WO2014194293A1 - Méthodes améliorées de sélection de patients pouvant être soumis à des thérapies ciblant pd-1 ou b7-h4, et polythérapies associées - Google Patents

Méthodes améliorées de sélection de patients pouvant être soumis à des thérapies ciblant pd-1 ou b7-h4, et polythérapies associées Download PDF

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WO2014194293A1
WO2014194293A1 PCT/US2014/040388 US2014040388W WO2014194293A1 WO 2014194293 A1 WO2014194293 A1 WO 2014194293A1 US 2014040388 W US2014040388 W US 2014040388W WO 2014194293 A1 WO2014194293 A1 WO 2014194293A1
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tumor
cancer
cells
targeted
patient
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Solomon Langermann
Rena May
Shannon Marshall
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Amplimmune, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer

Definitions

  • the present invention generally relates to improved methods for selecting patients who would be amenable for PD-1 and B7-H4 pathway targeted therapies and combination therapies.
  • the immune system of humans and other mammals is responsible for providing protection against infection and disease. Such protection is provided both by a humoral immune response and by a cell-mediated immune response.
  • the humoral response results in the production of antibodies and other biomolecules that are capable of recognizing and neutralizing foreign targets (antigens).
  • the cell-mediated immune response involves the activation of macrophages, natural killer cells (NK), and antigen- specific cytotoxic T-lymphocytes ("CTLs”), and the release of various cytokines in response to the recognition of an antigen (Dong, C. et al. (2003) "Immune Regulation by Novel Costimulatory Molecules,"
  • T cells T cells to optimally mediate an immune response against an antigen requires two distinct signaling interactions (Viglietta, V. et al. (2007) “Modulating Co-Stimulation,” Neurotherapeutics 4:666-675; Korman, A.J. et al. (2007) “Checkpoint Blockade in Cancer Immunotherapy,” Adv.
  • antigen that has been arrayed on the surface of antigen-presenting cells must be presented to an antigen-specific naive CD4 + T cell.
  • Such presentation delivers a signal via the T cell receptor (TCR) that directs the T cell to initiate an immune response that will be specific to the presented antigen.
  • TCR T cell receptor
  • a series of co- stimulatory and co- inhibitory signals mediated through interactions between the APC and distinct T cell surface molecules, triggers first the activation and proliferation of the T cells and ultimately their inhibