (+) ovarian cancer in the patient. In some embodiments, the method further comprises in step (b) determining that the ovarian cancer is CD226 positive and optionally in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) ovarian cancer in the patient. In some embodiments, the method further comprises in step (b) determining that the ovarian cancer is CD226 positive (+) and CD8 positive (+) and optionally in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) and CD8 positive (+) ovarian cancer in the patient.

[0011] In another aspect, the invention provides a method of treating ovarian cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody to the patient, wherein the ovarian cancer is PVR positive (+) and PD-L1 negative (-). In some embodiments, the ovarian cancer is PVR positive (+), PD-L1 negative (-) and TIGIT positive (+). In some embodiments, the ovarian cancer is CD226 positive (+) and optionally CD8 positive (+).

[0012] The inventors have identified that a combination of an anti-TIGIT antibody and an anti-PD-1 antibody is effective at treating uveal melanomas that are PVR positive (+) and PD-L1 negative (-). Therefore, in some aspects the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is uveal melanoma, wherein the method comprises (a) obtaining a tissue sample of the uveal melanoma from the patient; (b) determining that the uveal melanoma is PVR positive (+) and PD-L1 negative (-); and optionally (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+) and PD-L1 negative (-) uveal melanoma in the patient. In some embodiments, the method further comprises in step (b) determining that the uveal melanoma is TIGIT negative (-) and in step (c) optionally administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) and TIGIT negative (-) uveal melanoma in the patient. In some embodiments, the method further comprises in step (b) determining that the uveal melanoma is CD226 positive and optionally in step (c) administering the anti-TIGIT antibody and the anti- PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) uveal melanoma in the patient. In some embodiments, the method further comprises in step (b) determining that the uveal melanoma is CD226 positive (+) and CD8 positive (+) and optionally in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD- L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) and CD8 positive (+) uveal melanoma in the patient.

[0013] In another aspect, the invention provides a method of treating uveal melanoma in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody to the patient, wherein the uveal melanoma is PVR positive (+) and PD-L1 negative (-). In some embodiments, the uveal melanoma is PVR positive (+), PD-L1 negative (-) and TIGIT negative (-). In some embodiments, the uveal melanoma is CD226 positive (+) and optionally CD8 positive (+).

[0014] The inventors have shown that a combination of an anti-TIGIT antibody and an anti-PD-1 antibody is effective at treating CD226 positive (+) cancers, such as CD226 positive (+) and CD8 positive (+). Therefore, in some aspects the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD- 1 antibody, wherein the method comprises (a) obtaining a tissue sample of the cancer from the patient; (b) determining that the cancer is CD226 positive (+) and optionally CD8 positive (+); and optionally (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the CD226 positive (+) and optionally CD8 positive (+) cancer in the patient. In one embodiment the cancer is selected from cervical cancer, ovarian cancer, and uveal melanoma. [0015] In another aspect, the invention provides a method of treating cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody to the patient, wherein the cancer is CD226 positive (+) and optionally CD8 positive (+). In one embodiment the cancer is selected from cervical cancer, ovarian cancer, and uveal melanoma.

[0016] The inventors have shown that a combination of an anti-TIGIT antibody and an anti-PD-1 antibody can be effective at treating cancers that have increased expression of IFNy- related markers, T cell exhaustion markers, Myeloid activation markers and/ or Tertiary lymphoid structure markers. Therefore, in some aspects the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD- 1 antibody, wherein the method comprises (a) obtaining a tissue sample of the cancer from the patient; (b) determining that the cancer has an increased expression of: (i) IFNy-related markers (ii) T cell exhaustion markers (iii) Myeloid activation markers and/ or (iv)Tertiary lymphoid structure markers and optionally (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the cancer with increased expression of IFNy, T cell exhaustion markers, Myeloid activation markers and/ or Tertiary lymphoid structures in the patient.

[0017] In another aspect, the invention provides a method of treating cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody to the patient, wherein the cancer has an increased expression of IFNy-related markers, T cell exhaustion markers, Myeloid activation markers and/ or Tertiary lymphoid structures. [0018] In one embodiment the cancer is selected from cervical cancer, ovarian cancer, and uveal melanoma.

[0019] In one embodiment the IFNy-related markers comprise one or more genes selected from the group consisting of IFNG, STAT1, CCR5, CXCL9, CXCL10, CXCL11, 1DO1, PRF1, GZMA, and MHCII HLA-DRA. In one embodiment the IFNy-related markers comprise at least two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more of said genes.

[0020] In one embodiment the T cell exhaustion markers comprise one or more genes selected from the group consisting of RPL13, ABCE1, ABLIM1, ACADM, ACP5, ADCY7, ADD1, ADH5, AKAP8, ANAPC5, ARHGAP1, ARHGEF1, ASCC1, ATP6V0A2, ATP6V0B, BN1P3L, BZW1, C5orf34, CCT3, CCT4, CCT5, CCT8, CD1D, CLK2, CRLF3, CTD- 2410N18.5, DGKA, DTX1, EEF2, E1F2S1, EPHB4, ETS1, EVPLL, FKBP4, GM2A, GTF21, HMGCS1, HSPA8, ICAM2, IFNAR1, ITGB7, KCNN4, KCTD10, KLF13, KLF2, KLF3, LBR, LEF1, MAP4K4, MAPK8, MAT2A, NFE2L2, NME1-NME2, NUMB, OSBPL11, PAK2, PDHA1, PDL1M1, P1K3CD, PLD3, PPP2R5A, PRPS1, RAP1GDS1, RP11-106M3.2, RPL10, RPL10A, RPL22, RPL3, RPL8, RPN2, RPS16, RPS3, RPS4X, RPS7, RPS8, SATB1, SEMA4A, S1AH1, SNRPD3, SNX4, SRPK1, SSI 8, STK38, TMC6, TUBB, UBP1, and ZNRF2. In one embodiment the T cell exhaustion markers comprise two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more of said genes. In one embodiment, the T cell exhaustion markers comprise 10 or more, 20 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, or 80 or more of said genes, such as 81, 82, 83, 84, 85 or 86 of said genes.

[0021] In one embodiment the Myeloid activation markers comprise one or more genes selected from the group consisting of Cxclll, Gbpl, and Idol. In one embodiment the Myeloid activation markers comprise at least two or more of said genes.

[0022] In one embodiment the Tertiary lymphoid structure markers comprise one or more genes selected from the group consisting of CD79A, MS4A1, LAMP3 and POU2AF1. In one embodiment the Tertiary lymphoid structure markers comprise at least two or more or three or more of said genes.

[0023] In some embodiments, the increased expression of said IFNy-related markers, T cell exhaustion markers, Myeloid activation markers and Tertiary lymphoid structures is determined by RNA sequencing (RNA-Seq). In other embodiments, the increased expression of said IFNy-related markers, T cell exhaustion markers, Myeloid activation markers and Tertiary lymphoid structures is determined by RT-PCR. [0024] In some embodiments, the anti-TIGIT antibody comprises a heavy chain variable region having at least 90% sequence identity to SEQ ID NO:7 and a light chain variable region having at least 90% sequence identity to SEQ ID NO: 8. In certain embodiments, the anti-TIGIT antibody comprises a heavy chain variable region comprising SEQ ID NO:7 and a light chain variable region comprising SEQ ID NO:8. In some embodiments, the anti-TIGIT antibody comprises a heavy chain having at least 90% sequence identity to SEQ ID NO:9 and a light chain having at least 90% sequence identity to SEQ ID NO: 10. In certain embodiments, the anti-TIGIT antibody comprises a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO: 10. In a preferred embodiment, the anti-TIGIT antibody is etigilimab. [0025] The anti-TIGIT antibody can be a monoclonal antibody, a humanized antibody, a human antibody, a chimeric antibody, a bispecific antibody, an IgGl antibody, an IgG2 antibody, an IgG4 antibody, or an antibody fragment comprising an antigen binding site. In some embodiments, the anti-PD-1 antibody is selected from the group consisting of pembrolizumab (Keytruda), nivolumab (Opdivo), cemiplimab (Libtayo), dostarlimab (Jemperli), Tislelizumab, Sintilimab, Zimberelimab, Toripalimab, Penpulimab, Balstilimab, Retifanlimab, Cetrelimab, Budigalimab, Pimivalimab, Spartalizumab, Serplulimab, Sasanlimab, Camrelizumab, Prolgolimab, Pucotenlimab, Ezabenlimab and Genolimzumab. In some embodiments, the expression of PVR, PD-L1 and TIGIT are determined using an IMF or IHC assay. In some embodiments, the expression of CD226 and CD8 are determined using an IMF or IHC assay.

BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1: FACS analysis was conducted with anti-TIGIT antibodies 313M32, 313M26 and 313R19 to assess the ability of these antibodies to block PVR binding to human TIGIT.

[0027] Figure 2: Inhibition of tumor growth by anti-TIGIT antibodies 313R19 and 313M32 in a humanized mouse model.

[0028] Figure 3 : Inhibition of tumor growth by anti-TIGIT antibodies. The colon tumor line CT26.WT was implanted subcutaneously into Balb/c mice (n = 10 mice/group). Mice were injected on days 10, 15, 18, 22, 25, and 29 with 0.25mg/mouse of anti-TIGIT antibody 313R11, anti-TIGIT antibody 313R12, mouse IgGl control antibody, and mouse IgG2 control antibody. Tumor growth was monitored and tumor volumes were measured with electronic calipers at the indicated time points. Data is shown as tumor volume (mm3) over days post injection. (A) The figure shows the mean values ± SEM for each group. (B) An additional study with anti- TIGIT antibody 313R12 and a control antibody. [0029] Figure 4: Figure 17A to 17F. In vivo tumor growth inhibition by anti-TIGIT antibody 313R12 and an anti-PD-Ll antibody. The murine colon tumor line CT26.WT was implanted subcutaneously (30,000 cells/mouse) in Balb/c mice. Mice were treated with 0.25mg/mouse of anti-TIGIT antibody 313R12, an anti-PD-Ll antibody, a combination of 313R12 and anti-PD-Ll antibody, or a control antibody (n = 10 per group). Mice were administered antibodies twice a week for 3 weeks. Tumor growth was monitored and tumor volumes were measured with electronic calipers at the indicated time points. (A) The tumor volumes of individual mice within group treated with control antibody. (B) The tumor volumes of individual mice within group treated with anti-TIGIT antibody 313R12. (C) The tumor volumes of individual mice within group treated with anti-PD-Ll antibody. (D) The tumor volumes of individual mice within group treated with anti-TIGIT antibody 313R12 and anti- PD-Ll antibody. (E) Average tumor growth of the four treatment groups. (F) Survival curve. [0030] Figure 5 : Historical overall response rate with checkpoint inhibitors for ovarian cancer, cervical cancer, and uveal melanoma.

[0031] Figure 6 : Scans of a cervical cancer tumor in a patient who was treated with an anti-TIGIT antibody and an anti-PD-1 antibody. The circles indicate the location of the tumor on the scan. The change in tumour volume resulted in a complete overall response after the patient was treated with the combination of an anti-TIGIT antibody and an anti-PD-1 antibody. [0032] Figure 7: PVR and TIGIT expression analysis

[0033] Figure 8 : PD-L1 expression analysis

[0034] Figure 9: Heavy and light chain sequence of Camrelizumab (PD-1 antibody) [0035] Figure 10: Heavy and light chain sequence of Prolgolimab (PD- 1 antibody)

[0036] Figure 11: Heavy and light chain sequence of Pucotenlimab (PD-1 antibody)

[0037] Figure 12: Heavy and light chain sequence of Ezabenlimab (PD-1 antibody)

[0038] Figure 13: Heavy and light chain sequence of Envafolimab (PD-L1 antibody)

[0039] Figure 14: Heavy and light chain sequence of Socazolimab (PD-L1 antibody)

[0040] Figure 15: A summary showing the length of time that patients have been part of the Phase lb/2 clinical trial.

[0041] Figures 16-21 disclose pharmacodynamic analysis of biomarkers after treatment with the combination of etigilimab and nivolumab. Figure 16 shows the change in Treg cells and CD8+ cells after treatment; Figures 17A and 17B show the change in Ki-67+ TIGIT+ CD4 cells after treatment; Figure 18 shows the change in the level of IFNy produced by CD4+ effector memory cells after treatment; Figure 19 shows the change in the level of Ki-67+ CD8+ PD-1+ cells after treatment and Figure 20 shows the change in Ki-67+ natural killer cells (NK cells) after treatment. Figure 21 shows the change in T Progenitor Exhausted like (TPEX) cells after treatment.

[0042] Figure 22: Scans of a cervical cancer tumor in a patient who was treated with an anti-TIGIT antibody and an anti-PD-1 antibody. The circles indicate the location of the tumor on the scan. The change in tumour volume resulted in a partial overall response after the patient was treated with the combination of an anti-TIGIT antibody and an anti-PD-1 antibody.

[0043] Figure 23: Summary of PVR expression in various tumours.

[0044] Figure 24: A summary showing the length of time that patients have been part of the Phase lb/2 clinical trial. Time on treatment and investigator-assessed RECIST 1.1 response. [0045] Figure 25: A summary of the preliminary efficacy of the combination of etigilimab with an anti-PD-1 antibody (nivolumab). PD = disease progression; SD = stable disease; cCR = confirmed complete response; uCR = unconfirmed complete response; cPR = confirmed partial response; uPR = unconfirmed partial response; TMB-H = high tumor mutational burden; MSS = microsatellite stable (MSS); and HGSOC = high-grade serous ovarian cancer.

[0046] Figure 26: A waterfall plot showing the percentage change compared to the baseline for each subject.

[0047] Figure 27: Coexpression of CD226+/CD8+ by multiplex immunofluorescence (MIF). Baseline tissue biomarker analysis showed co-expression of CD226 and CD8 in tumor regions of cervical and uveal melanoma subjects with objective response (Key: DAPI- blue, CD226- red, CD8- green)

[0048] Figure 28 (Cont. from Fig. 27): Coexpression of CD226+/CD8+ by multiplex immunofluorescence. Percent of cells positive for CD226 and CD8 were highest in 030 followed by 081 and 040 respectively (Key: 040, 081=CR; 030=PR; 056, 025, 020=SD; 064,072 =PD; * tissue tested, but not evaluable by MIF; cervical subject #001 was not tested due to no tumor tissues; subject #030 tumor tissue shows high immune infiltration).

[0049] Figure 29: Gene signatures in baseline tissues and responses. Baseline differences in immune related gene signatures determined by mRNAseq of FFPE tissues were noted between objective responders (CR+PR) and non-responders (SD+PD) corresponding to IFNy-related markers (10 gene panel: see [1]), T-cell exhaustion markers (87 genes panel: see [2]), myeloid activation markers (3 gene panel: see [3]) and tertiary lymphoid structures (TLS) markers (4 gene panel: see [4]) (Response= best percent change from baseline of target lesions; n=5 (R)esponders (CR/PR); n=33 (N)on-responders (SD/PD).

[0050] Figure 30: InSituPlex Assay Workflow. (A) Tissue section (B) Primary antibodies conjugated to DNA barcodes added to the tissue section. All the conjugated antibodies unique to each target are bound to the tissue in a single step. (C) Once the sample has been incubated with conjugated antibodies, DNA barcodes are amplified simultaneously for all targets to increase assay sensitivity. (D) Mixture of fluorescent probes complementary to the DNA barcodes are added to the sample, each target labelled with a spectrally distinct fluorophore.

DISCLOSURE OF THE INVENTION

[0051] The inventors have surprisingly found that human patients with cancers that express particular biomarker combinations appear to respond particularly well to combination treatment with an anti-TIGIT antibody and an anti-PD-1 antibody. The biomarkers in question include PVR, PD-L1, TIGIT, CD226, CD8 as well as IFNy-related markers, T cell exhaustion markers, Myeloid activation markers and Tertiary lymphoid structure markers. The identification of sub-groups of patients who respond particularly well to combination treatment with an anti-TIGIT antibody and an anti-PD-1 antibody or for whom this treatment is particularly beneficial is advantageous because it can help ensure that patients who will most benefit from the combination of an anti-TIGIT antibody and an anti-PD- 1 antibody are targeted with and receive this combination therapy treatment. Thus, the invention provides methods of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD- 1 antibody. The invention further provides methods of treating cancer in a human patient comprising administering an anti-TIGIT antibody and an anti-PD-1 antibody to the patient.

Methods of identifying a patient and methods of treating cancer

[0052] The inventors have surprisingly found that patients who have cancers that are PVR positive appear to have an improved clinical benefit when treated with the combination of an anti-TIGIT antibody and an anti-PD-1 antibody. Furthermore, and as shown in the examples, cancer patients with high PVR expression appear to show a clinical benefit when treated with an anti-TIGIT antibody and an anti-PD-1 antibody, whereas cancer patients with low PVR expression were observed to have disease progression when treated with the same combination therapy. The inventors also surprisingly found that the presence or absence of PD- L1 on a cancer appeared to alter the clinical benefit of treatment with an anti-TIGIT antibody and an anti-PD-1 antibody depending on the type of cancer. Therefore, in one aspect, the invention provides a method of identifying a human cancer patient for treatment with an anti- TIGIT antibody and an anti-PD-1 antibody, wherein the method comprises (a) obtaining a tissue sample of the cancer from the patient; and (b) determining that the cancer is PVR positive (+) and PD-L1 negative (-) or PD-L1 positive (+). [0053] In some embodiments, the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the method comprises (a) obtaining a tissue sample of the cancer from the patient; (b) determining that the cancer is PVR positive (+) and PD-L1 negative (-) or PD-L1 positive (+) and (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+) and PD-L1 negative (-) or PD-L1 positive (+) cancer in the patient. In some embodiments, the method further comprises in step (b) determining that the cancer is CD226 positive and optionally in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) cancer in the patient. In some embodiments, the method further comprises in step (b) determining that the cancer is CD226 positive (+) and CD8 positive (+) and optionally in step (c) administering the anti-TIGIT antibody and the anti-PD- 1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) and CD8 positive (+) cancer in the patient.

[0054] In another aspect, the invention provides a method of treating cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody to the patient, wherein the cancer is PVR positive (+) and PD-L1 negative (-) or PD-L1 positive (+).

[0055] In some embodiments, the methods herein identify or treat cancers that are TIGIT positive (+). In other embodiments, the methods herein identify or treat cancers that are TIGIT negative. For example, in some embodiments, the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the method comprises (a) obtaining a tissue sample of the cancer from the patient; and (b) determining that the cancer is PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+) and TIGIT positive (+).

[0056] In some embodiments, the methods herein identify or treat cancers that are TIGIT positive (+). In other embodiments, the methods herein identify or treat cancers that are TIGIT negative. For example, in some embodiments, the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the method comprises (a) obtaining a tissue sample of the cancer from the patient; (b) determining that the cancer is PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+) and TIGIT positive (+) and (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+) and PD-L1 negative (-) or PD-L1 positive (+) and TIGIT positive (+) cancer in the patient. [0057] In some embodiments, the invention provides a method of treating cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody to the patient, wherein the cancer is PVR positive (+) and PD-L1 negative (-) or PD-L1 positive (+) and TIGIT positive (+).

[0058] In some embodiments, the cancer is CD226 positive (+) and optionally CD8 positive (+).

[0059] In one aspect, the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the method comprises (a) obtaining a tissue sample of the cancer from the patient; and (b) determining that the cancer is CD226 positive (+) and optionally CD8 positive (+).

[0060] In another aspect, the invention provides a method of treating cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody to the patient, wherein the cancer is CD226 positive (+) and optionally CD8 positive (+).

[0061] In some aspects the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the method comprises (a) obtaining a tissue sample of the cancer from the patient; (b) determining that the cancer has an increased expression of: (i) IFNy-related markers (ii) T cell exhaustion markers (iii) Myeloid activation markers and/ or (iv) Tertiary lymphoid structure markers and optionally (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the cancer with increased expression of IFNy, T cell exhaustion markers, Myeloid activation markers and/ or Tertiary lymphoid structures in the patient.

[0062] In another aspect, the invention provides a method of treating cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody to the patient, wherein the cancer has an increased expression of IFNy-related markers, T cell exhaustion markers, Myeloid activation markers and/ or Tertiary lymphoid structures.

[0063] In one embodiment the IFNy-related markers comprise one or more genes selected from the group consisting of IFNG, STAT1, CCR5, CXCL9, CXCL10, CXCL11, 1DO1, PRF1, GZMA, and MHCII HLA-DRA. In one embodiment the IFNy-related markers comprise at least two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more of said genes.

[0064] In one embodiment the T cell exhaustion markers comprise one or more genes selected from the group consisting of RPL13, ABCE1, ABLIM1, ACADM, ACP5, ADCY7, ADD1, ADH5, AKAP8, ANAPC5, ARHGAP1, ARHGEF1, ASCC1, ATP6V0A2, ATP6V0B, BN1P3L, BZW1, C5orf34, CCT3, CCT4, CCT5, CCT8, CD1D, CLK2, CRLF3, CTD- 2410N18.5, DGKA, DTX1, EEF2, E1F2S1, EPHB4, ETS1, EVPLL, FKBP4, GM2A, GTF21, HMGCS1, HSPA8, ICAM2, IFNAR1, ITGB7, KCNN4, KCTD10, KLF13, KLF2, KLF3, LBR, LEF1, MAP4K4, MAPK8, MAT2A, NFE2L2, NME1-NME2, NUMB, 0SBPL11, PAK2, PDHA1, PDL1M1, P1K3CD, PLD3, PPP2R5A, PRPS1, RAP1GDS1, RP11-106M3.2, RPL10, RPL10A, RPL22, RPL3, RPL8, RPN2, RPS16, RPS3, RPS4X, RPS7, RPS8, SATB1, SEMA4A, S1AH1, SNRPD3, SNX4, SRPK1, SSI 8, STK38, TMC6, TUBB, UBP1, and ZNRF2. In one embodiment the T cell exhaustion markers comprise two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more of said genes. In one embodiment, the T cell exhaustion markers comprise 10 or more, 20 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, or 80 or more of said genes, such as 81, 82, 83, 84, 85 or 86 of said genes.

[0065] In one embodiment the Myeloid activation markers comprise one or more genes selected from the group consisting of Cxclll, Gbpl, and Idol. In one embodiment the Myeloid activation markers comprise at least two or more of said genes.

[0066] In one embodiment the Tertiary lymphoid structure markers comprise one or more genes selected from the group consisting of CD79A, MS4A1, LAMP3 and POU2AF1. In one embodiment the Tertiary lymphoid structure markers comprise at least two or more or three or more of said genes.

[0067] In some embodiments, the increased expression of said IFNy-related markers, T cell exhaustion markers, Myeloid activation markers and Tertiary lymphoid structures is determined by RNA sequencing (RNA-Seq). In other embodiments, the increased expression of said IFNy-related markers, T cell exhaustion markers, Myeloid activation markers and Tertiary lymphoid structures is determined by RT-PCR.

[0068] In some embodiments, the cancer is selected from the group consisting of endometrial cancer, head and neck cancer, cervical cancer, endometrial cancer, ovarian cancer, rare tumours, including soft tissue sarcomas, testicular germ cell tumours and uveal melanomas, high tumor mutational burden (TMB-H) and microsatellite stable (MSS) cancers. In certain embodiments, the cancer is selected from the group consisting of cervical cancer, ovarian cancer and uveal melanomas. In certain embodiments, the cancer is selected from the group consisting of cervical cancer, ovarian cancer and endometrial.

[0069] In one embodiment of the methods disclosed herein, determining that the cancer is positive (+) for a given marker means that the tissue sample of the cancer taken from the patient is positive (+) for the given marker. In another embodiment of the methods disclosed herein, reference to a cancer as being positive (+) or negative (-) for a given marker means that the mass of cells making up the cancer, which includes cancer cells as well as non-cancerous cells that have infiltrated the tumour (e.g. immune cells) are positive (+) or negative (-) for the given marker. By way of example, and in one embodiment, the CD8 marker is identifying immune cells that have infiltrated the tumor rather than identifying cancer cells per se. In this context, and in embodiment, the term cancer can be used interchangeably with the term tumour. [0070] In one aspect of the invention, a method of identifying a human cancer patient may be based on one or more of the markers described herein. Each marker may be used individually or in combination with one or more of the other markers disclosed herein and every possible combination of markers is explicitly envisaged and encompassed as an embodiment of the present invention. Thus, for example, CD226 and CD8 could be used alone or in combination with PVR, PD-L1 and TIGIT. In another non-exhaustive example, the PVR, PD- Ll, TIGIT, CD226 and CD8 markers could be combined with the IFNy-related markers, T cell exhaustion markers, Myeloid activation markers and Tertiary lymphoid structure markers described herein.

Assays

[0071] The expression of PD-L1, PVR and/or TIGIT can be determined using PT-PCR, next generation sequencing, an immunofluorescence assay or an IHC assay. Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. Immunohistochemistry is also widely used in basic research to understand the distribution and localization of biomarkers and differentially expressed proteins in different parts of a biological tissue.

[0072] As described in the examples, IHC was used to determine the expression of PD- Ll, PVR and TIGIT on various types of cancer, including cervical cancer, ovarian cancer and uveal melanoma. In some embodiments, the expression of PD-L1, PVR and/or TIGIT is/are determined using an IHC assay.

[0073] In some embodiments, a cancer is determined to be positive for PD-L1 if it has a CPS value of greater than 1%, greater than 2%, greater than 5%, greater than 7.5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%. In a certain embodiment, a cancer is determined to be positive for PD-L1 if it has a CPS value of greater than 1% (>1%). The expression of PD-L1 can be measured using the IHC assay described in the examples. The expression of PD-L1 can be measured using an IHC assay selected from the group consisting of PD-L1 IHC 28-8 pharmDx assay (Agilent), PD-L1 IHC 22C3 pharmDx assay system (Agilent), PD-L1 SP142 assay (Ventana) and PD-L1 SP263 assay (Ventana). In some embodiments, a cancer is determined to be positive for PD-L1 if it has a CPS value of greater than 1% by the PD-L1 IHC 28-8 pharmDx assay (Agilent), PD-L1 IHC 22C3 pharmDx assay system (Agilent), PD-L1 SP142 assay (Ventana) or PD-L1 SP263 assay (Ventana). In certain embodiments, the PD-L1 IHC 22C3 pharmDx assay system (Agilent) can be used to determine the PD-L1 expression of a cancer. In a certain embodiment, the cancer is determined to be positive for PD-L1 if it has a CPS value of greater than 1% by the PD-L1 IHC 22C3 pharmDx assay system.

[0074] In some embodiments, a cancer is determined to be positive for TIGIT if it has a CPS value of greater than 1%, greater than 2%, greater than 5%, greater than 7.5%, greater than 10%, greater than 20% greater than 30%, greater than 40%, greater than 50%. In a certain embodiment, a cancer is deemed positive for TIGIT if it has a CPS value of greater than 1% (>1%). The expression of TIGIT can be measured using the IHC assay described in the examples. In some embodiments, the expression of TIGIT is measured using an IHC assay with a clone E5Y1W. In some embodiments, the cancer is determined to be positive for TIGIT if it has a CPS value of greater than 1 % using an IHC assay with E5Y 1 W.

[0075] The expression of PVR on a cell is determined based on a combination of (1) the percentage of cells in a sample that express PVR (%PVR) and (2) the intensity of the staining on the cells (1+, 2+, 3+). In some embodiments, the cancer is determined to be positive for PVR if the percentage of cells in a sample that express PVR is 30% or more, 40% or more, 50% or more, 60% or more, 70% or more or 80% or more. In certain embodiments, the cancer is determined to be positive for PVR if the percentage of cells in a sample that express PVR is 50% or more. In some embodiments, the cancer is determined to be positive for PVR if the tumour cells have a staining intensity of 1+, 2+ or 3+. In certain embodiments, the cancer is determined to be positive for PVR if the tumour cells have a staining intensity of 2+. In one embodiment, a cancer is determined to be positive for PVR if 50% of the cells in a sample express PVR with a staining intensity of 2+.

[0076] In some embodiments, the cancer is determined to have high PVR expression if the percentage of cells in a sample that express PVR is 50% or more, 60% or more, 70% or more or 80% or more. In some embodiments, the cancer is determined to have high PVR expression if 50% or more, 60% or more, 70% or more or 80% or more cells in a sample express PVR with a staining intensity of 2+. In certain embodiments, a cancer is determined to have high PVR expression if 50% or more of the cells express PVR with a staining intensity of 2+. [0077] The expression of PVR can be measured using the IHC assay described in the examples. In some embodiments, the expression of PVR is measured using an IHC assay with a clone EPR17302. In certain embodiments, the cancer is determined to be positive for PVR if 50% or more of cells in a sample express PVR with a staining intensity of 2+ using an IHC assay with EPR17302.

[0078] The expression of CD226 and/or CD8 can be determined, for example, by using PT-PCR, next generation sequencing, an immunofluorescence assay or an IHC assay. As described in the examples, multiplex immunofluorescence (MIF) technology was used to determine the expression of CD226 and CD8. In some embodiments, the expression of CD226 and/or CD8 is/are determined using a MIF assay. In some embodiments, the expression of CD226 and/or CD8 is/are determined using an IHC assay.

[0079] In some embodiments, a cancer is determined to be positive (+) for CD226 by a MIF assay if the percentage of cells that is positive for this marker is 2% or more, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45 or 50% or more. In one embodiment the MIF assay is as performed in the examples. In one embodiment the percentage of cells that is positive for CD226 is 2% or more.

[0080] In some embodiments, a cancer is determined to be positive (+) for CD8 by a MIF assay if the percentage of cells that is positive for this marker is 2% or more, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45 or 50% or more. In one embodiment the MIF assay is as performed in the examples. In one embodiment the percentage of cells that is positive for CD8 is 2% or more.

[0081] In some embodiments, a cancer is determined to be positive (+) for CD226 and CD8 by a MIF assay if the percentage of cells that are dual positive for these markers is 2% or more, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45 or 50% or more. In one embodiment the MIF assay is as performed in the examples. In one embodiment the percentage of cells that are dual positive for these markers is 2% or more.

[0082] The expression of IFNy-related markers, T cell exhaustion markers, Myeloid activation markers and Tertiary lymphoid structure markers can be determined, for example, by RNA sequencing (RNA-Seq), or RT-PCR. As described in the examples, RNA-Seq was used to determine expression of T cell exhaustion markers, Myeloid activation markers and Tertiary lymphoid structure markers. In some embodiments the expression of IFNy-related markers, T cell exhaustion markers, Myeloid activation markers and/or Tertiary lymphoid structure markers is/ are determined by RNA-Seq. In one such embodiment the RNA-Seq assay is as performed in the examples. In other embodiments the expression of IFNy-related markers, T cell exhaustion markers, Myeloid activation markers and/or Tertiary lymphoid structure markers is/ are determined by RT-PCR. [0083] In some embodiments, expression of IFNy-related markers is determined to be increased above a threshold value of 0.3 or more, such as 0.4, 0.5, 0.6 or 0.7 or more. In one embodiment the expression of IFNy-related markers is determined to be increased above a threshold value of 0.42 or more. In one embodiment the expression of IFNy-related markers is determined to be increased above a threshold value of 0.54 or more.

[0084] In some embodiments, expression of T cell exhaustion markers is determined to be increased above a threshold value of 0.3 or more, such as 0.4, 0.5, 0.6 or 0.7 or more. In one embodiment the expression of T cell exhaustion markers is determined to be increased above a threshold value of 0.57 or more. In one embodiment the expression of T cell exhaustion markers is determined to be increased above a threshold value of 0.51 or more.

[0085] In some embodiments, expression of Myeloid activation markers is determined to be increased above a threshold value of 0.3 or more, such as 0.4, 0.5, 0.6 or 0.7 or more. In one embodiment the expression of Myeloid activation markers is determined to be increased above a threshold value of 0.52 or more. In one embodiment the expression of Myeloid activation markers is determined to be increased above a threshold value of 0.63 or more.

[0086] In some embodiments, expression of Tertiary lymphoid structure markers is determined to be increased above a threshold value of 0.3 or more, such as 0.4, 0.5, 0.6, 0.7 or 0.8 or more. In one embodiment the expression of Tertiary lymphoid structure markers is determined to be increased above a threshold value of 0.74 or more. In one embodiment the expression of Tertiary lymphoid structure markers is determined to be increased above a threshold value of 0.58 or more.

Patients of interest

[0087] The human patient can be an infant (between the ages 0-1 years), a child (between the ages of 1-18 years) or an adult (with an age above 18 years). In some embodiments, the human patient is aged above 50 years old, for example 55 years or older, 60 years or older, 65 years or older, 70 years or older, 75 years or older or 80 years or older.

[0088] In some embodiments, anti-TIGIT antibody and the anti-PD-1 antibody will be administered to patients that have previously undergone treatment with an additional therapeutic agent. In certain other embodiments, the anti-TIGIT antibody, the anti-PD-1 antibody and an additional therapeutic agent will be administered substantially simultaneously or concurrently. For example, a patient may be given a the anti-TIGIT antibody and the anti- PD-1 antibody while undergoing a course of treatment with an additional therapeutic agent (e.g., chemotherapy). In certain embodiments, the anti-TIGIT antibody and the anti-PD-1 antibody will be administered within 1 year of the treatment with the additional therapeutic agent. In certain alternative embodiments, the anti-TIGIT antibody and the anti-PD-1 antibody will be administered within 10, 8, 6, 4, or 2 months of any treatment with the additional therapeutic agent. In certain other embodiments, the anti-TIGIT antibody and the anti-PD-1 antibody will be administered within 4, 3, 2, or 1 weeks of any treatment with the additional therapeutic agent. In some embodiments, the anti-TIGIT antibody and the anti-PD-1 antibody will be administered within 5, 4, 3, 2, or 1 days of any treatment with the additional therapeutic agent. It will further be appreciated that the two (or more) agents or treatments may be administered to the patient within a matter of hours or minutes (i.e., substantially simultaneously).

[0089] In some embodiments, the human patient has not received prior treatment been treated with a checkpoint inhibitor. In some embodiments, the human patient is naive to checkpoint inhibitor therapy. In some embodiments, the human patient has not been previously treated with a checkpoint inhibitor. In some embodiments, the human patient has not received prior treatment/ been treated with an anti-PD-1 antibody therapy. In some embodiments, the human patient is naive to anti-PD-1 antibody therapy. In some embodiments, the human patient has not been previously treated with an anti-PD-1 antibody therapy. In some embodiments, the human patient has not received prior treatment/ been treated with an anti-PD-Ll antibody therapy. In some embodiments, the human patient is naive to anti-PD-Ll antibody therapy. In some embodiments, the human patient has not been previously treated with an anti-PD-Ll antibody therapy. In some embodiments, the human patient has not received prior treatment/ been treated with a bispecific antibody that comprises a first arm that binds to PD-1 or PD-L1. In some embodiments, the human patient is naive to a bispecific antibody that comprises a first arm that binds to PD-1 or PD-L1. In some embodiments, the human patient has not been previously treated with a bispecific antibody that comprises a first arm that binds to PD-1 or PD-L1.

[0090] In some embodiments, the human patient has not received prior radiotherapy. In some embodiments, the human patient has not been previously treated with radiotherapy. In some embodiments, the human patient has not received prior chemotherapy. In some embodiments, the human patient has not been previously treated with chemotherapy.

[0091] In some embodiments, the human patient has previously treated with a checkpoint inhibitor and there is tumor growth, progression, or recurrence during or after treatment with the checkpoint inhibitor. In certain embodiments, the human patient has been previously treated with an anti-PD-1 antibody and there is tumor growth, progression, or recurrence during or after treatment with the human PD-1 antibody. In certain embodiments, the human patient has been previously treated with an anti-PD-Ll antibody and there is tumor growth, progression, or recurrence during or after treatment with the human PD-L1 antibody.

[0092] In some embodiments, the human cancer patient has previously treated with a chemotherapeutic agent and there is tumor growth, progression, or recurrence during or after treatment with the chemotherapeutic agent, for example a chemotherapeutic agent or in combination with a cocktail of chemotherapeutic agents. Classes of chemotherapeutic agents include, for example, anti-tubulin agents, auristatins, DNA minor groove binders, DNA replication inhibitors, alkylating agents (e.g., platinum complexes such as cisplatin, mono(platinum), bis(platinum) and tri-nuclear platinum complexes and carboplatin), anthracyclines, antibiotics, anti-folates, antimetabolites, chemotherapy sensitizers, duocarmycins, etoposides, fluorinated pyrimidines, ionophores, lexitropsins, nitrosoureas, platinols, purine antimetabolites, puromycins, radiation sensitizers, steroids, taxanes, topoisomerase inhibitors, vinca alkaloids, or the like.

[0093] Possible chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamime; nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5- fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercap topurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytosine arabinoside, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenishers such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2- ethylhydrazide; procarbazine; PSK; razoxane; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); taxoids, e.g. paclitaxel (TAXOL) and docetaxel (TAXOTERE); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; ibandronate; CPT11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine (XELODA); and pharmaceutically acceptable salts, acids or derivatives of any of the above. Chemotherapeutic agents also include anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (FARESTON); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above..

[0094] In certain embodiments, the chemotherapeutic agent is a topoisomerase inhibitor. Topoisomerase inhibitors are chemotherapy agents that interfere with the action of a topoisomerase enzyme (e.g., topoisomerase I or II). Topoisomerase inhibitors include, but are not limited to, doxorubicin HC1, daunorubicin citrate, mitoxantrone HC1, actinomycin D, etoposide, topotecan HC1, teniposide (VM-26), and irinotecan, as well as pharmaceutically acceptable salts, acids, or derivatives of any of these. In some embodiments, the chemotherapeutic agent is irinotecan.

[0095] In certain embodiments, the chemotherapeutic agent is an anti-metabolite. An anti-metabolite is a chemical with a structure that is similar to a metabolite required for normal biochemical reactions, yet different enough to interfere with one or more normal functions of cells, such as cell division. Anti-metabolites include, but are not limited to, gemcitabine, fluorouracil, capecitabine, methotrexate sodium, ralitrexed, pemetrexed, tegafur, cytosine arabinoside, thioguanine, 5-azacytidine, 6-mercaptopurine, azathioprine, 6-thioguanine, pentostatin, fludarabine phosphate, and cladribine, as well as pharmaceutically acceptable salts, acids, or derivatives of any of these. In certain embodiments, the chemotherapeutic agent is gemcitabine. [0096] In certain embodiments, the chemotherapeutic agent is an antimitotic agent, including, but not limited to, agents that bind tubulin. In some embodiments, the agent is a taxane. In certain embodiments, the agent is paclitaxel or docetaxel, or a pharmaceutically acceptable salt, acid, or derivative of paclitaxel or docetaxel. In certain embodiments, the agent is paclitaxel (TAXOL), docetaxel (TAXOTERE), albumin-bound paclitaxel (ABRAXANE®), DHA-paclitaxel, or PG-paclitaxel. In certain alternative embodiments, the antimitotic agent comprises a vinca alkaloid, such as vincristine, vinblastine, vinorelbine, or vindesine, or pharmaceutically acceptable salts, acids, or derivatives thereof. In some embodiments, the antimitotic agent is an inhibitor of kinesin Eg5 or an inhibitor of a mitotic kinase such as Aurora A or Plkl. In certain embodiments, the chemotherapeutic agent is paclitaxel. In certain embodiments, the chemotherapeutic agent is albumin-bound paclitaxel (ABRAXANE®).

[0097] In some embodiments, the human patient has previously treated with 2 or more chemotherapeutic agents and there is tumor growth, progression, or recurrence during or after treatment with the chemotherapeutic agents. For example, the human patient has previously treated with 2 or more, 3 or more, 4 or more, or 5 or more chemotherapeutic agents.

Cervical cancer

[0098] Cervical cancer is a cancer that is found anywhere in the cervix. The cervix is the opening between the vagina and the womb (uterus). Nearly all cervical cancers are caused by an infection from certain types of human papillomaviruses (HPV). Women 35 to 44 years old are most likely to get cervical cancer. There are three different types of cervical cancer (a) squamous cell carcinoma, which forms in the lining of your cervix and is found in up to 90% of cases; (b) adenocarcinoma, which forms in the cells that produce mucus; and (c) mixed carcinoma, which has features of the two other types. Cervical cancer can be described as a Stage I, Stage II, Stage III or Stage IV cervical cancer.

[0099] The examples support the finding that patients with a cervical cancer that is PVR positive (+) and PD-L1 positive (+) can be treated with an anti-TIGIT antibody and an anti- PD-1 antibody. Therefore, it is beneficial to identify patients with cervical cancer that are PVR positive (+) and PD-L1 positive (+) so that they can be treated with a combination of an anti- TIGIT antibody and an anti-PD-1 antibody. Therefore, the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD- 1 antibody, wherein the cancer is cervical cancer, wherein the method comprises (a) obtaining a tissue sample of the cervical cancer from the patient; and (b) determining that the cervical cancer is PVR positive (+) and PD-L1 positive (+). [00100] In some embodiments, the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is cervical cancer, wherein the method comprises (a) obtaining a tissue sample of the cervical cancer from the patient; (b) determining that the cervical cancer is PVR positive (+) and PD-L1 positive (+); and (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+) and PD-L1 positive (+) cervical cancer in the patient.

[00101] In some aspects, the invention provides a method of treating cervical cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody to the patient, wherein the cervical cancer is PVR positive (+) and PD-L1 positive (+).

[00102] In some embodiments, the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is cervical cancer, wherein the method comprises (a) obtaining a tissue sample of the cervical cancer from the patient; and (b) determining that the cervical cancer is PVR positive (+), PD-L1 positive (+) and TIGIT positive (+).

[00103] In some embodiments, the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is cervical cancer, wherein the method comprises (a) obtaining a tissue sample of the cervical cancer from the patient; (b) determining that the cervical cancer is PVR positive (+), PD-L1 positive (+) and TIGIT positive (+) and (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 positive (+) and TIGIT positive (+) cervical cancer in the patient.

[00104] In some embodiments, the invention provides a method of treating cervical cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody to the patient, wherein the cervical cancer is PVR positive (+), PD-L1 positive (+) and TIGIT positive (+).

[00105] In some embodiments, the cervical cancer is a squamous cell carcinoma, adenocarcinoma or mixed carcinoma. In some embodiments, the cervical cancer is a Stage I cervical cancer, a Stage II cervical cancer, a Stage III cervical cancer or a Stage IV cervical cancer. In some embodiments, the cervical cancer is a TMB-H/MSS cervical cancer.

[00106] In some embodiments, the cervical cancer patient has been pre-treated with a chemotherapeutic agent. In some embodiments, the cervical cancer patient has previously treated with a chemotherapeutic agent and there is tumour growth, progression, or recurrence during or after treatment with the chemotherapeutic agent. Exemplary chemotherapeutic agents that can be used to treat cervical cancer are Avastin (Bevacizumab), Bevacizumab, Bleomycin Sulfate, Hycamtin (Topotecan Hydrochloride), Keytruda (Pembrolizumab), Mvasi (Bevacizumab), Pembrolizumab, Tisotumab Vedotin-tftv, Tivdak (Tisotumab Vedotin-tftv), Herceptin, Abraxane, Carboplatin, Topotecan Hydrochloride, Zirabev (Bevacizumab).

[00107] In certain embodiments, the human patient has been previously treated with Taxol and there is tumour growth, progression, or recurrence during or after treatment with the Taxol. In certain embodiments, the human patient has been previously treated with Carboplatin and there is tumour growth, progression, or recurrence during or after treatment with the Carboplatin. In certain embodiments, the human patient has been previously treated with Avastin and there is tumour growth, progression, or recurrence during or after treatment with the Avastin. In certain embodiments, the human patient has been previously treated with Abraxane and there is tumour growth, progression, or recurrence during or after treatment with the Abraxane. In certain embodiments, the human patient has been previously treated with Herceptin and there is tumour growth, progression, or recurrence during or after treatment with the Herceptin.

[00108] In some embodiments, the human patient has previously treated with 2 or more chemotherapeutic agents and there is tumour growth, progression, or recurrence during or after treatment with the chemotherapeutic agents. For example, the human patient has previously treated with 2 or more, 3 or more, 4 or more, or 5 or more chemotherapeutic agents. Exemplary combinations of chemotherapeutic agents include: (a) Paclitaxel and Carboplatin; (b) Paclitaxel, Carboplatin and Avastin; and Gemcitabine Hydrochloride and Cisplatin.

[00109] In some embodiments, the cervical cancer patient has previously undergone surgery. In some embodiments, the cervical cancer patient has previously treated with radiotherapy and there is tumour growth, progression, or recurrence during or after treatment with the radiotherapy.

[00110] In some embodiments, the cervical cancer patient is aged above 50 years old, for example 55 years or older, 60 years or older, 65 years or older, 70 years or older, 75 years or older or 80 years or older. In some embodiments, the cervical cancer patient is aged between 20-60 years old, 25-50 years old, 30-50 years old or 35-50 years old. In certain embodiments, the patient is aged between 35 and 45 years old.

Ovarian cancer

[00111] Ovarian cancer, or cancer of the ovaries, is one of the most common types of cancer in women. The ovaries are a pair of small organs located low in the tummy that are connected to the womb and store a woman's supply of eggs. Ovarian cancer mainly affects women who have been through the menopause (usually over the age of 50), but it can sometimes affect younger women. The ovaries consist of three types of cells - epithelial, stromal and germ cells - all of which can develop into cancer. The majority of ovarian cancers (95%) arise from epithelial cells which include high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous ovarian cancers. Types of ovarian cancer include ovarian epithelial cancer, ovarian germ cell tumors, ovarian low malignant potential tumors and childhood ovarian cancer treatment. Ovarian cancer can be described as a Stage I, Stage II, Stage III or Stage IV ovarian cancer.

[00112] High-grade serous epithelial ovarian carcinoma, fallopian tube, and peritoneal carcinomas share outcomes and treatments, therefore fallopian tube, and peritoneal carcinomas can be considered a type of ovarian cancer.

[00113] The examples support the finding that patients with an ovarian cancer that is PVR positive (+) and PD-L1 negative (-) can be treated with an anti-TIGIT antibody and an anti- PD-1 antibody. Therefore, it is beneficial to identify patients with ovarian cancer that are PVR positive (+) and PD-L1 negative (-) so that they can be treated with a combination of an anti- TIGIT antibody and an anti-PD-1 antibody. Therefore, in one aspect the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is ovarian cancer, wherein the method comprises (a) obtaining a tissue sample of the ovarian cancer from the patient; and (b) determining that the cervical cancer is PVR positive (+) and PD-L1 negative (-).

[00114] In some embodiments, the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is ovarian cancer, wherein the method comprises (a) obtaining a tissue sample of the ovarian cancer from the patient; (b) determining that the cervical cancer is PVR positive (+) and PD-L1 negative (-) and (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+) and PD-L1 negative (-) ovarian cancer in the patient.

[00115] In another aspect, the invention provides a method of treating ovarian cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody to the patient, wherein the ovarian cancer is PVR positive (+), PD-L1 negative (-), and TIGIT positive (+).

[00116] In some embodiments, the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is ovarian cancer, wherein the method comprises (a) obtaining a tissue sample of the ovarian cancer from the patient; and (b) determining that the ovarian cancer is PVR positive (+), PD-L1 negative (-) and TIGIT positive (+). [00117] In some embodiments, the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is cervical cancer, wherein the method comprises (a) obtaining a tissue sample of the ovarian cancer from the patient; (b) determining that the ovarian cancer is PVR positive (+) and PD-L1 negative (-) and (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the ovarian cancer is PVR positive (+), PD-L1 negative (-) and TIGIT positive (+).

[00118] In some embodiments, the invention provides a method of treating ovarian cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody to the patient, wherein the ovarian cancer is PVR positive (+), PD-L1 negative (-) and TIGIT positive (+).

[00119] In some embodiments, the ovarian cancer is an epithelial ovarian cancer, a stromal ovarian cancer or a germ cell ovarian cancer. In certain embodiments, the epithelial ovarian cancer is a high-grade serous, a low-grade serous, an endometrioid, a clear cell or mucinous ovarian cancer. In some embodiments, the ovarian cancer is a high-grade serous epithelial ovarian carcinoma, a fallopian tube cancer or a peritoneal carcinoma.

[00120] In some embodiments, the ovarian cancer is ovarian low malignant potential tumors or childhood ovarian cancer treatment. In some embodiments, the ovarian cancer is a Stage I ovarian cancer, a Stage II ovarian cancer, a Stage III ovarian cancer or a Stage IV ovarian cancer.

[00121] In some embodiments, the ovarian cancer patient has been pre-treated with a chemotherapeutic agent. In some embodiments, the ovarian cancer patient has previously treated with a chemotherapeutic agent and there is tumour growth, progression, or recurrence during or after treatment with the chemotherapeutic agent. Exemplary chemotherapeutic agents that can be used to treat ovarian cancer are Alkeran (Melphalan), Avastin (Bevacizumab), Bevacizumab, Carboplatin, Cisplatin, Cyclophosphamide, Doxorubicin Hydrochloride, Doxil (Doxorubicin Hydrochloride Liposome), Doxorubicin Hydrochloride Liposome, Gemcitabine Hydrochloride, Gemzar (Gemcitabine Hydrochloride), Hycamtin (Topotecan Hydrochloride), Infugem (Gemcitabine Hydrochloride), Lynparza (Olaparib), Melphalan, Niraparib Tosylate Monohydrate, Olaparib, Paclitaxel, Paraplatin (Carboplatin), Rubraca (Rucaparib Camsylate), Rucaparib Camsylate, Tepadina (Thiotepa), Thiotepa, Topotecan Hydrochloride and Zejula (Niraparib Tosylate Monohydrate).

[00122] In some embodiments, the human patient has previously treated with a chemotherapeutic agent and there is tumour growth, progression, or recurrence during or after treatment with the chemotherapeutic agent. In certain embodiments, the human patient has been previously treated with Cisplatin and there is tumour growth, progression, or recurrence during or after treatment with the Cisplatin. In certain embodiments, the human patient has been previously treated with Rubraca and there is tumour growth, progression, or recurrence during or after treatment with the Rubraca. In certain embodiments, the human patient has been previously treated with Doxil and there is tumour growth, progression, or recurrence during or after treatment with the Doxil. In certain embodiments, the human patient has been previously treated with Olaparib and there is tumour growth, progression, or recurrence during or after treatment with the Olaparib. In certain embodiments, the human patient has been previously treated with Gemzar and there is tumour growth, progression, or recurrence during or after treatment with the Gemzar.

[00123] In some embodiments, the human patient has previously treated with 2 or more chemotherapeutic agents and there is tumour growth, progression, or recurrence during or after treatment with the chemotherapeutic agents. For example, the human patient has previously treated with 2 or more, 3 or more, 4 or more, or 5 or more chemotherapeutic agents. Exemplary combinations of chemotherapeutic agents include: (a) Bleomycin, Etoposide Phosphate and Cisplatin (Platinol); (b) Paclitaxel and Carboplatin; (c) Gemcitabine Hydrochloride and Cisplatin; (d) Carboplatin (JM8), Etoposide Phosphate and Bleomycin; (e) Vincristine Sulfate, Dactinomycin (Actinomycin-D) and Cyclophosphamide and (f) Vinblastine Sulfate (Velban), Ifosfamide and Cisplatin (Platinol).

[00124] In some embodiments, the ovarian cancer patient has previously undergone surgery. In some embodiments, the ovarian cancer patient has previously treated with radiotherapy and there is tumour growth, progression, or recurrence during or after treatment with the radiotherapy.

[00125] In some embodiments, the ovarian cancer patient is aged above 50 years old, for example 55 years or older, 60 years or older, 65 years or older, 70 years or older, 75 years or older or 80 years or older.

Uveal melanoma

[00126] Uveal melanoma is a rare cancer of the eye involving the iris, ciliary body, or choroid (collectively referred to as the uvea). Tumors arise from the pigment cells (melanocytes) that reside within the uvea and give color to the eye. These melanocytes are distinct from the retinal pigment epithelium cells underlying the retina that do not form melanomas. Uveal melanomas are sometimes referred to by their location, choroidal melanoma, ciliary body melanoma, or iris melanoma. Iris and ciliary body melanomas can be described as anterior melanomas, whereas a choroidal melanoma behind the equator of the eye would be considered posterior uveal melanomas. Examples of uveal melanomas include posterior uveal melanoma, choroidal melanoma, ciliary body melanoma and iris melanoma.

[00127] The examples support the finding that patients with uveal melanoma that is PVR positive (+) and PD-L1 negative (-) can be treated with an anti-TIGIT antibody and an anti- PD-1 antibody. Therefore, it is beneficial to identify patients with uveal melanoma that are PVR positive (+) and PD-L1 negative (-) so that they can be treated with a combination of an anti-TIGIT antibody and an anti-PD-1 antibody. Therefore, in one aspect the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is uveal melanoma, wherein the method comprises (a) obtaining a tissue sample of the uveal melanoma from the patient; and (b) determining that the cervical cancer is PVR positive (+) and PD-L1 negative (-).

[00128] In some embodiments, the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is uveal melanoma, wherein the method comprises (a) obtaining a tissue sample of the uveal melanoma from the patient; (b) determining that the cervical cancer is PVR positive (+) and PD-L1 negative (-) and (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+) and PD-L1 negative (-) uveal melanoma in the patient.

[00129] In another aspect, the invention provides a method of treating uveal melanoma in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody to the patient, wherein the uveal melanoma is PVR positive (+) and PD-L1 negative (-).

[00130] In some embodiments, the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is uveal melanoma and wherein the method comprises (a) obtaining a tissue sample of the uveal melanoma from the patient; and (b) determining that the uveal melanoma is PVR positive (+), PD-L1 positive (+) and TIGIT negative (-).

[00131] In some embodiments, the invention provides a method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is uveal melanoma and wherein the method comprises (a) obtaining a tissue sample of the uveal melanoma from the patient; (b) determining that the uveal melanoma is PVR positive (+), PD-L1 positive (+) and TIGIT negative (-); and (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) and TIGIT negative (-) uveal melanoma in the patient.

[00132] In some embodiments, the invention provides a method of treating uveal melanoma in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody to the patient, wherein the uveal melanoma is PVR positive (+), PD-L1 negative (-) and TIGIT negative (-).

[00133] In some embodiments, the uveal melanoma is selected from the group consisting of posterior uveal melanoma, choroidal melanoma, ciliary body melanoma and iris melanoma. [00134] Known treatments for uveal melanoma include surgery, photocoagulation and thermotherapy. The following types of surgery may be used: (a) Resection: Surgery to remove the tumor and a small amount of healthy tissue around it; (b) Enucleation: Surgery to remove the eye and part of the optic nerve. This is done if vision cannot be saved and the tumor is large, has spread to the optic nerve, or causes high pressure inside the eye. After surgery, the patient is usually fitted for an artificial eye to match the size and color of the other eye; and (c) Exenteration: Surgery to remove the eye and eyelid, and muscles, nerves, and fat in the eye socket. After surgery, the patient may be fitted for an artificial eye to match the size and color of the other eye or a facial prosthesis. In some embodiments, the human patient has previously undergone surgery. In some embodiments, the surgery was resection, enucleation or exenteration.

[00135] Photocoagulation is a procedure that uses laser light to destroy blood vessels that bring nutrients to the tumor, causing the tumor cells to die. Photocoagulation may be used to treat small tumors. This is also called light coagulation. In some embodiments, the human patient has previously received photocoagulation therapy. In some embodiments, the human patient has previously been treated with photocoagulation therapy. Thermotherapy is the use of heat from a laser to destroy cancer cells and shrink the tumor. In some embodiments, the human patient has previously received thermo therapy. In some embodiments, the human patient has previously been treated with thermotherapy.

Mode of administration

[00136] The anti-TIGIT antibody can be administered prior to, concurrently with and/or subsequently to the administration of the anti-PD-1 antibody in order to treat the cancer in human patient. Combined administration can include co-administration, either in a single pharmaceutical formulation or using separate formulations, or consecutive administration in either order but generally within a time period such that all active agents can exert their biological activities simultaneously. It will be appreciated that the combination of an anti- TIGIT antibody and an anti-PD- 1 antibody may be administered in any order or concurrently. [00137] The anti-TIGIT antibody and the anti-PD-1 antibody can be administered in any number of ways for either local or systemic treatment. In some embodiments, administration is (i) topical by epidermal or transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders; (ii) pulmonary by inhalation or insufflation of powders or aerosols, including by nebulizer, intratracheal, and intranasal; (iii) oral; or (iv) parenteral including intravenous, intraarterial, intratumoral, subcutaneous, intraperitoneal, intramuscular (e.g., injection or infusion), or intracranial (e.g., intrathecal or intraventricular). [00138] In certain embodiments, the anti-TIGIT antibodies and the anti-PD- 1 antibodies described herein are administered intravenously. In certain embodiments, the anti-TIGIT antibodies and the anti-PD- 1 antibodies described herein are administered subcutaneously.

Dosing

[00139] In some embodiments, the anti-TIGIT antibody is administered once every week, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, the anti-TIGIT antibody is administered once every two weeks. In some embodiments, the anti-PD- 1 antibody is administered once every week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, both the anti-TIGIT antibody and the anti-PD- 1 antibody are administered once every week, once every two weeks, once every three weeks, or once every four weeks. In other embodiments, the anti-TIGIT antibody and the anti-PD- 1 antibody are administered at different intervals. For example, the anti-TIGIT antibody is administered once every two weeks and the anti-PD- 1 antibody is administered once every week, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, etigilimab is administered once every two weeks and the anti-PD- 1 antibody is administered once every week, once every two weeks, once every three weeks, or once every four weeks.

[00140] In some embodiments, the anti-TIGIT antibody is administered once every two weeks and the anti-PD- 1 antibody is administered once every week, once every two weeks, once every three weeks, or once every four weeks, once every five weeks or once every six weeks.

[00141] In some embodiments, etigilimab is administered once every two weeks and the anti-PD- 1 antibody is administered once every week, once every two weeks, once every three weeks, once every four weeks, once every five weeks or once every six weeks.

[00142] In some embodiments, etigilimab is administered once every two weeks and pembrolizumab is administered once every three weeks, or once every six weeks. In some embodiments, etigilimab is administered once every two weeks and nivolumab is administered once every two weeks, or once every four weeks. In some embodiments, etigilimab is administered once every two weeks and cemiplimab is administered once every three weeks. In some embodiments, etigilimab is administered once every two weeks and dostarlimab is administered once every three weeks, or once every six weeks.

[00143] In some embodiments, the anti-TIGIT antibody is administered once every two weeks at a flat dose of 1000 mg. In some embodiments, the anti-PD-1 antibody is administered at a flat dose of 200 mg-1000 mg. In some embodiments, the anti-PD-1 antibody is administered at a flat dose of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg. In certain embodiments, the -PD-1 antibody is administered at a flat dose of 200 mg, 240 mg, 350 mg, 400mg, 500 mg or 1000 mg.

[00144] In some embodiments, etigilimab is administered once every two weeks at a flat dose of 1000 mg and pembrolizumab is administered once every three weeks at a flat dose of 200 mg, or once every six weeks at a flat dose of 400 mg. In some embodiments, etigilimab is administered once every two weeks at a flat dose of 1000 mg and nivolumab is administered once every two weeks at a flat dose of 240 mg, or once every four weeks at a flat dose of 480 mg. In some embodiments, etigilimab is administered once every two weeks at a flat dose of 1000 mg and cemiplimab is administered once every three weeks at a flat dose of 350 mg. In some embodiments, etigilimab is administered once every two weeks at a flat dose of 1000 mg and dostarlimab is administered once every three weeks at a flat dose of 500 mg, or once every six weeks at a flat dose of 1000 mg.

Anti-TIGIT antibodies

[00145] T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is a type I transmembrane glycoprotein that contains an immunoglobulin variable (IgV) domain. TIGIT belongs to the poliovirus receptor (PVR) family and binds to the poliovirus receptor (PVR; CD155) with high affinity and to PVRL-2 (CD112) and PVRL-3 (CD113) with a lower affinity. TIGIT is expressed on T-cells, including regulatory T-cells (Tregs) and memory T-cells, as well as on NK cells and is upregulated following activation of naive CD4+ T-cells.

[00146] Exemplary anti-TIGIT antibodies include Tiragolumab, Ociperlimab, Vibostolimab, Domvanalimab, and Etigilimab [5]. In some embodiments, the anti-TIGIT antibody is selected from the group consisting of Tiragolumab, Ociperlimab, Vibostolimab, Domvanalimab, and Etigilimab.

[00147] Further anti-TIGT antibodies are described in WO2016/191643, WO2018/102536, W02004/024068, W02015/009856, W02016/011264, WO2017/053748, WO2017/021526, WO2017/048824, WO2006/124667, WO2018/222711, WO2019/165434, WO2018/160704, WO2018/129559, W02020/041541, W02019/023504, W02016/106302, WO2009/126688, WO2017/152088, WO2021139777, W02020/020281 , W02020/098734, WO2019/129221, WO2019/062832, WO2018/102746, WO2018/128939, WO2016/028656, W02020/096915, WO2019/168382, WO2019137548, WO2019154415, WO2019129261, WO2018204363, W02020020281, W02020098734, WO2021/147854, WO2021/092196, WO2021/216468, WO2020/251187, W02020/257760, W02021/008523, WO2020/242919, W02021/043206, WO2020257789, WO2021/217893, WO2021/147854, which are hereby all incorporated in their entirety by reference thereto.

[00148] In some embodiments, the anti-TIGIT antibody is Tiragolumab which comprises a heavy chain comprising SEQ ID NO:76 and a light chain sequence comprising SEQ ID NO:77. In some embodiments, the anti-TIGIT antibody is Tiragolumab which consists of a heavy chain comprising SEQ ID NO:76 and a light chain sequence comprising SEQ ID NO:77. In some embodiments, the anti-TIGIT antibody is Ociperlimab which comprises a heavy chain comprising SEQ ID NO:78 and a light chain sequence comprising SEQ ID NO:79. In some embodiments, the anti-TIGIT antibody is Ociperlimab which consists of a heavy chain comprising SEQ ID NO:78 and a light chain sequence comprising SEQ ID NO:79. In some embodiments, the anti-TIGIT antibody is Vibostolimab which comprises a heavy chain comprising SEQ ID NO: 80 and a light chain sequence comprising SEQ ID NO:81. In some embodiments, the anti-TIGIT antibody is Vibostolimab which consists of a heavy chain comprising SEQ ID NO: 80 and a light chain sequence comprising SEQ ID NO:81. In some embodiments, the anti-TIGIT antibody is Domvanalimab which comprises a heavy chain comprising SEQ ID NO:82 and a light chain sequence comprising SEQ ID NO:83. In some embodiments, the anti-TIGIT antibody is Domvanalimab which consists of a heavy chain comprising SEQ ID NO: 82 and a light chain sequence comprising SEQ ID NO: 83.

[00149] In one aspect, the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NOG), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NOG), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NOG), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6).

[00150] In some embodiments, the anti-TIGIT antibody is a monoclonal antibody, a humanized antibody, a human antibody, a recombinant antibody, a chimeric antibody, a bispecific antibody or a multi-specific antibody. In some embodiments, the antibody is monovalent. In some embodiments, the antibody is bivalent. In some embodiments, the antibody is monospecific. In some embodiments, the antibody is bispecific. In some embodiments, the anti-TIGIT antibody is an IgA, IgD, IgE, IgG, or IgM antibody. In certain embodiments, the anti-TIGIT antibody is an IgGl antibody. In certain embodiments, the anti- TIGIT antibody is an IgG2 antibody. In some embodiments, the anti-TIGIT antibody is an IgG4 antibody. In some embodiments, the anti-TIGIT antibody is conjugated to a cytotoxic moiety. In some embodiments, the anti-TIGIT antibody is isolated. In some embodiments, the anti- TIGIT antibody is substantially pure.

[00151] In some embodiments, the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NOG), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NOG), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NOH), a light chain CDR2 comprising SASYRYT (SEQ ID NOG), a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and a Fc region. In some embodiments, the Fc region is IgGl, IgG2, or IgG4. In a certain embodiment, the Fc region is IgGl. In some embodiments, the Fc region is ADCC competent. In a certain embodiment, the Fc region is ADCC competent and IgGl.

[00152] In a certain embodiment, the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NOG), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NOG), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NOG), a light chain CDR2 comprising SASYRYT (SEQ ID NOG), a light chain CDR3 comprising QQHYSTP (SEQ ID NOG), and an ADCC competent IgGl Fc region. In a certain embodiment, the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NOG), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NOG), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NOH), a light chain CDR2 comprising SASYRYT (SEQ ID NOG), a light chain CDR3 comprising QQHYSTP (SEQ ID NOG), and an ADCC competent IgG2 Fc region. In a certain embodiment, the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NOG), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NOG), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NOH), a light chain CDR2 comprising SASYRYT (SEQ ID NOG), a light chain CDR3 comprising QQHYSTP (SEQ ID NOG), and an ADCC competent IgG4 Fc region.

[00153] In some embodiments, the anti-TIGIT antibody is that full length antibody that comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NOG), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NOG), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6). [00154] In some embodiments, the anti-TIGIT antibody comprises a heavy chain variable region having at least 90%, 95%, 96%, 97%, 98%, 99% sequence identity to SEQ ID NO:7 and/or a light chain variable region having at least 90%, 95%, 96%, 97%, 98%, 99% sequence identity to SEQ ID NO:8. In some embodiments, the anti-TIGIT antibody comprises a heavy chain variable region comprising SEQ ID NO:7 and a light chain variable region comprising SEQ ID NO:8. In some embodiments, the anti-TIGIT antibody comprises a heavy chain variable region consisting of SEQ ID NO:7 and a light chain variable region consisting of SEQ ID NO:8. [00155] In some embodiments, the anti-TIGIT antibody comprises a heavy chain having at least 90%, 95%, 96%, 97%, 98%, 99% sequence identity to SEQ ID NO:9 and/or a light chain having at least 90%, 95%, 96%, 97%, 98%, 99% sequence identity to SEQ ID NO:10. In some embodiments, the anti-TIGIT antibody comprises a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO:10. In some embodiments, the anti-TIGIT antibody comprises a heavy chain consisting of SEQ ID NO:9 and a light chain consisting of SEQ ID NO:10. In certain embodiments, the anti-TIGIT antibody is etigilimab. The heavy chain of etigilimab consists of SEQ ID NO:9 and the light chain of etigilimab consists of SEQ ID NO:10. [00156] In some embodiments, the anti-TIGIT antibody comprises the variable regions of etigilimab wherein the heavy chain variable region (SEQ ID NO: 7) and/or the light chain variable region (SEQ ID NO: 8) of etigilimab have been affinity-matured. In certain embodiments, the anti-TIGIT antibody comprises the heavy chain and light chain of etigilimab (with or without the leader sequence). In certain embodiments, the anti-TIGIT antibody is etigilimab. In certain embodiments, the anti-TIGIT antibody comprises the heavy chain variable region of etigilimab as part of an IgG1, IgG2, or IgG4 heavy chain. In certain embodiments, the anti-TIGIT antibody comprises the heavy chain variable region of the etigilimab as part of a human IgG1 heavy chain. In certain embodiments, the anti-TIGIT antibody comprises the heavy chain variable region of the etigilimab as part of a human IgG2 heavy chain. In certain embodiments, the anti-TIGIT antibody comprises the heavy chain variable region of the etigilimab as part of a human IgG4 heavy chain. [00157] In some embodiments, the anti-TIGIT antibody is a monoclonal antibody. Monoclonal antibodies can be prepared using hybridoma methods known to one of skill in the art. In some embodiments, using the hybridoma method, a mouse, rat, rabbit, hamster, or other appropriate host animal, is immunized as described above to elicit the production of antibodies that specifically bind the immunizing antigen. In some embodiments, lymphocytes can be immunized in vitro. In some embodiments, the immunizing antigen can be a human protein or a fragment thereof. In some embodiments, the immunizing antigen can be a mouse protein or a fragment thereof.

[00158] Following immunization, lymphocytes are isolated and fused with a suitable myeloma cell line using, for example, polyethylene glycol. The hybridoma cells are selected using specialized media as known in the art and unfused lymphocytes and myeloma cells do not survive the selection process. Hybridomas that produce monoclonal antibodies directed specifically against a chosen antigen may be identified by a variety of methods including, but not limited to, immunoprecipitation, immunoblotting, and in vitro binding assays (e.g., flow cytometry, FACS, ELISA, and radioimmunoassay). The hybridomas can be propagated either in in vitro culture using standard methods or in vivo as ascites tumors in an animal. The monoclonal antibodies can be purified from the culture medium or ascites fluid according to standard methods in the art including, but not limited to, affinity chromatography, ion-exchange chromatography, gel electrophoresis, and dialysis.

[00159] In certain embodiments, monoclonal antibodies can be made using recombinant DNA techniques as known to one skilled in the art. The polynucleotides encoding a monoclonal antibody are isolated from mature B-cells or hybridoma cells, such as by RT-PCR using oligonucleotide primers that specifically amplify the genes encoding the heavy and light chains of the antibody, and their sequence is determined using standard techniques. The isolated polynucleotides encoding the heavy and light chains are then cloned into suitable expression vectors which produce the monoclonal antibodies when transfected into host cells such as E. coli, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin proteins. In certain other embodiments, recombinant monoclonal antibodies, or fragments thereof, can be isolated from phage display libraries expressing variable domains or CDRs of a desired species.

[00160] Polynucleotide(s) encoding a monoclonal antibody can be modified, for example, by using recombinant DNA technology to generate alternative antibodies. In some embodiments, the constant domains of the light chain and heavy chain of, for example, a mouse monoclonal antibody can be substituted for constant regions of, for example, a human antibody to generate a chimeric antibody, or for a non-immunoglobulin polypeptide to generate a fusion antibody. In some embodiments, the constant regions are truncated or removed to generate a desired antibody fragment of a monoclonal antibody. Site-directed or high-density mutagenesis of the variable region(s) can be used to optimize specificity, affinity, etc. of a monoclonal antibody. [00161] In some embodiments, the anti-TIGIT antibody is a humanized antibody. Typically, humanized antibodies are human immunoglobulins in which the amino acid residues of the CDRs are replaced by amino acid residues from CDRs of a non-human species (e.g., mouse, rat, rabbit, hamster, etc.) that have the desired specificity, affinity, and/or binding capability using methods known to one skilled in the art. In some embodiments, some of the framework variable region amino acid residues of a human immunoglobulin are replaced with corresponding amino acid residues in an antibody from a non-human species. In some embodiments, a humanized antibody can be further modified by the substitution of additional residues either in the framework variable region and/or within the replaced non-human residues to further refine and optimize antibody specificity, affinity, and/or capability. In general, a humanized antibody will comprise variable domain regions containing all, or substantially all, of the CDRs that correspond to the non-human immunoglobulin whereas all, or substantially all, of the framework regions are those of a human immunoglobulin sequence. In some embodiments, the framework regions are those of a human consensus immunoglobulin sequence. In some embodiments, a humanized antibody can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. In certain embodiments, such humanized antibodies are used therapeutically because they may reduce antigenicity and HAMA (human anti-mouse antibody) responses when administered to a human patient.

[00162] In certain embodiments, the anti-TIGIT antibody is a human antibody. Human antibodies can be directly prepared using various techniques known in the art. In some embodiments, human antibodies may be generated from immortalized human B lymphocytes immunized in vitro or from lymphocytes isolated from an immunized individual. In either case, cells that produce an antibody directed against a target antigen can be generated and isolated. In some embodiments, the human antibody can be selected from a phage library, where that phage library expresses human antibodies. Alternatively, phage display technology can be used to produce human antibodies and antibody fragments in vitro, from immunoglobulin variable domain gene repertoires from unimmunized donors. Techniques for the generation and use of antibody phage libraries are well known in the art. Once antibodies are identified, affinity maturation strategies known in the art, including but not limited to, chain shuffling and site- directed mutagenesis, may be employed to generate higher affinity human antibodies. In some embodiments, human antibodies can be made in transgenic mice that contain human immunoglobulin loci. Upon immunization these mice are capable of producing the full repertoire of human antibodies in the absence of endogenous immunoglobulin production. [00163] In some embodiments, the anti-TIGIT antibody binds with TIGIT and interferes with the interaction of TIGIT with a second protein, for example PVR, PVRL2 or PVLR3. In some embodiments, the anti-TIGIT antibody binds TIGIT and disrupts binding of TIGIT to PVR, and/or disrupts PVR activation of TIGIT signalling. [00164] The full-length amino acid sequence for human TIGIT (UniProtKB No. Q495A1) is known in the art and are provided herein as SEQ ID NO:11. As used herein, reference to amino acid positions refer to the numbering of full-length amino acid sequences including the signal sequence. [00165] In certain embodiments, the anti-TIGIT antibody is an antibody that specifically binds the extracellular domain of human TIGIT, or a fragment thereof. In some embodiments, the anti-TIGIT antibody is an antibody that specifically binds the Ig-like domain of human TIGIT. In some embodiments, the anti-TIGIT antibody is an antibody that specifically binds the IgV domain of human TIGIT. In some embodiments, the anti-TIGIT antibody is an antibody that binds within amino acids 22-141 of human TIGIT. In some embodiments, the anti-TIGIT antibody is an antibody that binds within amino acids 22-141 of SEQ ID NO:12. In some embodiments, the antibody binds within amino acids 22-124 of human TIGIT. In some embodiments, the antibody binds within amino acids 22-124 of SEQ ID NO:11. In certain embodiments, the anti-TIGIT antibody binds within SEQ ID NO:12, or a fragment thereof. In some embodiments, the anti-TIGIT antibody is an antibody that binds within amino acids 50- 124 of human TIGIT. In some embodiments, the anti-TIGIT antibody is an antibody that binds within amino acids 50-124 of SEQ ID NO:11. In certain embodiments, the anti-TIGIT antibody binds within SEQ ID NO:12, or a fragment thereof. [00166] In some embodiments, the anti-TIGIT antibody is an antibody that binds an epitope comprising amino acids within SEQ ID NO:13. In some embodiments, the anti-TIGIT antibody is an antibody that binds an epitope comprising amino acids within SEQ ID NO:14. In some embodiments, the anti-TIGIT antibody is an antibody that binds an epitope comprising amino acids within SEQ ID NO:13 and SEQ ID NO:14. In some embodiments, the anti-TIGIT antibody is an antibody that binds an epitope comprising amino acids Q62 and I109 of SEQ ID NO:11. In some embodiments, the anti-TIGIT antibody is an antibody that binds an epitope comprising amino acids Q62 and T119 of SEQ ID NO:11. In some embodiments, the anti- TIGIT antibody is an antibody that binds an epitope comprising amino acids Q64 and I109 of SEQ ID NO:11. In some embodiments, the anti-TIGIT antibody is an antibody that binds an epitope comprising amino acids Q64 and T119 of SEQ ID NO:11. In some embodiments, the anti-TIGIT antibody is an antibody that binds an epitope comprising amino acids Q62, Q64, and I109 of SEQ ID NO:11. In some embodiments, the anti-TIGIT antibody is an antibody that binds an epitope comprising amino acids Q62, Q64, and T119 of SEQ ID NO:11. In some embodiments, the anti-TIGIT antibody is an antibody that binds an epitope comprising amino acids Q62, I109, and T119 of SEQ ID NO:11. In some embodiments, the anti-TIGIT antibody is an antibody that binds an epitope comprising amino acids Q64, I109, and T119 of SEQ ID NO:11. In some embodiments, the anti-TIGIT antibody is an antibody that binds an epitope comprising amino acids Q62, Q64, I109, and T119 of SEQ ID NO:11. In some embodiments, the anti-TIGIT antibody is an antibody that binds an epitope comprising at least one amino acid selected from the group consisting of: N58, E60, Q62, Q64, L65, F107, I109, H111, T117, T119, G120, and R121 of SEQ ID NO:11. In some embodiments, the epitope is a conformational epitope. In some embodiments, the anti-TIGIT antibody is an antibody that binds an epitope which does not comprise amino acid V100 of SEQ ID NO:11. [00167] In certain embodiments, the anti-TIGIT antibody binds TIGIT with a dissociation constant (KD) of about 1μM or less, about 100nM or less, about 40nM or less, about 20nM or less, about 10nM or less, about 1nM or less, about 0.1nM or less, 50pM or less, 10pM or less, or 1pM or less. In some embodiments, an anti-TIGIT antibody binds TIGIT with a KD of about 20nM or less. In some embodiments, an anti-TIGIT antibody binds TIGIT with a KD of about 10nM or less. In some embodiments, an anti-TIGIT antibody binds TIGIT with a KD of about 1nM or less. In some embodiments, an anti-TIGIT antibody binds TIGIT with a KD of about 0.5nM or less. In some embodiments, an anti-TIGIT antibody binds TIGIT with a KD of about 0.1nM or less. In some embodiments, an anti-TIGIT antibody binds TIGIT with a KD of about 50pM or less. In some embodiments, an anti-TIGIT antibody binds TIGIT with a KD of about 25pM or less. In some embodiments, an anti-TIGIT antibody binds TIGIT with a KD of about 10pM or less. In some embodiments, an anti-TIGIT antibody binds TIGIT with a KD of about 1pM or less. In some embodiments, the dissociation constant of the antibody to TIGIT is the dissociation constant determined using a TIGIT fusion protein comprising at least a portion of the extracellular domain of TIGIT protein immobilized on a Biacore chip. In some embodiments, the dissociation constant of the antibody to TIGIT is the dissociation constant determined using the antibody captured by an anti-human IgG antibody on a Biacore chip and a soluble TIGIT protein. In certain embodiments, the anti-TIGIT antibody binds TIGIT with a KD of about 0.4nM or less determined using a TIGIT fusion protein comprising at least a portion of the extracellular domain of TIGIT protein immobilized on a Biacore chip. In certain embodiments, the anti-TIGIT antibody binds TIGIT with a KD of about 0.4nM or less determined using the antibody captured by an anti-human IgG antibody on a Biacore chip and a soluble TIGIT protein. [00168] In certain embodiments, the anti-TIGIT antibody binds TIGIT with a half maximal effective concentration (EC50) of about 1µM or less, about 100nM or less, about 40nM or less, about 20nM or less, about 10nM or less, about 1nM or less, or about 0.1nM or less. In certain embodiments, the anti-TIGIT antibody binds to human TIGIT with a half maximal effective concentration (EC50) of about 1µM or less, about 100nM or less, about 40nM or less, about 20nM or less, about 10nM or less, about 1nM or less, or about 0.1nM or less. [00169] Non-limiting examples of anti-TIGIT antibodies are described in [6], [7], [8] and [9], which are hereby incorporated in their entirety herein by reference thereto. [00170] Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune cells to unwanted cells. It is also contemplated that the heteroconjugate antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4- mercaptobutyrimidate. [00171] For the purposes of the present invention, it should be appreciated that modified antibodies can comprise any type of variable region that provides for the association of the antibody with the target (i.e., TIGIT). In this regard, the variable region may comprise or be derived from any type of mammal that can be induced to mount a humoral response and generate immunoglobulins against the desired antigen. As such, the variable region of the modified antibodies can be, for example, of human, murine, rat, rabbit, non-human primate (e.g. cynomolgus monkeys, macaques, etc.), or rabbit origin. In some embodiments, both the variable and constant regions of the modified immunoglobulins are human. In other embodiments, the variable regions of compatible antibodies (usually derived from a non-human source) can be engineered or specifically tailored to improve the binding properties or reduce the immunogenicity of the molecule. In this respect, variable regions useful in the present invention can be humanized or otherwise altered through the inclusion of imported amino acid sequences. [00172] In certain embodiments, the variable domains in both the heavy and light chains are altered by at least partial replacement of one or more CDRs and, if necessary, by partial framework region replacement and sequence modification and/or alteration. Although the CDRs may be derived from an antibody of the same class or even subclass as the antibody from which the framework regions are derived, it is envisaged that the CDRs may be derived from an antibody of different class and often from an antibody from a different species. It may not be necessary to replace all of the CDRs with all of the CDRs from the donor variable region to transfer the antigen binding capacity of one variable domain to another. Rather, it may only be necessary to transfer those residues that are required to maintain the activity of the antigenbinding site.

[00173] Alterations to the variable region notwithstanding, those skilled in the art will appreciate that the modified antibodies of this invention will comprise antibodies (e.g., full- length antibodies or immunoreactive fragments thereof) in which at least a fraction of one or more of the constant region domains has been deleted or otherwise altered so as to provide desired biochemical characteristics such as increased tumor localization or increased serum half-life when compared with an antibody of approximately the same immunogenicity comprising a native or unaltered constant region. In some embodiments, the constant region of the modified antibodies will comprise a human constant region. Modifications to the constant region compatible with this invention comprise additions, deletions or substitutions of one or more amino acids in one or more domains. The modified antibodies disclosed herein may comprise alterations or modifications to one or more of the three heavy chain constant domains (CHI, CH2 or CH3) and/or to the light chain constant domain (CL). In some embodiments, one or more domains are partially or entirely deleted from the constant regions of the modified antibodies. In some embodiments, the modified antibodies will comprise domain deleted constructs or variants wherein the entire CH2 domain has been removed (ACH2 constructs). In some embodiments, the omitted constant region domain is replaced by a short amino acid spacer (e.g., 10 amino acid residues) that provides some of the molecular flexibility typically imparted by the absent constant region.

[00174] In some embodiments, the modified antibodies are engineered to fuse the CH3 domain directly to the hinge region of the antibody. In other embodiments, a peptide spacer is inserted between the hinge region and the modified CH2 and/or CH3 domains. For example, constructs may be expressed wherein the CH2 domain has been deleted and the remaining CH3 domain (modified or unmodified) is joined to the hinge region with a 5-20 amino acid spacer. Such a spacer may be added to ensure that the regulatory elements of the constant domain remain free and accessible or that the hinge region remains flexible. However, it should be noted that amino acid spacers may, in some cases, prove to be immunogenic and elicit an unwanted immune response against the construct. Accordingly, in certain embodiments, any spacer added to the construct will be relatively non-immunogenic so as to maintain the desired biological qualities of the modified antibodies. [00175] In some embodiments, the modified antibodies may have only a partial deletion of a constant domain or substitution of a few or even a single amino acid. For example, the mutation of a single amino acid in selected areas of the CH2 domain may be enough to substantially reduce Fc binding.. In some embodiments, the mutation of a single amino acid in selected areas of the CH2 domain may be enough to substantially reduce Fc binding and increase cancer cell localization and/or tumor penetration. Similarly, it may be desirable to simply delete the part of one or more constant region domains that control a specific effector function (e.g. complement C1q binding) to be modulated. Such partial deletions of the constant regions may improve selected characteristics of the antibody (serum half-life) while leaving other desirable functions associated with the subject constant region domain intact. Moreover, as alluded to above, the constant regions of the disclosed antibodies may be modified through the mutation or substitution of one or more amino acids that enhances the profile of the resulting construct. In this respect it may be possible to disrupt the activity provided by a conserved binding site (e.g., Fc binding) while substantially maintaining the configuration and immunogenic profile of the modified antibody. In certain embodiments, the modified antibodies comprise the addition of one or more amino acids to the constant region to enhance desirable characteristics such as decreasing or increasing effector function or provide for more cytotoxin or carbohydrate attachment sites. [00176] It is known in the art that the constant region mediates several effector functions. For example, binding of the C1 component of complement to the Fc region of IgG or IgM antibodies (bound to antigen) activates the complement system. Activation of complement is important in the opsonization and lysis of cell pathogens. The activation of complement also stimulates the inflammatory response and can also be involved in autoimmune hypersensitivity. In addition, the Fc region of an antibody can bind a cell expressing a Fc receptor (FcR). There are a number of Fc receptors which are specific for different classes of antibody, including IgG (gamma receptors), IgE (epsilon receptors), IgA (alpha receptors) and IgM (mu receptors). Binding of antibody to Fc receptors on cell surfaces triggers a number of important and diverse biological responses including engulfment and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody-coated target cells by killer cells (called antibody-dependent cell cytotoxicity or ADCC), release of inflammatory mediators, placental transfer, and control of immunoglobulin production. [00177] In certain embodiments, the modified antibodies provide for altered effector functions that, in turn, affect the biological profile of the administered antibody. For example, in some embodiments, the deletion or inactivation (through point mutations or other means) of a constant region domain may reduce Fc receptor binding of the circulating modified antibody. In some embodiments, the deletion or inactivation (through point mutations or other means) of a constant region domain may reduce Fc receptor binding of the circulating modified antibody thereby increasing cancer cell localization and/or tumor penetration. In other embodiments, the constant region modifications increase the serum half-life of the antibody. In other embodiments, the constant region modifications reduce the serum half-life of the antibody. In some embodiments, the constant region is modified to eliminate disulfide linkages or oligosaccharide moieties. Modifications to the constant region in accordance with this invention may easily be made using well known biochemical or molecular engineering techniques. [00178] In certain embodiments, the anti-TIGIT antibody does not have one or more effector functions. For instance, in some embodiments, the antibody has no ADCC activity, and/or no complement-dependent cytotoxicity (CDC) activity. In certain embodiments, the antibody does not bind an Fc receptor and/or complement factors. In certain embodiments, the antibody has no effector function(s). [00179] In certain embodiments, the anti-TIGIT antibody has one or more effector functions. For instance, in some embodiments, the antibody has ADCC activity, and/or complement-dependent cytotoxicity (CDC) activity. In certain embodiments, the antibody binds an Fc receptor and/or complement factors. In certain embodiments, the antibody has effector function(s). [00180] In certain embodiments, the anti-TIGIT antibody binds the Fc receptor. In certain embodiments, the anti-TIGIT antibody activates ADCC. In some embodiments, the anti-TIGIT antibody recruits activated myeloid cells to the tumor. In some embodiments, the anti-TIGIT antibody activates T cells. In some embodiments, the anti-TIGIT antibody activates NK cells. In some embodiments, the anti-TIGIT antibody reduces the number of T-regulatory cells. In some embodiments, the anti-TIGIT antibody increases the CD8/Treg ratio. In some embodiments, the anti-TIGIT antibody increases the CD8/Treg ratio. [00181] The present invention further embraces variants and equivalents which are substantially homologous to the recombinant, monoclonal, chimeric, humanized, and human antibodies, or antibody fragments thereof, described herein. These variants can contain, for example, conservative substitution mutations, i.e. the substitution of one or more amino acids by similar amino acids. [00182] In certain embodiments, the antibodies described herein are isolated. In certain embodiments, the antibodies described herein are substantially pure. [00183] The anti-TIGIT antibodies of the present invention can be assayed for specific binding by any method known in the art. The immunoassays which can be used include, but are not limited to, competitive and non-competitive assay systems using techniques such as Biacore analysis, FACS analysis, immunofluorescence, immunocytochemistry, Western blot analysis, radioimmunoassay, ELISA, “sandwich” immunoassay, immunoprecipitation assay, precipitation reaction, gel diffusion precipitin reaction, immunodiffusion assay, agglutination assay, complement-fixation assay, immunoradiometric assay, fluorescent immunoassay, and protein A immunoassay. Such assays are routine and well-known in the art (see, e.g., Ausubel et al., Editors, 1994-present, Current Protocols in Molecular Biology, John Wiley & Sons, Inc., New York, NY). [00184] In a non-limiting example, screening for specific binding of an antibody to human TIGIT may be determined using ELISA. An ELISA comprises preparing antigen (e.g., TIGIT or a fragment thereof), coating wells of a 96-well microtiter plate with antigen, adding the test antibodies conjugated to a detectable compound such as an enzymatic substrate (e.g. horseradish peroxidase or alkaline phosphatase) to the well, incubating for a period of time, and detecting the presence of an antibody bound to the antigen. In some embodiments, the test antibodies are not conjugated to a detectable compound, but instead a secondary antibody that recognizes the antibody (e.g., an anti-Fc antibody) and is conjugated to a detectable compound is added to the wells. In some embodiments, instead of coating the well with the antigen, the test antibodies can be coated to the wells, the antigen (e.g., TIGIT) is added to the wells, followed by a secondary antibody conjugated to a detectable compound. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the signal detected as well as other variations of ELISAs known in the art. [00185] In another non-limiting example, the specific binding of an antibody to TIGIT may be determined using FACS. A FACS screening assay may comprise generating a cDNA construct that expresses an antigen as a full-length protein (TIGIT) or a fusion protein (e.g., TIGIT-CD4TM), transfecting the construct into cells, expressing the antigen on the surface of the cells, mixing the test antibodies with the transfected cells, and incubating for a period of time. The cells bound by the test antibodies may be identified using a secondary antibody conjugated to a detectable compound (e.g., PE-conjugated anti-Fc antibody) and a flow cytometer. One of skill in the art would be knowledgeable as to the parameters that can be modified to optimize the signal detected as well as other variations of FACS that may enhance screening (e.g., screening for blocking antibodies). [00186] The binding affinity of an antibody and the off-rate of an antibody-antigen interaction can be determined by competitive binding assays. One example of a competitive binding assay is a radioimmunoassay comprising the incubation of labeled antigen (e.g., 3H or 125I-TIGIT), or fragment or variant thereof, with the antibody of interest in the presence of increasing amounts of unlabeled antigen followed by the detection of the antibody bound to the labeled antigen. The affinity of the antibody for the antigen and the binding off-rates can be determined from the data by Scatchard plot analysis. In some embodiments, Biacore kinetic analysis is used to determine the binding on and off rates of antibodies. In some embodiments, Biacore kinetic analysis comprises analyzing the binding and dissociation of antibodies from chips with immobilized antigen (e.g., TIGIT) on their surface. In some embodiments, Biacore kinetic analysis comprises analyzing the binding and dissociation of antigen (e.g., TIGIT) from chips with immobilized antibody (e.g., anti-TIGIT antibody) on their surface. [00187] Many proteins, including antibodies, contain a signal sequence that directs the transport of the proteins to various locations. Generally, signal sequences (also referred to as signal peptides or leader sequences) are located at the N-terminus of nascent polypeptides. They target the polypeptide to the endoplasmic reticulum and the proteins are sorted to their destinations, for example, to the inner space of an organelle, to an interior membrane, to the cell's outer membrane, or to the cell exterior via secretion. Most signal sequences are cleaved from the protein by a signal peptidase after the proteins are transported to the endoplasmic reticulum. The cleavage of the signal sequence from the polypeptide usually occurs at a specific site in the amino acid sequence and is dependent upon amino acid residues within the signal sequence. Although there is usually one specific cleavage site, more than one cleavage site may be recognized and/or may be used by a signal peptidase resulting in a non-homogenous N- terminus of the polypeptide. For example, the use of different cleavage sites within a signal sequence can result in a polypeptide expressed with different N-terminal amino acids. Accordingly, in some embodiments, the polypeptides as described herein may comprise a mixture of polypeptides with different N-termini. In some embodiments, the N-termini differ in length by 1, 2, 3, 4, or 5 amino acids. In some embodiments, the polypeptide is substantially homogeneous, i.e., the polypeptides have the same N-terminus. In some embodiments, the signal sequence of the polypeptide comprises one or more (e.g., one, two, three, four, five, six, seven, eight, nine, ten, etc.) amino acid substitutions and/or deletions as compared to a “native” or “parental” signal sequence. In some embodiments, the signal sequence of the polypeptide comprises amino acid substitutions and/or deletions that allow one cleavage site to be dominant, thereby resulting in a substantially homogeneous polypeptide with one N-terminus. In some embodiments, a signal sequence of the polypeptide affects the expression level of the polypeptide, e.g., increased expression or decreased expression. [00188] Experiments determining the epitope of etigilimab are described in WO2016/191643 and are hereby incorporated herein by reference in their entirety. In certain embodiments, the anti-TIGIT antibodies compete for specific binding to TIGIT with the anti- TIGIT antibody comprising: (a) a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), and a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3) and (b) a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6). [00189] In certain embodiments, the anti-TIGIT antibodies competes for specific binding to human TIGIT with the anti-TIGIT antibody comprising a heavy chain variable region comprising SEQ ID NO:7 and a light chain variable region comprising SEQ ID NO:8. In certain embodiments, the anti-TIGIT antibodies competes for specific binding to human TIGIT with the anti-TIGIT antibody comprising a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO:10. [00190] In certain embodiments, the anti-TIGIT antibodies compete with etigilimab for specific binding to human TIGIT. In some embodiments, the anti-TIGIT antibody competes with a reference antibody for specific binding to human TIGIT, wherein the reference antibody is etigilimab. In certain embodiments, the anti-TIGIT antibody binds the same epitope, or essentially the same epitope, on TIGIT as etigilimab. [00191] In another embodiment, the anti-TIGIT antibody binds an epitope on TIGIT that overlaps with the epitope on human TIGIT bound by etigilimab. [00192] In some embodiments, the anti-TIGIT antibody competes for binding to an epitope comprising amino acids within SEQ ID NO:13 with the anti-TIGIT antibody described herein. In some embodiments, the anti-TIGIT antibody competes for binding to an epitope comprising amino acids within SEQ ID NO:14 with the anti-TIGIT antibody described herein. In some embodiments, the anti-TIGIT antibody competes for binding to an epitope comprising amino acids within SEQ ID NO:13 and SEQ ID NO:14 with the anti-TIGIT antibody described herein. In some embodiments, the anti-TIGIT antibody competes for binding to an epitope comprising amino acids Q62 and I109 of SEQ ID NO:11 with the anti-TIGIT antibody described herein. In some embodiments, the anti-TIGIT antibody competes for binding to an epitope comprising amino acids Q62 and T119 of SEQ ID NO:11 with the anti-TIGIT antibody described herein. In some embodiments, the anti-TIGIT antibody competes for binding with an epitope comprising amino acids Q64 and I109 of SEQ ID NO:11 with the anti-TIGIT antibody described herein. In some embodiments, the anti-TIGIT antibody competes for binding to an epitope comprising amino acids Q64 and T119 of SEQ ID NO:11 with the anti-TIGIT antibody described herein. In some embodiments, the anti-TIGIT antibody competes for binding to an epitope comprising amino acids Q62, Q64, and I109 of SEQ ID NO:11 with the anti-TIGIT antibody described herein. In some embodiments, the anti-TIGIT antibody competes for binding to an epitope comprising amino acids Q62, Q64, and T119 of SEQ ID NO:11 with the anti-TIGIT antibody described herein. In some embodiments, the anti-TIGIT antibody competes for binding to an epitope comprising amino acids Q62, I109, and T119 of SEQ ID NO:11 with the anti-TIGIT antibody described herein. In some embodiments, the anti-TIGIT antibody competes for binding to an epitope comprising amino acids Q64, I109, and T119 of SEQ ID NO:11 with the anti-TIGIT antibody described herein. In some embodiments, the anti- TIGIT antibody competes for binding to an epitope comprising amino acids Q62, Q64, I109, and T119 of SEQ ID NO:11 with the anti-TIGIT antibody described herein. In some embodiments, the anti-TIGIT antibody competes for binding to an epitope comprising at least one amino acid selected from the group consisting of: N58, E60, Q62, Q64, L65, F107, I109, H111, T117, T119, G120, and R121 of SEQ ID NO:11 with the anti-TIGIT antibody described herein. [00193] In certain embodiments, the anti-TIGIT antibody binds TIGIT and modulates TIGIT activity. In some embodiments, the anti-TIGIT antibody is a TIGIT antagonist and decreases TIGIT activity. In certain embodiments, the anti-TIGIT antibody inhibits TIGIT activity by at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 90%, or about 100%. In certain embodiments, the anti-TIGIT antibody inhibits TIGIT activity is etigilimab. [00194] In some embodiments, the anti-TIGIT antibody binds TIGIT and inhibits or reduces TIGIT signalling. In certain embodiments, the anti-TIGIT antibody inhibits TIGIT signalling by at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 90%, or about 100%. [00195] TIGIT is phosphorylated at its cytoplasmic tail after interaction with its counter- receptor PVR. The phosphorylation of TIGIT is the beginning of a cascade that includes downstream events affecting other known signalling pathways. Therefore, evaluating TIGIT phosphorylation can give information about TIGIT activity and TIGIT signalling. [00196] Phosphorylation assays are known to those of skill in the art and are commonly used to monitor protein activation and/or pathway activation. The assays may be used to monitor the effect of various treatments on activation of a target protein and/or a target pathway. For example, an in vitro phosphorylation assay can be used to evaluate the effect of a TIGIT antagonist on the PVR-induced activation of TIGIT. [00197] In certain embodiments, the anti-TIGIT antibody inhibits binding of TIGIT to a receptor. In certain embodiments, the anti-TIGIT antibody inhibits binding of TIGIT to PVR. In some embodiments, the anti-TIGIT antibody inhibits binding of TIGIT to PVR-L2, PVR- L3, and/or PVR-L4. In certain embodiments, the inhibition of binding of the anti-TIGIT antibody to PVR is at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, or at least about 95%. In certain embodiments, the inhibition of binding of the anti-TIGIT antibody to PVR-L2, PVR-L3, and/or PVR-L4 is at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, or at least about 95%. In certain embodiments, the anti-TIGIT antibody that inhibits binding of TIGIT to PVR is etigilimab. In certain embodiments, the anti-TIGIT antibody that inhibits binding of TIGIT to PVR-L2, PVR-L3, and/or PVR-L4 is etigilimab. [00198] In certain embodiments, the anti-TIGIT antibody blocks binding of TIGIT to a receptor. In certain embodiments, the anti-TIGIT antibody blocks binding of TIGIT to PVR. In certain embodiments, the blocking of binding of the anti-TIGIT antibody to PVR is at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, or at least about 95%. In some embodiments, the anti-TIGIT antibody blocks binding of TIGIT to PVRL2, PVRL3, and/or PVRL4. In certain embodiments, the blocking of binding of the anti- TIGIT antibody to PVRL2, PVRL3, and/or PVRL4 is at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, or at least about 95%. In certain embodiments, the anti-TIGIT antibody that blocks binding of TIGIT to PVR is etigilimab. [00199] Binding assays are known to those of skill in the art and are described herein. Binding assays may be used to monitor the effect of a test agent on the interaction between a target protein and the protein’s binding partner (e.g., receptor or ligand). For example, an in vitro binding assay can be used to evaluate if a TIGIT antagonist blocks the interaction of TIGIT to PVR. [00200] In certain embodiments, the anti-TIGIT antibodies described herein have one or more of the following effects: inhibit proliferation of tumor cells, inhibit tumor growth, reduce the tumorigenicity of a tumor, reduce the tumorigenicity of a tumor by reducing the frequency of cancer stem cells in the tumor, trigger cell death of tumor cells, enhance or boost the immune response, enhance or boost the anti-tumor response, increase cytolytic activity of immune cells, increase killing of tumor cells, increase killing of tumor cells by immune cells, induce cells in a tumor to differentiate, differentiate tumorigenic cells to a non-tumorigenic state, induce expression of differentiation markers in the tumor cells, prevent metastasis of tumor cells, decrease survival of tumor cells, increase cell contact-dependent growth inhibition, increase tumor cell apoptosis, reduce epithelial mesenchymal transition (EMT), or decrease survival of tumor cells. [00201] In certain embodiments, the anti-TIGIT antibodies inhibit tumor growth. In certain embodiments, the anti-TIGIT antibodies inhibit tumor growth in vivo (e.g., in a mouse model, and/or in a human having cancer). In certain embodiments, tumor growth is inhibited at least about two-fold, about three-fold, about five-fold, about ten-fold, about 50-fold, about 100- fold, or about 1000-fold as compared to an untreated tumor. [00202] In certain embodiments, the anti-TIGIT antibodies bind TIGIT and modulate an immune response. In some embodiments, the anti-TIGIT antibody activates and/or increases an immune response. In some embodiments, the anti-TIGIT antibody increases, promotes, or enhances cell-mediated immunity. In some embodiments, the anti-TIGIT antibody increases, promotes, or enhances innate cell-mediated immunity. In some embodiments, the anti-TIGIT antibody increases, promotes, or enhances adaptive cell-mediated immunity. In some embodiments, the anti-TIGIT antibody increases, promotes, or enhances T-cell activity. In some embodiments, the anti-TIGIT antibody increases, promotes, or enhances cytolytic T-cell (CTL) activity. In certain embodiments, the antibody increases the activity by at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 90%, or about 100%. In some embodiments, the anti-TIGIT antibody increases, promotes, or enhances NK cell activity. In certain embodiments, the antibody increases the activity by at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 90%, or about 100%. In some embodiments, the anti-TIGIT antibody increases, promotes, or enhances lymphokine-activated killer cell (LAK) activity. In some embodiments, the anti-TIGIT antibody increases, promotes, or enhances tumor- infiltrating lymphocyte (TIL) activity. In some embodiments, the anti-TIGIT antibody inhibits or decreases Treg cell activity. In some embodiments, the anti-TIGIT antibody inhibits or decreases MDSC activity. In some embodiments, the anti-TIGIT antibody increases, promotes, or enhances tumor cell killing. In some embodiments, the anti-TIGIT antibody increases, promotes, or enhances the inhibition of tumor growth. [00203] In some embodiments, the anti-TIGIT antibody induces and/or enhances a Th1- type immune response. In general, a Th1-type immune response includes production of interferon-gamma (IFN-γ), IL-2, and tumor necrosis factor-beta (TNF-β). In comparison, a Th2-type immune response generally includes production of IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. In some embodiments, the anti-TIGIT antibody induces and/or increases cytokine or lymphokine production. In some embodiments, the induction and/or increase in cytokine or lymphokines production may be an indirect effect. [00204] In certain embodiments, the anti-TIGIT antibody increases activation of NK cells. In certain embodiments, the anti-TIGIT antibody increases activation of T-cells. In certain embodiments, the activation of NK cells and/or T-cells by the anti-TIGIT antibody results in an increase in the level of activation of NK cells and/or T-cells of at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, or at least about 95%. In certain embodiments, the anti-TIGIT antibody that increases activation of NK cells is etigilimab. [00205] In certain embodiments, the anti-TIGIT antibody is an antagonist of regulatory T- cell (Treg) activity. In certain embodiments, the anti-TIGIT antibody inhibits or decreases the activity of Tregs. In certain embodiments, the inhibition of activity of Tregs by the anti-TIGIT antibody results in an inhibition of suppressive activity of a Treg cell of at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or about 100%. In certain embodiments, the anti-TIGIT antibody that inhibits Treg activity is etigilimab. [00206] In certain embodiments, the anti-TIGIT antibody is an antagonist of myeloid- derived suppressor cells (MDSCs). In certain embodiments, the anti-TIGIT antibody inhibits MDSC activity. In certain embodiments, the anti-TIGIT antibody inhibits MDSC activity by at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 90%, or about 100%. In certain embodiments, the anti-TIGIT antibody that inhibits MDSC activity is etigilimab. [00207] In certain embodiments, the anti-TIGIT antibody increases natural killer (NK) cell activity. In certain embodiments, the anti-TIGIT antibody increases NK cell activity by at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 90%, or about 100%. In certain embodiments, the anti-TIGIT antibody that increases NK cell activity is etigilimab. [00208] In certain embodiments, the anti-TIGIT antibody increases tumor-infiltrating lymphocyte (TIL) activity. In certain embodiments, the anti-TIGIT antibody increases TIL activity by at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 90%, or about 100%. In certain embodiments, the anti-TIGIT antibody that increases TIL cell activity is etigilimab. [00209] In certain embodiments, the anti-TIGIT antibody increases or enhances lymphokines-activated killer cell (LAK) activity. In certain embodiments, the anti-TIGIT antibody increases LAK activity by at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 90%, or about 100%. In certain embodiments, the anti-TIGIT antibody that increases LAK cell activity is etigilimab. [00210] In vivo and in vitro assays for determining whether the anti-TIGIT antibody modulates an immune response are known in the art or are being developed. In some embodiments, a functional assay that detects T-cell activation may be used. In some embodiments, a functional assay that detects T-cell proliferation may be used. In some embodiments, a functional assay that detects NK activity may be used. In some embodiments, a functional assay that detects CTL activity may be used. In some embodiments, a functional assay that detects Treg activity may be used. In some embodiments, a functional assay that detects MDSC activity may be used. In some embodiments, a functional assay that detects production of cytokines or lymphokines or cells producing cytokines or lymphokines may be used. In some embodiments, an ELISpot assay is used to measure antigen-specific T-cell frequency. In some embodiments, an ELISpot assay is used to measure cytokine release/production and/or used to measure the number of cytokine producing cells. In some embodiments, cytokine assays are used to identify a Th1-type response. In some embodiments, cytokine assays are used to identify a Th2-type response. In some embodiments, cytokine assays are used to identify a Th17-type response. In some embodiments, FACS analysis is used to measure activation markers on immune cells, including but not limited to, T-cells, B-cells, NK cells, macrophages, and/or myeloid cells. [00211] In certain embodiments, the anti-TIGIT antibodies have a circulating half-life in humans of at least about 2 hours, at least about 5 hours, at least about 10 hours, at least about 24 hours, at least about 3 days, at least about 1 week, or at least about 2 weeks. In certain embodiments, the anti-TIGIT antibody is an IgG (e.g., IgG1, IgG2, or IgG4) antibody that has a circulating half-life in humans of at least about 2 hours, at least about 5 hours, at least about 10 hours, at least about 24 hours, at least about 3 days, at least about 1 week, or at least about 2 weeks. Methods of increasing (or decreasing) the half-life of agents such as polypeptides and antibodies are known in the art. For example, known methods of increasing the circulating half- life of IgG antibodies include the introduction of mutations in the Fc region which increase the pH-dependent binding of the antibody to the neonatal Fc receptor (FcRn) at pH 6.0. Known methods of increasing the circulating half-life of antibody fragments lacking the Fc region include such techniques as PEGylation. [00212] In certain embodiments, the anti-TIGIT antibodies are used in any one of a number of conjugated (i.e. an immunoconjugate or radioconjugate) or non-conjugated forms. In certain embodiments, the antibodies can be used in a non-conjugated form to harness the patient’s natural defense mechanisms including complement-dependent cytotoxicity (CDC) and antibody dependent cellular cytotoxicity (ADCC) to eliminate malignant or cancer cells. [00213] In some embodiments, the anti-TIGIT antibody is conjugated to a cytotoxic agent. In some embodiments, the anti-TIGIT antibody is conjugated to a cytotoxic agent as an ADC (antibody-drug conjugate). In some embodiments, the cytotoxic agent is a chemotherapeutic agent including, but not limited to, methotrexate, adriamycin/doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin, pyrrolobenzodiazepines (PBDs), or other intercalating agents. In some embodiments, the cytotoxic agent is an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof, including, but not limited to, diphtheria A chain, non-binding active fragments of diphtheria toxin, exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), Momordica charantia inhibitor, curcin, crotin, Sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. In some embodiments, the cytotoxic agent is a radioisotope to produce a radioconjugate or a radioconjugated antibody. A variety of radionuclides are available for the production of radioconjugated antibodies including, but not limited to, 90Y, 125I, 131I, 123I, 111In, 131In, 105Rh, 153Sm, 67Cu, 67Ga, 166Ho, 177Lu, 186Re, 188Re and 212Bi. Conjugates of an antibody and one or more small molecule toxins, such as calicheamicins, maytansinoids, trichothenes, and CC1065, and the derivatives of these toxins that have toxin activity, can also be used. Conjugates of an antibody and cytotoxic agent may be made using a variety of bifunctional protein-coupling agents such as N-succinimidyl- 3-(2-pyridyidithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p- azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)- ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). Fragments [00214] In some embodiments, the invention provides a fragment of an anti-TIGIT antibody, wherein the antibody fragment comprises an antigen-binding site. In some embodiments, the antibody fragment comprises an IgG antibody, an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody. Antibody fragments may have different functions or capabilities than intact antibodies; for example, antibody fragments can have increased tumor penetration. Various techniques are known for the production of antibody fragments including, but not limited to, proteolytic digestion of intact antibodies. In some embodiments, antibody fragments include a F(ab')2 fragment produced by pepsin digestion of an antibody molecule. In some embodiments, antibody fragments include a Fab fragment generated by reducing the disulfide bridges of an F(ab')2 fragment. In other embodiments, antibody fragments include a Fab fragment generated by the treatment of the antibody molecule with papain and a reducing agent. In certain embodiments, antibody fragments are produced by recombinant methods. In some embodiments, antibody fragments include Fv or single chain Fv (scFv) fragments. Fab, Fv, and scFv antibody fragments can be expressed in and secreted from E. coli or other host cells, allowing for the production of large amounts of these fragments. In some embodiments, antibody fragments are isolated from antibody phage libraries as discussed herein. For example, methods can be used for the construction of Fab expression libraries to allow rapid and effective identification of monoclonal Fab fragments with the desired specificity for TIGIT or derivatives, fragments, analogs or homologs thereof. In some embodiments, antibody fragments are linear antibody fragments. In certain embodiments, antibody fragments are monospecific or bispecific. In certain embodiments, the anti-TIGIT antibody is a scFv. Various techniques can be used for the production of single-chain antibodies specific to TIGIT. [00215] In some embodiments, especially in the case of antibody fragments, an antibody is modified in order to alter (e.g., increase or decrease) its serum half-life. This can be achieved, for example, by incorporation of a salvage receptor binding epitope into the antibody fragment by mutation of the appropriate region in the antibody fragment or by incorporating the epitope into a peptide tag that is then fused to the antibody fragment at either end or in the middle (e.g., by DNA or peptide synthesis). Bispecific antibodies and heterodimeric agents [00216] In some embodiments, the anti-TIGIT antibody is a bispecific antibody. Thus, this invention encompasses bispecific anti-TIGIT antibody that specifically recognize TIGIT and at least one additional target. Bispecific antibodies are capable of specifically recognizing and binding at least two different antigens or epitopes. The different epitopes can either be within the same molecule (e.g., two epitopes on TIGIT) or on different molecules (e.g., one epitope on TIGIT and one epitope on a different protein). In some embodiments, a bispecific antibody has enhanced potency as compared to an individual antibody or to a combination of more than one antibody. In some embodiments, a bispecific antibody has reduced toxicity as compared to an individual antibody or to a combination of more than one antibody. It is known to those of skill in the art that any therapeutic agent may have unique pharmacokinetics (PK) (e.g., circulating half-life). In some embodiments, a bispecific antibody has the ability to synchronize the PK of two active binding agents wherein the two individual binding agents have different PK profiles. In some embodiments, a bispecific antibody has the ability to concentrate the actions of two agents in a common area (e.g., a tumor and/or tumor microenvironment). In some embodiments, a bispecific antibody has the ability to concentrate the actions of two agents to a common target (e.g., a tumor or a tumor cell). In some embodiments, a bispecific antibody has the ability to target the actions of two agents to more than one biological pathway or function. In some embodiments, a bispecific antibody has the ability to target two different cells and bring them closer together (e.g., an immune cell and a tumor cell). [00217] In some embodiments, the bispecific antibody is a monoclonal antibody. In some embodiments, the bispecific antibody is a humanized antibody. In some embodiments, the bispecific antibody is a human antibody. In some embodiments, the bispecific antibody is an IgG1 antibody. In some embodiments, the bispecific antibody is an IgG2 antibody. In some embodiments, the bispecific antibody is an IgG4 antibody. In some embodiments, the bispecific antibody has decreased toxicity and/or side effects. In some embodiments, the bispecific antibody has decreased toxicity and/or side effects as compared to a mixture of the two individual antibodies or the antibodies as single agents. In some embodiments, the bispecific antibody has an increased therapeutic index. In some embodiments, the bispecific antibody has an increased therapeutic index as compared to a mixture of the two individual antibodies or the antibodies as single agents. [00218] In some embodiments, the bispecific antibodies can specifically recognize and bind TIGIT as well as a second antigen target, such as CD2, CD3, CD28, CTLA4, PD-1, PD- L1, CD80, CD86, CD64, CD32, or CD16, TIM-3, LAG-3, OX-40, 4-1BB, or GITR. In certain embodiments, the bispecific antibodies can specifically recognize and bind TIGIT as well as specifically recognizing and binding to PD-1 or PD-L1. In some embodiments, the antibodies can be used to direct cytotoxic agents to cells which express a particular target antigen. These antibodies possess an antigen-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. [00219] Techniques for making bispecific antibodies are known by those skilled in the art. In some embodiments, the bispecific antibodies comprise heavy chain constant regions with modifications in the amino acids which are part of the interface between the two heavy chains. In some embodiments, the bispecific antibodies can be generated using a “knobs-into-holes” strategy. In some cases, the “knobs” and “holes” terminology is replaced with the terms “protuberances” and “cavities”. In some embodiments, the bispecific antibodies may comprise variant hinge regions incapable of forming disulfide linkages between the heavy chains. In some embodiments, the modifications may comprise changes in amino acids that result in altered electrostatic interactions. In some embodiments, the modifications may comprise changes in amino acids that result in altered hydrophobic/hydrophilic interactions. [00220] Bispecific antibodies can be intact antibodies or antibody fragments comprising antigen-binding sites. Antibodies with more than two valencies are also contemplated. For example, trispecific antibodies can be prepared. Thus, in certain embodiments the antibodies to TIGIT are multispecific. [00221] In some embodiments, the bispecific antibodies bind both TIGIT and the second target with a KD of about 100nM or less. In some embodiments, the anti-TIGIT antibody binds both TIGIT and the second target with a KD of about 50nM or less. In some embodiments, the anti-TIGIT antibody binds both TIGIT and the second target with a K_D of about 20nM or less. In some embodiments, the anti-TIGIT antibody binds both TIGIT and the second target with a KD of about 10nM or less. In some embodiments, the anti-TIGIT antibody binds both TIGIT and the second target with a K_D of about 1nM or less. In some embodiments, the affinity of one of the antigen-binding sites may be weaker than the affinity of the other antigen-binding site. For example, the K_D of one antigen binding site may be about 1nM and the K_D of the second antigen-binding site may be about 10nM. In some embodiments, the difference in affinity between the two antigen-binding sites may be about 2-fold or more, about 3-fold or more, about 5-fold or more, about 8-fold or more, about 10-fold or more, about 15-fold or more, about 20- fold or more, about 30-fold or more, about 50-fold or more, or about 100-fold or more. Modulation of the affinities of the two antigen-binding sites may affect the biological activity of the bispecific antibody. For example, decreasing the affinity of the antigen-binding site for TIGIT or the second target, may have a desirable effect, for example decreased toxicity of the binding agent and/or increased therapeutic index. [00222] In some embodiments, the anti-TIGIT antibody is a heterodimeric agent or heterodimeric molecule. In some embodiments, a heterodimeric molecule comprises a first arm which binds human TIGIT and a second arm which binds a second target. In some embodiments, a heterodimeric molecule comprises a first arm that specifically binds human TIGIT and a second arm, wherein the first arm comprises an anti-TIGIT antibody. In some embodiments, a heterodimeric molecule comprises a first arm that binds human TIGIT and a second arm which comprises an antigen-binding site from an antibody that specifically binds a second target. In some embodiments, a heterodimeric molecule is a bispecific antibody. In some embodiments, a heterodimeric molecule comprises a first arm that binds human TIGIT and a second arm that specifically binds a tumor antigen. In some embodiments, a heterodimeric molecule comprises a first arm that binds human TIGIT and a second arm that specifically binds PD-1, PD-L1, CTLA-4, CD2, CD3, CD28, CD80, CD86, CD64, CD32, CD16, TIM-3, LAG-3, OX-40, 4-1BB, or GITR. In some embodiments, a heterodimeric molecule comprises a first arm that binds TIGIT and a second arm that comprises an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is selected from the group consisting of: granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF), granulocyte colony stimulating factor (G-CSF), interleukin 2 (IL-2), interleukin 3 (IL-3), interleukin 12 (IL-12), interleukin 15 (IL-15), B7-1 (CD80), B7-2 (CD86), 4-1BB ligand, GITRL, OX-40L, anti-CD3 antibody, anti-CTLA-4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-4-1BB antibody, anti-GITR antibody, anti-OX-40 antibody, anti-LAG-3 antibody, and anti-TIM-3 antibody. Anti-PD-1 antibodies [00223] As described above, the invention provides methods of treating various cancers using a combination of an anti-TIGIT antibody and an anti-PD-1 antibody. Non-limiting examples of anti-PD-1 antibodies include pembrolizumab (Keytruda), nivolumab (Opdivo), cemiplimab (Libtayo),dostarlimab (Jemperli), Tislelizumab, Sintilimab, Zimberelimab, Toripalimab, Penpulimab, Balstilimab, Retifanlimab, Cetrelimab, Budigalimab, Pimivalimab, Spartalizumab, Serplulimab, Sasanlimab, Camrelizumab, Prolgolimab, Pucotenlimab, Ezabenlimab and Genolimzumab. Therefore, in some embodiments the anti-PD-1 antibody is selected from the group consisting of pembrolizumab (Keytruda), nivolumab (Opdivo), cemiplimab (Libtayo), dostarlimab (Jemperli), Tislelizumab, Sintilimab, Zimberelimab, Toripalimab, Penpulimab, Balstilimab, Retifanlimab, Cetrelimab, Budigalimab, Pimivalimab, Spartalizumab, Serplulimab, Sasanlimab, Camrelizumab, Prolgolimab, Pucotenlimab, Ezabenlimab and Genolimzumab. [00224] The invention is exemplified with data based on the combination of etigilimab and the anti-PD-1 antibody nivolumab. Without wishing to be bound by theory, the inventors rationalise that the surprising technical effects achieved by this combination would also be seen with other anti-PD-1 antibodies described herein. The surprising technical effects of this combination are thought to be principally attributable to etigilimab and its functionality rather than the anti-PD-1 antibody component of the combination therapy. [00225] In the tumor microenvironment, PD-1 and its ligand PD-L1 perform a role in tumor progression and survival by escaping tumor neutralizing immune surveillance. Anti-PD- 1 and anti-PD-L1 antibodies act by blocking the binding of PD-1 to its ligand PD-L1 which prevents cancer cells from evading the immune system. The inventors hypothesize that the surprising technical effects achieved by nivolumab (anti-PD-1 antibody) in combination with etigilimab would also be seen with other anti-PD-1 and PD-L1 antibodies described herein as all of these antibodies act by blocking PD-1/PD-L1 signalling. [00226] The heavy chain sequence of pembrolizumab is SEQ ID NO:15. The light chain sequence of pembrolizumab is SEQ ID NO:16. The heavy chain sequence of nivolumab is SEQ ID NO:17. The light chain sequence of nivolumab is SEQ ID NO:18. The heavy chain sequence of cemiplimab is SEQ ID NO:19. The light chain sequence of cemiplimab is SEQ ID NO:20. The heavy chain sequence of dostarlimab is SEQ ID NO:21. The light chain sequence of dostarlimab is SEQ ID NO:22. The heavy chain sequence of Tislelizumab is SEQ ID NO:40. The light chain sequence of Tislelizumab is SEQ ID NO:41. The heavy chain sequence of Sintilimab is SEQ ID NO:42. The light chain sequence of Sintilimab is SEQ ID NO:43. The heavy chain sequence of Zimberelimab is SEQ ID NO:44. The light chain sequence of Zimberelimab is SEQ ID NO:45. The heavy chain sequence of Toripalimab is SEQ ID NO:46. The light chain sequence of Toripalimab is SEQ ID NO:47. The heavy chain sequence of Penpulimab is SEQ ID NO:48. The light chain sequence of Penpulimab is SEQ ID NO:49. The heavy chain sequence of Balstilimab is SEQ ID NO:50. The light chain sequence of Balstilimab is SEQ ID NO:51. The heavy chain sequence of Retifanlimab is SEQ ID NO:52. The light chain sequence of Retifanlimab is SEQ ID NO:53. The light chain sequence of Cetrelimab is SEQ ID NO:54. The heavy chain sequence of Cetrelimab is SEQ ID NO:55. The light chain sequence of Budigalimab is SEQ ID NO:56. The light chain sequence of Budigalimab is SEQ ID NO:57. The heavy chain sequence of Pimivalimab is SEQ ID NO:58. The light chain sequence of Pimivalimab is SEQ ID NO:59. The light chain sequence of Spartalizumab is SEQ ID NO:60. The heavy chain sequence of Spartalizumab is SEQ ID NO:61. The light chain sequence of Serplulimab is SEQ ID NO:62. The light chain sequence of Serplulimab is SEQ ID NO:63. The heavy chain sequence of Sasanlimab is SEQ ID NO:63. The light chain sequence of Sasanlimab is SEQ ID NO:65. [00227] In some embodiments, the anti-PD-1 antibody comprises a heavy chain comprising SEQ ID NO:15 and a light chain comprising SEQ ID NO:16. In some embodiments, the anti-PD-1 antibody comprises a heavy chain comprising SEQ ID NO:17 and a light chain comprising SEQ ID NO:18. In some embodiments, the anti-PD-1 antibody comprises a heavy chain comprising SEQ ID NO:19 and a light chain comprising SEQ ID NO:20. In some embodiments, the anti-PD-1 antibody comprises a heavy chain comprising SEQ ID NO:21 and a light chain comprising SEQ ID NO:22. [00228] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and nivolumab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00229] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and pembrolizumab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00230] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and cemiplimab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00231] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and dostarlimab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00232] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and Tislelizumab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00233] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and Sintilimab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00234] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and Zimberelimab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00235] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and Toripalimab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00236] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and Penpulimab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00237] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and Balstilimab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00238] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and Retifanlimab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00239] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and Cetrelimab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00240] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and Budigalimab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00241] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and Pimivalimab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00242] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and spartalizumab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00243] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and Camrelizumab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00244] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and Prolgolimab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00245] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and Pucotenlimab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00246] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and serplulimab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00247] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and sasanlimab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00248] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and ezabenlimab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00249] In some embodiments, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and genolimzumab, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00250] In alternative aspects, the invention provides methods of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-L1 antibody, wherein: the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:3), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NO:5), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6), and wherein the cancer is selected from the group consisting of a soft tissue sarcoma, a testicular germ cell tumor and uveal melanoma. [00251] Non-limiting examples of anti-PD-L1 antibodies include atezolizumab (Tecentriq), avelumab (Bavencio),durvalumab (Imfinzi), Envafolimab, Sugemalimab, Socazolimab, Adebrelimab, Pacmilimab, Lodapolimab and Cosibelimab. Therefore, in some embodiments, the anti-PD-L1 antibody is selected from the group consisting of atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), Envafolimab, Sugemalimab, Socazolimab, Adebrelimab, Pacmilimab, Lodapolimab and Cosibelimab. The heavy chain sequence of atezolizumab is SEQ ID NO:23. The light chain sequence of atezolizumab is SEQ ID NO:24. The heavy chain sequence of avelumab is SEQ ID NO:25. The light chain sequence of avelumab is SEQ ID NO:26. The heavy chain sequence of durvalumab is SEQ ID NO:27. The light chain sequence of durvalumab is SEQ ID NO:28. [00252] In some embodiments, the anti-PD-L1 antibody comprises a heavy chain comprising SEQ ID NO:23 and a light chain comprising SEQ ID NO:24. In some embodiments, the anti-PD-L1 antibody comprises a heavy chain comprising SEQ ID NO:25 and a light chain comprising SEQ ID NO:26. In some embodiments, the anti-PD-L1 antibody comprises a heavy chain comprising SEQ ID NO:27 and a light chain comprising SEQ ID NO:28. In some embodiments, the anti-PD-L1 antibody comprises a heavy chain comprising SEQ ID NO:66 and a light chain comprising SEQ ID NO:67. In some embodiments, the anti-PD-L1 antibody comprises a heavy chain comprising SEQ ID NO:68 and a light chain comprising SEQ ID NO:69. In some embodiments, the anti-PD-L1 antibody comprises a heavy chain comprising SEQ ID NO:70 and a light chain comprising SEQ ID NO:71. In some embodiments, the anti- PD-L1 antibody comprises a heavy chain comprising SEQ ID NO:72 and a light chain comprising SEQ ID NO:73. In some embodiments, the anti-PD-L1 antibody comprises a heavy chain comprising SEQ ID NO:74 and a light chain comprising SEQ ID NO:75. [00253] Any of the aspects/ embodiments described herein in relation to anti-PD-1 antibodies apply equally to the anti-PD-L1 antibodies described above. Pharmaceutical compositions [00254] The anti-TIGIT and anti-PD-1 antibodies can be provided as a pharmaceutical composition. The pharmaceutical composition may be formulated with a pharmaceutically acceptable carrier. [00255] Formulations are prepared for storage and use by combining a purified antibody with a pharmaceutically acceptable vehicle (e.g., a carrier or excipient). Pharmaceutically acceptable carriers include a sterile aqueous solution. Those of skill in the art generally consider pharmaceutically acceptable carriers, excipients, and/or stabilizers to be inactive ingredients of a formulation or pharmaceutical composition. Suitable pharmaceutically acceptable vehicles include, but are not limited to, nontoxic buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens, such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol; low molecular weight polypeptides (e.g., less than about 10 amino acid residues); proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; carbohydrates such as monosaccharides, disaccharides, glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes such as Zn-protein complexes; and non-ionic surfactants such as TWEEN or polyethylene glycol (PEG) [10]. [00256] The pharmaceutical compositions of the present invention can be administered in any number of ways for either local or systemic treatment. Administration can be topical by epidermal or transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders; pulmonary by inhalation or insufflation of powders or aerosols, including by nebulizer, intratracheal, and intranasal; oral; or parenteral including intravenous, intraarterial, intratumoral, subcutaneous, intraperitoneal, intramuscular (e.g., injection or infusion), or intracranial (e.g., intrathecal or intraventricular). In certain embodiments, the pharmaceutical compositions comprising the anti-TIGIT and anti-PD-1 antibodies is administered intravenously. Kits of the invention [00257] The present invention provides kits that comprise the anti-TIGIT antibodies and anti-PD-1 antibodies as described herein and that can be used to perform the methods described herein. In certain embodiments, a kit comprises at least one purified anti-TIGIT antibody in one or more containers. One skilled in the art will readily recognize that the disclosed anti- TIGIT antibodies and anti-PD-1 antibodies can be readily incorporated into one of the established kit formats which are well known in the art. Definitions [00258] The practice of the present invention will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, molecular biology, immunology and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., references [11-18], etc. [00259] The term “comprising” encompasses “including” as well as “consisting”, “consisting of” and/or “consisting essentially of” e.g. a composition “comprising” X may consist exclusively of X or may include something additional e.g. X + Y. It is also understood that wherever embodiments are described herein with the language “consisting essentially of” otherwise analogous embodiments described in terms of “consisting of” are also provided. [00260] The term “about” or “approximately” in relation to a numerical value x is optional and means, for example, x+10%. [00261] The word “substantially” does not exclude “completely” e.g. a composition which is “substantially free” from Y may be completely free from Y. Where necessary, the word “substantially” may be omitted from the definition of the invention. [00262] Unless specifically stated, a process or method comprising numerous steps may comprise additional steps at the beginning or end of the method, or may comprise additional intervening steps. Also, steps may be combined, omitted or performed in an alternative order, if appropriate. [00263] Various embodiments of the invention are described herein. It will be appreciated that the features specified in each embodiment may be combined with other specified features, to provide further embodiments. In particular, embodiments highlighted herein as being suitable, typical or preferred may be combined with each other (except when they are mutually exclusive). [00264] All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety. [00265] Any reference to a method for treatment comprising administering an agent to a patient, also covers that agent for use in said method for treatment, as well as the use of the agent in said method for treatment, and the use of the agent in the manufacture of a medicament. [00266] The terms “agonist” and “agonistic” as used herein refer to or describe an agent that is capable of, directly or indirectly, substantially inducing, activating, promoting, increasing, or enhancing the biological activity of a target and/or a pathway. The term “agonist” is used herein to include any agent that partially or fully induces, activates, promotes, increases, or enhances the activity of a protein. [00267] The terms “antagonist” and “antagonistic” as used herein refer to or describe an agent that is capable of, directly or indirectly, partially or fully blocking, inhibiting, reducing, or neutralizing a biological activity of a target and/or pathway. The term “antagonist” is used herein to include any agent that partially or fully blocks, inhibits, reduces, or neutralizes the activity of a protein. [00268] The terms “modulation” and “modulate” as used herein refer to a change or an alteration in a biological activity. Modulation includes, but is not limited to, stimulating an activity or inhibiting an activity. Modulation may be an increase or a decrease in activity, a change in binding characteristics, or any other change in the biological, functional, or immunological properties associated with the activity of a protein, a pathway, a system, or other biological targets of interest. [00269] The term “antibody” as used herein refers to an immunoglobulin molecule that recognizes and specifically binds a target through at least one antigen-binding site. The target may be a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination of any of the foregoing. As used herein, the term encompasses intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (such as Fab, Fab', F(ab')2, and Fv fragments), single chain Fv (scFv) antibodies, multispecific antibodies, bispecific antibodies, monospecific antibodies, monovalent antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antigen-binding site of an antibody, and any other modified immunoglobulin molecule comprising an antigen-binding site as long as the antibodies exhibit the desired biological activity. An antibody can be any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), based on the identity of their heavy-chain constant domains referred to as alpha, delta, epsilon, gamma, and mu, respectively. The different classes of immunoglobulins have different and well-known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated to other molecules, including but not limited to, toxins and radioisotopes. [00270] The term “antibody fragment” refers to a portion of an intact antibody and generally refers to the antigenic determining variable regions of an intact antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, single chain antibodies, and multispecific antibodies formed from antibody fragments. “Antibody fragment” as used herein comprises an antigen-binding site or epitope- binding site. [00271] The term “variable region” of an antibody refers to the variable region of an antibody light chain or the variable region of an antibody heavy chain, either alone or in combination. Generally, the variable region of a heavy chain or a light chain consists of four framework regions connected by three complementarity determining regions (CDRs), also known as “hypervariable regions”. The CDRs in each chain are held together in close proximity by the framework regions and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site(s) of the antibody. There are at least two techniques for determining CDRs: (1) an approach based on cross-species sequence variability (i.e., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Edition, National Institutes of Health, Bethesda MD.), and (2) an approach based on crystallographic studies of antigen-antibody complexes (Al Lazikani et al., 1997, J. Mol. Biol., 273:927-948). In addition, combinations of these two approaches are sometimes used in the art to determine CDRs. [00272] The term “monoclonal antibody” as used herein refers to a homogenous antibody population involved in the highly specific recognition and binding of a single antigenic determinant or epitope. This is in contrast to polyclonal antibodies that typically include a mixture of different antibodies that recognize different antigenic determinants. The term “monoclonal antibody” encompasses both intact and full-length monoclonal antibodies as well as antibody fragments (e.g., Fab, Fab', F(ab')2, Fv), single chain (scFv) antibodies, fusion proteins comprising an antibody fragment, and any other modified immunoglobulin molecule comprising an antigen-binding site. Furthermore, “monoclonal antibody” refers to such antibodies made by any number of techniques, including but not limited to, hybridoma production, phage selection, recombinant expression, and transgenic animals. [00273] The term “humanized antibody” as used herein refers to antibodies that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human sequences. Typically, humanized antibodies are human immunoglobulins in which amino acid residues of the CDRs are replaced by amino acid residues from the CDRs of a non-human species (e.g., mouse, rat, rabbit, or hamster) that have the desired specificity, affinity, and/or binding capability. In some instances, the framework variable region amino acid residues of a human immunoglobulin may be replaced with the corresponding amino acid residues in an antibody from a non-human species. The humanized antibody can be further modified by the substitution of additional amino acid residues either in the framework variable region and/or within the replaced non-human amino acid residues to further refine and optimize antibody specificity, affinity, and/or binding capability. The humanized antibody may comprise variable domains containing all or substantially all of the CDRs that correspond to the non- human immunoglobulin, whereas all or substantially all of the framework variable regions are those of a human immunoglobulin sequence. In some embodiments, the variable domains comprise the framework regions of a human immunoglobulin sequence. In some embodiments, the variable domains comprise the framework regions of a human immunoglobulin consensus sequence. The humanized antibody can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. [00274] The term “human antibody” as used herein refers to an antibody produced by a human or an antibody having an amino acid sequence corresponding to an antibody produced by a human made using any of the techniques known in the art. [00275] The term “chimeric antibody” as used herein refers to an antibody wherein the amino acid sequence of the immunoglobulin molecule is derived from two or more species. Typically, the variable regions of the light and heavy chains correspond to the variable regions of an antibody derived from one species of mammal (e.g., mouse, rat, rabbit, etc.) with the desired specificity, affinity, and/or binding capability, while the constant regions are homologous to the sequence in an antibody derived from another species. [00276] The terms “epitope” and “antigenic determinant” are used interchangeably herein and refer to that portion of an antigen or target capable of being recognized and specifically bound by a particular antibody. When the antigen or target is a polypeptide, epitopes can be formed both from contiguous amino acids and noncontiguous amino acids juxtaposed by tertiary folding of the protein. Epitopes formed from contiguous amino acids (also referred to as linear epitopes) are typically retained upon protein denaturing, whereas epitopes formed by tertiary folding (also referred to as conformational epitopes) are typically lost upon protein denaturing. An epitope typically includes at least 3, and more usually, at least 5, 6, 7, or 8-10 amino acids in a unique spatial conformation. [00277] The terms “selectively binds” or “specifically binds” mean that an agent interacts more frequently, more rapidly, with greater duration, with greater affinity, or with some combination of the above to the epitope, protein, or target molecule than with alternative substances, including related and unrelated proteins. In certain embodiments “specifically binds” means, for instance, that an agent binds a protein or target with a KD of about 0.1mM or less, but more usually less than about 1µM. In certain embodiments, “specifically binds” means that an agent binds a target with a K_D of at least about 0.1µM or less, at least about 0.01µM or less, or at least about 1nM or less. Because of the sequence identity between homologous proteins in different species, specific binding can include an agent that recognizes a protein or target in more than one species (e.g., mouse TIGIT and human TIGIT). Likewise, because of homology within certain regions of polypeptide sequences of different proteins, specific binding can include an agent that recognizes more than one protein or target. It is understood that, in certain embodiments, an agent that specifically binds a first target may or may not specifically bind a second target. As such, “specific binding” does not necessarily require (although it can include) exclusive binding, i.e. binding to a single target. Thus, an agent may, in certain embodiments, specifically bind more than one target. In certain embodiments, multiple targets may be bound by the same antigen-binding site on the agent. For example, an antibody may, in certain instances, comprise two identical antigen-binding sites, each of which specifically binds the same epitope on two or more proteins. In certain alternative embodiments, an antibody may be bispecific and comprise at least two antigen-binding sites with differing specificities. Generally, but not necessarily, reference to binding means specific binding. [00278] As used herein, “selecting” and “selected” in reference to a patient is used to mean that a particular patient is specifically chosen from a larger group of patients on the basis of (due to) the particular patient having a predetermined criteria, e.g., the patient has a tumor with an elevated expression level of PVR and/or PVRL2. Similarly, “selectively treating a patient having a tumor” refers to providing treatment to a cancer patient that is specifically chosen from a larger group of patients on the basis of (due to) the particular patient having a predetermined criteria, e.g., the patient has a tumor with an elevated expression level of PVR and/or PVRL2. Similarly, “selectively administering” refers to administering a drug to a cancer patient that is specifically chosen from a larger group of patients on the basis of (due to) the particular patient having a predetermined criteria, e.g., the patient the patient has a tumor with an elevated expression level of PVR and/or PVRL2. By selecting, selectively treating and selectively administering, it is meant that a patient is delivered a personalized therapy for cancer based on the patient's cancer biology, rather than being delivered a standard treatment regimen based solely on the patient having a cancer, such as CRC or NSCLC. [00279] The terms “polypeptide” and “peptide” and “protein” are used interchangeably herein and refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids), as well as other modifications known in the art. It is understood that, because the polypeptides of this invention may be based upon antibodies or other members of the immunoglobulin superfamily, in certain embodiments, a “polypeptide” can occur as a single chain or as two or more associated chains. [00280] The terms “polynucleotide” and “nucleic acid” and “nucleic acid molecule” are used interchangeably herein and refer to polymers of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase. [00281] The terms “identical” or percent “identity” in the context of two or more nucleic acids or polypeptides, refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned (introducing gaps, if necessary) for maximum correspondence, not considering any conservative amino acid substitutions as part of the sequence identity. The percent identity may be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software that may be used to obtain alignments of amino acid or nucleotide sequences are well-known in the art. These include, but are not limited to, BLAST, ALIGN, Megalign, BestFit, GCG Wisconsin Package, and variants thereof. In some embodiments, two nucleic acids or polypeptides of the invention are substantially identical, meaning they have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, and in some embodiments at least 95%, 96%, 97%, 98%, 99% nucleotide or amino acid residue identity, when compared and aligned for maximum correspondence, as measured using a sequence comparison algorithm or by visual inspection. In some embodiments, identity exists over a region of the sequences that is at least about 10, at least about 20, at least about 40-60 nucleotides or amino acid residues, at least about 60-80 nucleotides or amino acid residues in length or any integral value there between. In some embodiments, identity exists over a longer region than 60-80 nucleotides or amino acid residues, such as at least about 80-100 nucleotides or amino acid residues, and in some embodiments the sequences are substantially identical over the full length of the sequences being compared, for example, the coding region of a nucleotide sequence. [00282] A “conservative amino acid substitution” is one in which one amino acid residue is replaced with another amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been generally defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). For example, substitution of a phenylalanine for a tyrosine is considered to be a conservative substitution. Generally, conservative substitutions in the sequences of polypeptides and/or antibodies of the invention do not abrogate the binding of the polypeptide or antibody containing the amino acid sequence, to the target binding site. Methods of identifying nucleotide and amino acid conservative substitutions which do not eliminate binding are well- known in the art. [00283] The term “vector” as used herein means a construct, which is capable of delivering, and usually expressing, one or more gene(s) or sequence(s) of interest in a host cell. Examples of vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmid, cosmid, or phage vectors, DNA or RNA expression vectors associated with cationic condensing agents, and DNA or RNA expression vectors encapsulated in liposomes. [00284] A polypeptide, soluble protein, antibody, polynucleotide, vector, cell, or composition which is “isolated” is a polypeptide, soluble protein, antibody, polynucleotide, vector, cell, or composition which is in a form not found in nature. Isolated polypeptides, soluble proteins, antibodies, polynucleotides, vectors, cells, or compositions include those which have been purified to a degree that they are no longer in a form in which they are found in nature. In some embodiments, a polypeptide, soluble protein, antibody, polynucleotide, vector, cell, or composition which is isolated is substantially pure. [00285] The term “substantially pure” as used herein refers to material which is at least 50% pure (i.e., free from contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure. [00286] The term “immune response” as used herein includes responses from both the innate immune system and the adaptive immune system. It includes both cell-mediated and/or humoral immune responses. It includes, but is not limited to, both T-cell and B-cell responses, as well as responses from other cells of the immune system such as natural killer (NK) cells, monocytes, macrophages, etc. [00287] The terms “cancer” and “cancerous” as used herein refer to or describe the physiological condition in mammals in which a population of cells are characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, blastoma, sarcoma, and hematologic cancers such as lymphoma and leukemia. [00288] The terms “tumor” and “neoplasm” as used herein refer to any mass of tissue that results from excessive cell growth or proliferation, either benign (non-cancerous) or malignant (cancerous) including pre-cancerous lesions. [00289] The term “metastasis” as used herein refers to the process by which a cancer spreads or transfers from the site of origin to other regions of the body with the development of a similar cancerous lesion at a new location. Generally, a “metastatic” or “metastasizing” cell is one that loses adhesive contacts with neighboring cells and migrates via the bloodstream or lymph from the primary site of disease to secondary sites throughout the body. [00290] The terms “cancer cell” and “tumor cell” refer to the total population of cells derived from a cancer or tumor or pre-cancerous lesion, including both non-tumorigenic cells, which comprise the bulk of the cancer cell population, and tumorigenic stem cells (cancer stem cells). As used herein, the terms “cancer cell” or “tumor cell” will be modified by the term “non-tumorigenic” when referring solely to those cells lacking the capacity to renew and differentiate to distinguish those tumor cells from cancer stem cells. [00291] The term “subject” refers to any animal (e.g., a mammal), including, but not limited to, humans, non-human primates, canines, felines, rabbits, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms “subject” and “patient” are used interchangeably herein in reference to a human subject. [00292] The term “pharmaceutically acceptable” refers to a substance approved or approvable by a regulatory agency of the Federal government or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans. [00293] The terms “pharmaceutically acceptable excipient, carrier, or adjuvant” or “acceptable pharmaceutical carrier” refer to an excipient, carrier, or adjuvant that can be administered to a patient, together with at least one agent of the present disclosure, and which does not destroy the pharmacological activity thereof and is non-toxic when administered in doses sufficient to deliver a therapeutic effect. In general, those of skill in the art and the U.S. FDA consider a pharmaceutically acceptable excipient, carrier, or adjuvant to be an inactive ingredient of any formulation. [00294] The terms “effective amount” or “therapeutically effective amount” or “therapeutic effect” refer to an amount of an agent, an antibody, a polypeptide, a polynucleotide, a small organic molecule, or other drug effective to “treat” a disease or disorder in a subject such as, a mammal. In the case of cancer or a tumor, the therapeutically effective amount of an antibody has a therapeutic effect and as such can enhance or boost the immune response, enhance or boost the anti-tumor response, increase cytolytic activity of immune cells, increase killing of tumor cells, increase killing of tumor cells by immune cells, reduce the number of tumor cells; decrease tumorigenicity, tumorigenic frequency, or tumorigenic capacity; reduce the number or frequency of cancer stem cells; reduce the tumor size; reduce the cancer cell population; inhibit or stop cancer cell infiltration into peripheral organs including, for example, the spread of cancer into soft tissue and bone; inhibit and stop tumor or cancer cell metastasis; inhibit and stop tumor or cancer cell growth; relieve to some extent one or more of the symptoms associated with the cancer; reduce morbidity and mortality; improve quality of life; or a combination of such effects. [00295] The terms “treating” or “treatment” or “to treat” or “alleviating” or “to alleviate” refers to therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder. In the case of cancer or a tumor, a patient is successfully “treated” according to the methods of the present invention if the patient shows one or more of the following: an increased immune response, an increased anti- tumor response, increased cytolytic activity of immune cells, increased killing of tumor cells, increased killing of tumor cells by immune cells, a reduction in the number of or complete absence of cancer cells; a reduction in the tumor size; inhibition of or an absence of cancer cell infiltration into peripheral organs including the spread of cancer cells into soft tissue and bone; inhibition of or an absence of tumor or cancer cell metastasis; inhibition or an absence of cancer growth; relief of one or more symptoms associated with the specific cancer; reduced morbidity and mortality; improvement in quality of life; reduction in tumorigenicity; reduction in the number or frequency of cancer stem cells; or some combination of effects. [00296] As used in the present disclosure and claims, the singular forms “a”, “an” and “the” include plural forms unless the context clearly dictates otherwise. [00297] The term “and/or” as used in a phrase such as “A and/or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). [00298] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to person skilled in the art and are to be included within the spirit and purview of this application. [00299] All publications, patents, patent applications, internet sites, and accession numbers/database sequences including both polynucleotide and polypeptide sequences cited herein are hereby incorporated by reference herein in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, internet site, or accession number/database sequence were specifically and individually indicated to be so incorporated by reference. MODES FOR CARRYING OUT THE INVENTION Example 1 – Binding properties of etigilimab [00300] Flow cytometry analysis was conducted to assess the ability of the anti-TIGIT antibodies 313M32 (etigilimab), 313M26 and 313R19 to bind to various forms of TIGIT from different species. The species tested were rat, guinea pig, rabbit, marmoset, pig, dog, rhesus monkey and human. The antibody 313M26 is the parental murine anti-hTIGIT antibody of 313M32 and therefore 313M26 and 313M32 share both comprise the heavy chain and light chain CDRs of SEQ ID Nos: 1-6. 313R19 is an anti-TIGIT antibody that does not share the same heavy and light chain CDRs. [00301] This analysis utilized human embryonic kidney 293 cells (HEK-293, American Type Culture Collection, Manassas, VA) that were transiently transfected with cDNA expression vectors encoding a membrane-anchored derivative of TIGIT from the species listed above. These cDNA expression vectors encoded the extracellular domains of TIGIT from different species each fused to the transmembrane domain of human CD4 and an intracellular domain comprised of green fluorescent protein. Cells were then exposed to 313M26, 313M26 or 313R19 and allophycocyanin (APC)- labeled anti-human Fc secondary antibody and then examined by flow cytometry. [00302] The results of these experiments are summarized in the table below: Binding to TIGIT

[00303] FACS analysis was conducted to assess the ability of anti-TIGIT antibodies 313M32, 313M26 and 313R19 to block PVR binding to human TIGIT. [00304] A cell surface human TIGIT protein was generated by ligating amino acids 22- 141 of human TIGIT to the transmembrane domain of CD4 and a C-terminal GFP protein tag using standard recombinant DNA techniques (hTIGIT-CD4TM-GFP). PVR-Fc constructs were generated using standard recombinant DNA techniques. Specifically, the extracellular domain of human PVR was ligated in-frame to a rabbit Fc region and the recombinant hPVR- rbFc protein was expressed in CHO cells. The fusion proteins were purified from cell culture medium using protein A chromatography. [00305] HEK-293T cells were transiently transfected with the hTIGIT-CD4TM-GFP construct. After 16 hours, transfected cells were suspended in ice cold HBSS containing 2% FBS and heparin and incubated on ice with 0.5µg/ml hPVR-rbFc fusion protein in the presence of anti-TIGIT antibodies 313R19, 313M26, or 313M32 for 60 minutes. The antibodies were tested at concentrations of 10, 2, and 0.4ug/ml. Cells were incubated without antibody or without hPVR-rbFc as controls. A second incubation with 100µl PE-conjugated anti-rabbit Fc secondary antibody was performed to detect cells bound by the hPVR-rbFc fusion protein. The cells were analyzed on a FACSCanto instrument (BD Biosciences) and the data was processed using FlowJo software. [00306] The results of these experiments are summarised in Figure 1. In the absence of any anti-TIGIT antibody, hPVR-rbFc bound strongly to hTIGIT expressed on the surface of the HEK-293T cells. At the lower concentrations of 2μg/ml and 0.4μg/ml antibody, the 313R19 antibody did not block binding of hPVR-rbFc to hTIGIT. In contrast, 313M32 strongly blocked binding of hPVR-rbFc to hTIGIT at 2μg/ml and the level of blockade was higher than the parental mouse antibody 313M26. Example 2 – In vivo tumor growth inhibition by etigilimab [00307] A humanized mouse model was used to study the efficacy of treatment with an anti-TIGIT antibody on a human tumor. The humanized mice were obtained from Jackson Laboratories. These mice are created by injecting human hematopoietic stem cells (CD34+ cells) into irradiated NSG mice. After 15 weeks, the presence of mature human lymphocytes is confirmed by flow cytometry. Each mouse was injected subcutaneously with patient-derived melanoma tumor cells (OMP-M9, 75,000 cells/mouse). Tumors were allowed to grow 19 days until they had reached an average volume of approximately 50mm³. Tumor-bearing mice were randomized into groups (n = 8 mice per group). Tumor-bearing mice were treated with either a control antibody, anti-TIGIT antibody 313R19, or anti-TIGIT antibody 313M32. Mice were dosed every 5 days at 1mg/kg or 5mg/kg. Tumor growth was monitored and tumor volumes were measured with electronic calipers at the indicated time points. [00308] Figure 2 demonstrates that etigilimab was able to significantly reduce tumour growth at a concentration of 1mg/kg compared to the control, whereas the anti-TIGIT antibody 313R19 was not able to significantly reduce tumour growth at the same concentration. In addition, these results demonstrated that humanized mouse models bearing patient-derived xenografts can be used to study the anti-hTIGIT antibody OMP-313M32 (which only binds human TIGIT) in parallel with pre-clinical studies carried out with the anti-TIGIT antibodies 313R12 and 313R19 and murine tumor models. Example 3 – In vivo tumor growth inhibition by anti-TIGIT antibody [00309] The murine colon tumor line CT26.WT was implanted subcutaneously (30,000 cells/mouse) in the rear flanks of 6-8 week old Balb/c mice. Tumors were allowed to grow for 10 days until they reached a volume of approximately 50mm³. Mice were treated with 0.25mg/mouse of anti-TIGIT antibody 313R11 (mIgG1 antibody), anti-TIGIT antibody 313R12 (mIgG2a antibody), a mIgG1 control antibody, or a mIgG2a control antibody (n = 10 per group for control antibodies and 20 per group for test antibodies). Mice were dosed by intraperitoneal injection twice a week for three weeks. Tumor growth was monitored and tumor volumes were measured with electronic calipers at Days 10, 15, 18, 22, 25, and 29. [00310] As shown in Figure 3A, anti-TIGIT antibody 313R12 inhibited tumor growth by almost 75% as compared to an isotype-matched control antibody. Tumors in nine mice had regressed to undetectable levels by Day 29. Anti-TIGIT antibody 313R11 inhibited tumor growth by only about 15% as compared to an isotype-matched control antibody. Antibody 313R11 and 313R12 differ only by their IgG isotypes, as 313R12 is an IgG2a antibody and 313R11 is an IgGl antibody. These results suggest that the isotype of the antibody may have a significant effect on the therapeutic efficacy of the anti-TIGIT antibodies. Mouse IgG2 antibodies (equivalent to human IgGl antibodies) are known to have increased ADCC activity as compared to mouse IgGl antibodies (equivalent of human IgG2) and this biological characteristic may play a part in the strong anti-tumor effect of antibody 313R12.

[00311] The experiment was repeated with anti-TIGIT antibody 313R12 and a control mIgG2a antibody. As described above, CT26.WT cells were implanted subcutaneously (30,000 cells/mouse) in the rear flanks of 6-8 week old Balb/c mice. Tumors were allowed to grow for 7 days until they reached a volume of approximately 55mm³. Mice were treated with 0.25mg/mouse of anti-TIGIT antibody 313R12 or a mIgG2a control antibody (n = 10 per group). Mice were dosed by intraperitoneal injection twice a week for 3 weeks. Tumor growth was monitored and tumor volumes were measured with electronic calipers at Days 7, 14, 17, 21, 25, 28, and 31.

[00312] As observed in the previous study, anti-TIGIT antibody 313R12 inhibited growth of the CT26.WT tumors, with inhibition of tumor growth seen in all ten mice (Fig. 3B). Furthermore, tumors in 9 of the 10 mice treated with antibody 313R12 regressed from the original tumor size with 8 tumors regressing to undetectable levels after 2 weeks of treatment. In this study, there were three tumors that regressed in the IgG2 antibody control group, but it is known that tumor regression may occur in untreated, immunocompetent mice, especially if the starting number of tumor cells is low. However, the complete growth inhibition and/or tumor regression in the antibody 313R12-treated group demonstrated that treatment with an anti-TIGIT antibody had a significant therapeutic effect and that this may be attributed to the modulation and/or enhancement of the subject’s immune response.

[00313] Successful immunotherapy against cancer will include generating long-term antitumor immunity. To study whether long-term immunity had been established, mice from studies described herein which had CT26.WT tumors that regressed to undetectable levels after anti-TIGIT antibody treatment were challenged with fresh CT26.WT tumor cells. Eleven mice with complete tumor regression were injected with an increased number of CT26.WT cells (60,000 cells/mouse) on Day 132 (102 days after the last dose of anti-TIGIT antibody 313R12). As a control, 10 naive mice were injected with CT26.WT cells with the same number of CT26.WT cells. Mice were not treated, tumor growth was monitored, and tumor volumes were measured with electronic calipers. [00314] In the control group all 10 mice developed large tumors by Day 23 and were euthanized. In contrast, no tumors grew in 10 of the mice that had previously rejected the CT26.WT tumors. The remaining mouse developed a small tumor growth 14 days after injection, but the tumor had completely regressed at day 21. These 11 mice were then rechallenged for a second time with 150,000 CT26.WT cells (5 times the number of cells of initial dose). Again as a control, 10 naive mice were injected with CT26.WT cells with the same number of CT26.WT cells (150,000 cells/mouse). As in the earlier experiment, all 10 mice in the control group developed large tumors and were euthanized at Day 22. No tumors grew in 6 of the mice and 2 additional mice developed small tumors that completely regressed by Day 22. The other 3 mice had small tumors that appeared to be regressing or stabilized. These results are summarized in the table below and presented as the percentage of tumor-free mice in each group.

[00315] These results indicate that treatment with various anti-TIGIT antibodies can generate a strong and effective anti-tumor response. Importantly, the anti-tumor response appeared to result in long-term immunity and protection against the tumor cells.

Example 4 - In vivo tumor growth inhibition by anti-TIGIT antibody and anti-PD-Ll antibody

[00316] The murine colon tumor line CT26.WT was implanted subcutaneously (30,000 cells/mouse) in Balb/c mice and on the first day of treatment (Day 10 post-implantation) the tumors were an average size of approximately 105mm³. Mice were treated with 0.25mg/mouse of anti-TIGIT antibody 313R12, an anti-PD-Ll antibody, a combination of 313R12 and anti- PD-Ll antibody, or a control antibody (n = 10-20 per group). Mice were administered antibodies twice a week for 3 weeks. Tumor growth was monitored and tumor volumes were measured with electronic calipers. [00317] As is shown in Figure 4B, treatment with anti-TIGIT antibody 313R12 strongly inhibited growth of the CT26.WT tumors in a high percentage of the mice. It should be noted that treatment with anti-TIGIT antibody 313R12 is not only able to inhibit growth of tumors in the majority of mice, but is able to induce regression of individual tumors, often to undetectable levels. Treatment with the anti-PD-Ll antibody was much less successful at inhibiting tumor growth as a single agent (Fig. 4C). Treatment with the combination of anti-TIGIT antibody 313R12 and an anti-PD-Ll antibody inhibited tumor growth to a greater extent than either agent alone (Fig. 4D). Average tumor volume is shown in Figure 4E and percent survival of the mice from each group is shown in Figure 4F.

[00318] One method of evaluating the presence and/or functionally of an anti-tumor memory cell population is to re -challenge previously treated mice with fresh tumor cells. Mice (from the studies described above) previously treated with anti-TIGIT antibody 313R12, anti- mPD-Ll antibody, or a combination of 313R12 and anti-mPD-Ll antibody were used for a rechallenge study. Mice whose tumors had regressed completely and were undetectable at least 128 days after the first tumor injection were re-challenged with CT26.WT tumor cells (30,000 cells). The mice subjected to tumor re-challenge had received a last treatment dose 100 days prior to re-challenge. Naive Balb/c mice (n = 10) were injected with CT26.WT tumor cells (30,000 cells) as a control group. Tumor growth was monitored and tumor volumes were measured with electronic calipers at the indicated time points. Data are expressed as mean ± S.E.M.

[00319] The average tumor volume of CT26.WT tumors in naive mice grew steadily up to Day 28 with an average tumor volume of approximately 1750mm³. From the previous experiment there were only two mice with completely regressed tumors that had been previously treated with the anti-PD-Ll antibody, but these two mice demonstrated complete immunity to the tumor re-challenge. There were 4 mice with completely regressed tumors that had been previously treated with anti-TIGIT antibody and tumors grew in none of these mice after re-challenge and demonstrated complete immunity to the tumor re-challenge. In addition, there were 7 mice with completely regressed tumors that had been previously treated with the combination of 313R12 and an anti-PD-Ll antibody and these mice demonstrated complete immunity to the tumor challenge.

[00320] The mice treated with anti-TIGIT antibody, either as a single agent or in combination with an anti-PD-Ll antibody, appeared to be strongly protected from re-challenge with the CT26.WT tumor cells. These results suggest the existence of immunogenic memory after treatment with an anti-TIGIT antibody, either as a single agent or in combination with a checkpoint inhibitor. Example 5 - A phase lb/2 clinical trial evaluating the efficacy of anti-TIGIT antibodies in combination with anti-PD-1 antibodies

[00321] A phase lb/2 open-label basket study of the anti-TIGIT antibody etigilimab in combination with an anti-PD-1 antibody (nivolumab) was conducted in patients with locally advanced or metastatic solid tumors. Patient populations selected for evaluation in this study all had advanced or refractory disease. These patients therefore had a high unmet therapeutic need for which limited therapeutic options exist.

[00322] The types of cancer included in the clinical trial were endometrial cancer, head and neck cancer, cervical cancer, ovarian cancer, rare tumours, including soft tissue sarcomas, testicular germ cell tumours and uveal melanomas, high tumor mutational burden (TMB-H) and microsatellite stable (MSS) cancers. Twenty two patients were included in the trial which were broken down into the following cohorts:

• Cohort B - head and neck (N=l)

• Cohort C - Cervical cancer (N=l)

• Cohort E - TMB-H/MSS cancer (N=4)

• Cohort F - rare tumours (N=12 - N=6 uveal melanoma, N=5 soft tissue sarcomas, N=1 testicular germ cell tumours)

• Cohort G - Ovarian cancer (N=4)

[00323] The demographics of the patients tested are summarised in the table below. As shown in the data below, a number of the patients in the clinical trial had been heavily pretreated (greater than 3 previous therapies prior to treatment with the anti-TIGIT antibody and the anti-PD-1 antibody).

[00324] The patients were naive to checkpoint inhibitor therapy. The patients were intravenously administered etigilimab every two weeks at a dose of 1000 mg and intravenously administered nivolumab every two weeks at a dose of 240 mg.

[00325] 18 adverse events occurred in 10 of the patients and are summarised in the table below. The most common treatment-related adverse events were due to skin reactions, but none of them required treatment with systemic steroids. As shown in the table below, the adverse events were mostly low grade (Grades 1-2). These data demonstrate that the combination of the anti-TIGIT antibody with the anti-PD-1 antibody is well tolerated in human patients.

[00326] The preliminary efficacy of the combination of the anti-TIGIT antibody with the anti-PD-1 antibody was assessed in 23 patients who had the following cancers after a minimum of one scan. The results are shown in the table below:

• Cohort C - Cervical cancer (N=3)

• Cohort E - TMB-H/MSS cancer (N=4)

• Cohort F - rare tumours (N=6 uveal melanomas, N=1 soft tissue sarcomas, N=3 testicular germ cell tumours)

• Cohort H - Ovarian cancer (N=6)

[00327] The objective response rate (which is a combination of complete response rates and partial response rates) was 13.0%. The disease control rate (which is a combination of complete response rates, partial response rates and stable diseases) was 34.7%.

[00328] Historical overall response rates for treating ovarian cancer ([19] and [20]), cervical cancer ([21]) and uveal cancer ([22] and [23] are provided in Figure 5. An overall response rate of greater than 10% is therefore a promising result when compared to these historical data. These preliminary efficacy data support the use of the combination of the anti- TIGIT antibody and an anti-PD-1 antibody to treat various cancers including cervical cancer, TMB-H/MSS cancers, ovarian cancers and rare cancers, such as uveal melanomas.

[00329] A summary of the cancers that resulted in a clinical benefit after treatment with the combination of the anti-TIGIT antibody with the anti-PD-1 antibody is provided below:

[00330] A complete response was observed in the cervical cancer patient after two scans following treatment with the combination of the anti-TIGIT antibody and the anti-PD-1 antibody. The lesions that the patient had at the beginning of the trial and their response to treatment with the combination of the anti-TIGIT antibody and the anti-PD- 1 antibody after the first and the second scan are summarised in the Table below. Figures 6a and 6b show the reduction in tumour size in a cervical cancer patient that occurred after treatment. These figures show that a complete response occurred as the tumour was no longer visible after the second scan.

[00331] Figures 21a and 21b show the reduction in tumour size in a cervical cancer patient that occurred after treatment. These figures show that a partial response occurred as the tumour was no longer visible after the second scan.

[00332] A partial response was observed in one of the ovarian cancer patients after one scan following treatment with the combination of the anti-TIGIT antibody and the anti-PD-1 antibody. The lesions that the patient had at the beginning of the trial and their response to treatment with the combination of the anti-TIGIT antibody and the anti-PD-1 antibody are summarised in the Table below.

[00333] These data support the ability of the combination of the anti-TIGIT antibody and the anti-PD-1 antibody to treat various cancers, including cervical cancer, TMB-H/MSS cancers, ovarian cancers and rare cancers, such as uveal melanomas, as the combination was able to reduce tumour volume and prevent cancer progression. Example 6 - Immunohistochemistry assays to determine the expression of PD-L1, PVR and

TIGIT

[00334] Immunohistochemistry (IHC) assays were conducted as set out below to determine the expression of PD-L1, PVR and TIGIT in biopsy samples from human cancer patients.

PD-L1 IHC assay

[00335] PD-L1 expression was analysed using PD-L1 IHC 22C3 pharmDx assay system (Agilent) which used monoclonal mouse anti-PD-Ll, Clone 22C3, to detect PD-L1 protein in formalin-fixed, paraffin-embedded (FFPE) tissue samples. PD-L1 protein expression was determined by using Combined Positive Score (CPS), which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. A CPS of greater than 1% (>1%) indicated that the cancer was positive for PD-L1, while a CPS of less than 1% indicated that the cancer was PD-L1 negative.

PVR and TIGIT IHC assays

[00336] PVR and TIGIT expression were analysed using IHC assays as set out below. The anti-TIGIT antibody employed was clone E5Y1W (Cell Signaling Technology, catalogue number 99567S). The anti-PVR antibody used was clone EPR17302 (Abeam, catalogue number ab205304).

[00337] Step 1 : Slide preparation - FFPE tissue blocks were cut at 4-5 pm thickness and sections were mounted onto positively charged glass slides. The slides were then baked (60°C, dry heat) for at least 1 hour.

[00338] Step 2; Dewaxing and antigen/epitope retrieval (antigen unmasking) was performed using the PT Link with a Heat Induced Epitope Recovery (HIER) solution. Slides were loaded in racks and placed in pre-heated (65°C) lx High pH Target Retrieval Solution in the PT Link. The PT Link was heated to 97°C for 20 minutes and automatically cooled to 65°C. After cooling, the racks were rinsed with lx FLEX wash buffer.

[00339] Step 3 : Automated Immunohistochemistry - All procedures were automated at room temperature using the Dako Autostainer Link 48 platform. EnVision FLEX+ Kit from Dako was used for IHC detection and stored ready to use at 2-8°C. The EnVision FLEX+ Kit included FLEX HP (hydrogen peroxide) block (endogenous enzyme block), FLEX HRP, and DAB substrate buffer/chromogen. Primary antibody was diluted with Dako Antibody Diluent. DAB was used at a concentration of 1 drop of chromogen per 1 mL of substrate buffer. The protocol was run as follows with intervening rinses in FLEX wash buffer:

[00340] Step 4: Dehydration/Coverslipping - Slides were immersed in room temperature deionized water and transferred to the coverslip area. Slides were rinsed in distilled water and dehydrated with washes in an alcohol series (95%, 100% ethanol) and organic solvent (xylene, 100%, four changes). After dehydration, slides were coverslipped using non-aqueous semipermanent mounting media.

[00341] A cancer was determined to be positive for TIGIT if it had a CPS of greater than 1%. The PVR expression was scored based on the percentage of cells across the slide that were positive for PVR and the intensity of stain (PVR% at 1+, PVR% at 2+, PVR% at 3+). A cancer was determined to be positive for PVR if it had tumour cells with a staining intensity of 1+. A cancer was determined to have high PVR expression if 50% of the cells had %PVR at 2+.

Example 7 - The effect of PVR expression levels on clinical outcome

[00342] The level of PVR expression on clinical outcome was investigated. PVR expression was established as set out in Example 4. PVR expression was considered to be high if 50% or more of the cells had a staining intensity of 2+. PVR was considered to be low if less than 50% or more of the cells had a staining intensity of 2+.

[00343] 16 of the patients in the clinical trial described in Example 3 had evaluable tissue for biomarker analysis. A breakdown of these patients is provided below:

• Cohort B - head and neck (N=l)

• Cohort C - Cervical cancer (N=l)

• Cohort E - TMB-H/MSS cancer (N=l)

• Cohort F - rare tumours (N=4 uveal melanomas, N=4 soft tissue sarcomas, N=1 testicular germ cell tumours)

• Cohort G - Ovarian cancer (N=4) [00344] The level of PVR expression and the clinical outcome for these cancers is provided in the Table below. Cancers with high PVR expression included 4 ovarian cancers, 1 sarcoma, 2 uveal melanomas, 1 colon cancer and 1 cervical cancer. Cancers with low PVR expression included 1 mediastinal germ cell tumour, 3 sarcomas, 2 uveal melanomas and 1 head and neck squamous cell carcinomas (HNSCC).

[00345] These data indicate that human patients with cancers that have high PVR expression respond particularly well to combination treatment with an anti-TIGIT antibody and an anti-PD-1 antibody.

Example 8 - Immunohistochemistry assays to establish key biomarkers that are associated with beneficial outcomes in patients

[00346] IHC assays as set out in Example 4 were performed on the patients in the clinical trial described in Example 3 to determine whether the cancers were positive or negative for PD-L1, PVR and TIGIT.

[00347] 20 of the patients in the clinical trial described in Example 3 had evaluable tissue for PD-L1, PVR and TIGIT analysis. A breakdown of these patients is provided below:

• Cohort B - head and neck (N=l)

• Cohort C - Cervical cancer (N=l)

• Cohort E - TMB-H/MSS cancer (N=3)

• Cohort F - rare tumours (N=5 uveal melanomas, N=5 soft tissue sarcomas, N=1 testicular germ cell tumours)

• Cohort G - Ovarian cancer (N=4)

[00348] The PVR and TIGIT expression of these cancer is provided in Figure 7 and the PD-L1 expression is provided in Figure 8.

[00349] A summary of the cancers that showed clinical benefit along with their biomarker expression profiles for PD-L1, PVR and TIGIT is provided below:

[00350] These data suggest that human patients with cervical cancer that are PVR positive (+), PD-L1 positive (+) and TIGIT positive (+) have an improved clinical benefit when treated with the combination of an anti-TIGIT antibody and an anti-PD-1 antibody. Accordingly, cancer patients with cervical cancer that is PVR positive (+), PD-L1 positive (+) and TIGIT positive (+) represent a sub-group of patients who should respond particularly well to combination treatment with an anti-TIGIT antibody and an anti-PD-1 antibody.

[00351] These data suggest that human patients with ovarian cancer that are PVR positive (+), PD-L1 negative (-) and TIGIT positive (+) have an improved clinical benefit when treated with the combination of an anti-TIGIT antibody and an anti-PD-1 antibody. Accordingly, cancer patients with ovarian cancer that are PVR positive (+), PD-L1 negative (-) and TIGIT positive (+) represent a sub-group of patients who should respond particularly well to combination treatment with an anti-TIGIT antibody and an anti-PD-1 antibody.

[00352] These data suggest that human patients with uveal melanoma that are PVR positive (+), PD-L1 negative (-) and TIGIT PD-L1 negative (-) have an improved clinical benefit when treated with the combination of an anti-TIGIT antibody and an anti-PD-1 antibody. Accordingly, cancer patients with uveal melanoma that are PVR positive (+), PD-L1 negative (-) and TIGIT PD-L1 negative (-) represent a sub-group of patients who should respond particularly well to combination treatment with an anti-TIGIT antibody and an anti- PD-1 antibody. Example 9 - Pharmacodynamic biomarkers

[00353] Pharmacodynamic biomarkers in the blood were analysed following etigilimab treatment in combination with nivolumab. Figure 16 demonstrates that the combination treatment decreased the number of Treg cells in circulation but had no effect on the number of CD8+ T cells. Figures 17A and 17B show that the combination treatment increased markers of cell proliferation in T cells. Figure 18 demonstrates that the combination treatment increased IFNy production in CD4+ effector memory cells. Figure 19 shows that the combination treatment increased the level of proliferating (Ki-67+) CD8+ PD-1+ cells. Figure 20 shows that the combination treatment increased markers of cell proliferation in natural killer cells. Figure 21 shows that the combination treatment reduced the number of exhausted T-cells.

[00354] The data presented in Figures 16-21 concur with the effects of etigilimab treatment observed in the Phase la/b clinical trial. These data confirm that the combination of etigilimab and nivolumab is robustly engaging with biological targets and activating downstream effects in human patients.

Example 10 - Updated clinical data from the phase lb/2 clinical trial evaluating the safety and efficacy of anti-TIGIT antibodies in combination with anti-PD-1 antibodies in the treatment of cancer

[00355] A phase lb/2 open-label basket study was conducted as described in Example 5. 50 patients were included in the trial and their baseline characteristics are summarised in the table below.

[00356] The patients were naive to checkpoint inhibitor therapy. The patients were intravenously administered etigilimab every two weeks at a dose of 1000 mg and intravenously administered nivolumab every two weeks at a dose of 240 mg.

[00357] The preliminary efficacy of the combination of etigilimab with an anti-PD-1 antibody (nivolumab) was assessed in 38 patients who had the following cancers after a minimum of one scan.

• Cohort A - Endometrial cancer CPI- naive (N=l)

• Cohort C - Cervical cancer (N=5)

• Cohort E - TMB-H/MSS tumor (N=6)

• Cohort F - rare tumours (N=6 uveal melanomas, N=7 soft tissue sarcomas, N=4 testicular germ cell tumours)

• Cohort H - Ovarian cancer (N=9)

[00358] The preliminary efficacy data are shown in the Figures 24-26. The objective response rate (which is a combination of complete response rates and partial response rates) was 15.8%. The disease control rate (which is a combination of complete response rates, partial response rates and stable diseases) was 47.4%. The median duration of stable disease was 3.7 months (0.0- 7.7 months). The median progression-free survival was 3.0 months (1.7-4.6 months).

[00359] These data support the ability of the combination of the anti-TIGIT antibody and the anti-PD-1 antibody to treat various cancers, including cervical cancer, TMB-H/MSS cancers, ovarian cancers and rare cancers, such as uveal melanomas or sarcomas, as the combination was able to reduce tumour volume and prevent cancer progression.

Example 11 - Multiplex immunofluorescence assay to determine the expression of CD226 and CD8

[00360] CD226/CD8 measurement by multiplex immunofluorescence technology is based on detection of conjugated antibodies by fluorophore-tagged probes. Antibodies specific for each marker/target are conjugated to short oligonucleotides, referred to as barcodes. For each barcode, a complementary oligonucleotide probe tagged with a fluorescent dye is used to label the antibody conjugates. Different fluorophores are used with each antibody/marker allowing spectral separation of the targets during imaging. An exemplary assay workflow is shown in Figure 30.

[00361] The antibody clone used for detection of CD226 was BLR063G with fluorophore Cy7. The antibody clone used for detection of CD8 was C8/144B with fluorophore FITC. Image acquisition was performed on tissues, once stained, using a ZEISS AxioScan.Zl (ZEISS, Thornwood, NY) automated slide scanner equipped with custom spectral filters. Stained images were analyzed by HALO® software (Indica Labs, Corrales, NM), with High-Plex FL module (V2.0).

[00362] A TIGIT-IO panel specific multiplex analysis algorithm, customized to perform cell segmentation and thresholds for each marker was used. Each individual Image was annotated to include only viable tissue and expression of each marker in combination with tumor marker in the panel (CK/SoxlO) was determined as follows: for each marker, average staining intensity across the tumor tissue was determined and used to set an appropriate intensity ‘threshold’ which eliminates non-specific signals and ensures only signals above the threshold are considered positive. The process was repeated to determine single positivity for each marker in the panel including CD226 and CD8. An additional analysis step was then performed to determine the number of cells that were positive for both fluorochromes corresponding to CD8 and CD226 and the percent of cells that were dual positive for both CD226 and CD8 were determined. The results are shown in Figure 28.

[00363] Based on the available data, >2% positivity for CD226+/CD8+ co-expression identified subjects in cervical and uveal melanoma that were objective responders with durable responses (as defined by on study > 100 days). Uveal Subject F030 (PR) was 41% positive; Cervical C081 (CR) was 10% positive, and cervical C040 was 2.3 % positive.

[00364] These data suggest that human patients with cancer, such as cervical cancer, ovarian cancer or uveal melanoma, that are CD226 positive (+) and CD8 positive (+)have an improved clinical benefit when treated with the combination of an anti-TIGIT antibody and an anti-PD-1 antibody. Accordingly, cancer patients, such as those having cervical cancer, ovarian cancer or uveal melanoma, that have cancer that are CD226 positive (+) and CD8 positive (+) represent a sub-group of patients who should respond particularly well to combination treatment with an anti-TIGIT antibody and an anti-PD-1 antibody. Example 12 - RNA-Seq to determine expression of immune related gene signatures

[00365] Total RNA was extracted from unstained baseline Formalin-Fixed Paraffin- Embedded (FFPE) tumor samples from patients in the Phase lb/2 study. Reverse transcription and second-strand cDNA synthesis were preformed to produce libraries for Whole- transcriptome RNA sequencing (2 x 100 bp paired-end reads). RNA-seq reads were mapped to the human reference genome GRCh38.pl3 using STAR [²⁴]. Gene expression was quantified using RSEM [²⁵]. Raw counts from RSEM were then normalized using and DESeq2 [²⁶]. DESeq2 was then used to apply a variance stabilizing transformation to the count data, yielding a matrix of values which are approximately homoskedastic (having constant variance along the range of mean values) in log2 space. We then renormalized the variance stabilized data by subtracting the arithmetic mean of a set of 20 reference (“housekeeping”) genes (ABCF1, DNAJC14, ERCC3, G6PD, GUSB, MRPL19, NRDE2, OAZ1, POLR2A, PSMC4, PUM1, SDHA, SF3A1, STK11IP, TBC1D10B, TBP, TFRC, TLK2, TMUB2, and UBB) with low variance across a set of banked tumor samples from a variety of cancer types [²⁷]. For the final gene signature score, we used the arithmetic mean (scaled such that it is in the range between zero and one) of the variance stabilized, housekeeping gene-normalized expression for each gene list - see Figure 29. Based on the available data a score threshold of 0.42 for IFNy, 0.57 for myeloid activation, 0.52 for TLS, and 0.74 for Tcell exhaustion shows a true positive rate of 57%-61%. Cutoff points for classification of responders and non-responders were decided by the Youden index [²⁸] of each gene signature

[00366] These data suggest that human patients with cancer, such as cervical cancer, ovarian cancer or uveal melanoma, that have increased expression of IFNy-related markers, T cell exhaustion markers, Myeloid activation markers and/ or Tertiary lymphoid structure markers have an improved clinical benefit when treated with the combination of an anti-TIGIT antibody and an anti-PD-1 antibody. Accordingly, cancer patients, such as those having cervical cancer, ovarian cancer or uveal melanoma, that have cancer having an increased expression of IFNy-related markers, T cell exhaustion markers, Myeloid activation markers and/ or Tertiary lymphoid structure markers represent a sub-group of patients who should respond particularly well to combination treatment with an anti-TIGIT antibody and an anti- PD-1 antibody.

[00368]

REFERENCES

[1] J.Clin.Invest 2017, 127(8):2930-2940

[2] Nature 2015, 523(7562):612-616

[3] Cancers 2020, 12(6): 1431

[4] J. ImmunoTherapy of Cancer 9, Suppl 2: A845

[5] Rotte et al. (2021) Biomedicines, 9, 1277

[6] WO/2016/191643

[7] WO 2016/106302

[8] WO 2016/028656

[9] US 2013/0251720

[10] Remington: The Science and Practice of Pharmacy, 22st Edition, 2012, Pharmaceutical Press, London

[11] Gennaro (2000) Remington: The Science and Practice of Pharmacy. 20th edition, ISBN: 0683306472.

[12] Molecular Biology Techniques: An Intensive Laboratory Course, (Ream et al., eds., 1998, Academic Press).

[13] Methods In Enzymology (S. Colowick and N. Kaplan, eds., Academic Press, Inc.)

[14] Handbook of Experimental Immunology, Vols. LIV (D.M. Weir and C.C. Blackwell, eds, 1986, Blackwell Scientific Publications)

[15] Sambrook et al. (2001) Molecular Cloning: A Laboratory Manual, 3rd edition (Cold Spring Harbor Laboratory Press).

[16] Handbook of Surface and Colloidal Chemistry (Birdi, K.S. ed., CRC Press, 1997)

[17] Ausubel et al. (eds) (2002) Short protocols in molecular biology, 5th edition (Current Protocols).

[18] PCR (Introduction to Biotechniques Series), 2nd ed. (Newton & Graham eds., 1997, Springer Verlag)

[19] Hamanishi et al. (2021) Journal of Clinical Oncology, 39, 33, 3671-3681

[20] Matulonis et al. (2019) annals of Oncology 30: 1080-1087

[21] Chung, et al. (2019) Journal of Clinical Oncology 37:17, 1470-1478

[22] Pelster et al. (2020) Journal of Clinical Oncology; 39(6):599-607 [23] JM Piulats et al. (2021) Journal of Clinical Oncology; 39(6):586-598

[24] Alexander, Dobin et al. STAR: Ultrafast universal RNA-seq aligner. Bioinformatics 29,15-21 (2013).

[25] Li, B. & Dewey, C. N. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. In: Bioinform. 12, 323 (2011).

[26] Anders, S., Huber, W. Differential expression analysis for sequence count data. Genome Biol 11, R106 (2010).

[27] Cui, Chuanliang, Canqiang Xu, Wenxian Yang, Zhihong Chi, Xinan Sheng, Lu Si, Yihong Xie, et al. “Ratio of the Interferon-y Signature to the Immunosuppression Signature Predicts Anti-PD-1 Therapy Response in Melanoma.” Npj Genomic Medicine 6, no. 1 (December 2021): 7.

[28] Youden, W. J. Index for rating diagnostic tests. Cancer 3,32-35 (1950).

Ill

Claims

1. A method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the method comprises:

(a) obtaining a tissue sample of the cancer from the patient;

(b) determining that the cancer is PVR positive (+) and PD-L1 negative (-) or PD-L1 positive (+); and optionally

(c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+) and PD-L1 negative (-) or PD-L1 positive (+) cancer in the patient.

2. A method of treating cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is PVR positive (+) and PD-L1 negative (-) or PD-L1 positive (+).

3. The method according to claim 1, wherein the method further comprises:

- in step (b) determining that the cancer is TIGIT positive (+) and optionally

- in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+) and TIGIT positive (+) cancer in the patient.

4. The method according to claim 1 or claim 3, wherein the method further comprises:

- in step (b) determining that the cancer is CD226 positive and optionally

- in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) cancer in the patient.

5. The method according to claim 1 or claim 3, wherein the method further comprises:

- in step (b) determining that the cancer is CD226 positive (+) and CD8 positive (+) and optionally

- in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) and CD8 positive (+) cancer in the patient.

6. The method according to claim 2, further wherein the cancer is TIGIT positive (+).

7. The method according to claim 2 or claim 6, further wherein the cancer is CD226 positive (+) and optionally CD8 positive (+).

8. A method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is cervical cancer, wherein the method comprises:

(a) obtaining a tissue sample of the cervical cancer from the patient;

(b) determining that the cervical cancer is PVR positive (+) and PD-L1 positive (+); and optionally

(c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+) and PD-L1 positive (+) cervical cancer in the patient.

9. A method of treating cervical cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti- PD-1 antibody, wherein the cervical cancer is PVR positive (+) and PD-L1 positive (+).

10. The method according to claim 9, wherein the method further comprises:

- in step (b) determining that the cervical cancer is TIGIT positive (+) and optionally

- in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 positive (+) and TIGIT positive (+) cervical cancer in the patient.

11. The method according to claim 8 or claim 10, wherein the method further comprises:

- in step (b) determining that the cervical cancer is CD226 positive and optionally

- in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) cervical cancer in the patient.

12. The method according to claim 8 or claim 10, wherein the method further comprises:

- in step (b) determining that the cervical cancer is CD226 positive (+) and CD8 positive (+) and optionally

- in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) and CD8 positive (+) cervical cancer in the patient.

13. The method according to claim 9, further wherein the cervical cancer is TIGIT positive (+).

14. The method according to claim 9 or claim 13, further wherein the cervical cancer is CD226 positive (+) and optionally CD8 positive (+).

15. A method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is ovarian cancer, wherein the method comprises:

(a) obtaining a tissue sample of the ovarian cancer from the patient;

(b) determining that the ovarian cancer is PVR positive (+) and PD-L1 negative (-); and optionally

(c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+) and PD-L1 negative (-) ovarian cancer in the patient.

16. A method of treating ovarian cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti- PD-1 antibody, wherein the ovarian cancer is PVR positive (+) and PD-L1 negative (-).

17. The method according to claim 15, wherein the method further comprises:

- in step (b) determining that the ovarian cancer is TIGIT positive (+) and optionally

- in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) and TIGIT positive (+) ovarian cancer in the patient.

18. The method according to claim 15 or claim 17, wherein the method further comprises:

- in step (b) determining that the ovarian cancer is CD226 positive and optionally

- in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) ovarian cancer in the patient.

19. The method according to claim 15 or claim 17, wherein the method further comprises:

- in step (b) determining that the ovarian cancer is CD226 positive (+) and CD8 positive (+) and optionally

- in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) and CD8 positive (+) ovarian cancer in the patient.

20. The method according to claim 16, further wherein the ovarian cancer is TIGIT positive (+).

21. The method according to claim 16 or claim 20, further wherein the ovarian cancer is CD226 positive (+) and optionally CD8 positive (+).

22. A method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is uveal melanoma, wherein the method comprises:

(a) obtaining a tissue sample of the uveal melanoma from the patient;

(b) determining that the uveal melanoma is PVR positive (+) and PD-L1 negative (-); and optionally

(c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+) and PD-L1 negative (-) uveal melanoma in the patient.

23. A method of treating uveal melanoma in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti- PD-1 antibody, wherein the uveal melanoma is PVR positive (+) and PD-L1 negative (-).

24. The method according to claim 22, wherein the method further comprises:

- in step (b) determining that the uveal melanoma is TIGIT negative (-) and optionally

- in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) and TIGIT negative (-) uveal melanoma in the patient.

25. The method according to claim 22 or claim 24, wherein the method further comprises:

- in step (b) determining that the uveal melanoma is CD226 positive and optionally

- in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) uveal melanoma in the patient.

26. The method according to claim 22 or claim 24, wherein the method further comprises:

- in step (b) determining that the uveal melanoma is CD226 positive (+) and CD8 positive (+) and optionally

- in step (c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the PVR positive (+), PD-L1 negative (-) or PD-L1 positive (+), TIGIT positive (+) and/or CD226 positive (+) and CD8 positive (+) uveal melanoma in the patient.

27. The method according to claim 23, further wherein the uveal melanoma is TIGIT negative (-).

28. The method according to claim 23 or claim 27, further wherein the uveal melanoma is CD226 positive (+) and optionally CD8 positive (+).

29. A method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the method comprises:

(a) obtaining a tissue sample of the cancer from the patient;

(b) determining that the cancer is CD226 positive (+) and optionally CD8 positive (+); and optionally

(c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the CD226 positive (+) and optionally CD8 positive (+) cancer in the patient.

30. A method of treating cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer is CD226 positive (+) and optionally CD8 positive (+).

31. The method according to claim 29 or claim 30, wherein the cancer is selected from cervical cancer, ovarian cancer, and uveal melanoma.

32. A method of identifying a human cancer patient for treatment with an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the method comprises:

(a) obtaining a tissue sample of the cancer from the patient;

(b) determining that the cancer has an increased expression of:

(i) IFNy-related markers

(ii) T cell exhaustion markers

(iii) Myeloid activation markers and/ or

(iv) Tertiary lymphoid structure markers and optionally

(c) administering the anti-TIGIT antibody and the anti-PD-1 antibody to treat the cancer with increased expression of IFNy, T cell exhaustion markers, Myeloid activation markers and/ or

Tertiary lymphoid structures in the patient.

33. A method of treating cancer in a human patient comprising administering to the human patient a therapeutically effective amount of an anti-TIGIT antibody and an anti-PD-1 antibody, wherein the cancer has an increased expression of IFNy-related markers, T cell exhaustion markers, Myeloid activation markers and/ or Tertiary lymphoid structures.

34. The method according to claim 32 or claim 33, wherein the cancer is selected from cervical cancer, ovarian cancer, and uveal melanoma.

35. The method according to any of claims 32-34, wherein the IFNy-related markers comprise one or more genes selected from the group consisting of IFNG, STAT1, CCR5, CXCL9, CXCL10, CXCL11, 1DO1, PRF1, GZMA, and MHC11 HLA-DRA.

36. The method according to any of claims 32-35, wherein the T cell exhaustion markers comprise one or more genes selected from the group consisting of RPL13, ABCE1, ABL1M1, ACADM, ACP5, ADCY7, ADD1, ADH5, AKAP8, ANAPC5, ARHGAP1, ARHGEF1, ASCC1, ATP6V0A2, ATP6V0B, BN1P3L, BZW1, C5orf34, CCT3, CCT4, CCT5, CCT8, CD1D, CLK2, CRLF3, CTD-2410N18.5, DGKA, DTX1, EEF2, E1F2S1, EPHB4, ETS1, EVPLL, FKBP4, GM2A, GTF21, HMGCS1, HSPA8, ICAM2, IFNAR1, ITGB7, KCNN4, KCTD10, KLF13, KLF2, KLF3, LBR, LEF1, MAP4K4, MAPK8, MAT2A, NFE2L2, NME1-NME2, NUMB, OSBPL11, PAK2, PDHA1, PDL1M1, P1K3CD, PLD3, PPP2R5A, PRPS1, RAP1GDS1, RP11- 106M3.2, RPL10, RPL10A, RPL22, RPL3, RPL8, RPN2, RPS16, RPS3, RPS4X, RPS7, RPS8, SATB1, SEMA4A, S1AH1, SNRPD3, SNX4, SRPK1, SSI 8, STK38, TMC6, TUBB, UBP1, and ZNRF2.

37. The method according to any of claims 32-36, wherein the Myeloid activation markers comprise one or more genes selected from the group consisting of Cxclll, Gbpl, and Idol.

38. The method according to any of claims 32-37, wherein the Tertiary lymphoid structure markers comprise one or more genes selected from the group consisting of CD79A, MS4A1, LAMPS and P0U2AF1.

39. The method according to any of claims 32-38, wherein the increased expression of said IFNy-related markers, T cell exhaustion markers, Myeloid activation markers and Tertiary lymphoid structures is determined by RNA sequencing (RNA-Seq).

40. The methods according to any one of claims 1-39, wherein the anti-TIGIT antibody comprises a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:1), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:2), a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NOG), a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:4), a light chain CDR2 comprising SASYRYT (SEQ ID NOG), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:6).

41. The method of according to any one of claims 1-40, wherein the anti-TIGIT antibody comprises a heavy chain variable region having at least 90% sequence identity to SEQ ID NO:7 and a light chain variable region having at least 90% sequence identity to SEQ ID NO:8.

42. The method of to any one of claims 1-41, wherein the anti-TIGIT antibody comprises a heavy chain variable region comprising SEQ ID NO:7 and a light chain variable region comprising SEQ ID NO:8.

43. The method of any one of claims 1-42, wherein the anti-TIGIT antibody is a monoclonal antibody, a humanized antibody, a human antibody, a chimeric antibody, a bispecific antibody, an IgGl antibody, an IgG2 antibody, an IgG4 antibody, or an antibody fragment comprising an antigen binding site.

44. The method of any one of claims 1-43, wherein the anti-TIGIT antibody comprises a heavy chain having at least 90% sequence identity to SEQ ID NO:9 and a light chain having at least 90% sequence identity to SEQ ID NO: 10.

45. The method of any one of claims 1-44, wherein the anti-TIGIT antibody comprises a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO: 10.

46. The method of any one of claims 1-45, wherein the anti-TIGIT antibody is etigilimab.

47. The method according to any one of claims 1-46, wherein the anti-PD-1 antibody is selected from the group consisting of pembrolizumab (Keytruda), nivolumab (Opdivo), cemiplimab (Libtayo), dostarlimab (Jemperli), Tislelizumab, Sintilimab, Zimberelimab, Toripalimab, Penpulimab, Balstilimab, Retifanlimab, Cetrelimab, Budigalimab, Pimivalimab, Spartalizumab, Serplulimab, Sasanlimab, Camrelizumab, Prolgolimab, Pucotenlimab, Ezabenlimab and Genolimzumab.

48. The method of any one of claims 1-47, wherein the expression of PVR, PD-L1 and TIGIT are determined using an IHC assay.

49. The method of any one of claims 1-48, wherein the expression of CD226 and CD8 are determined using a MIF assay.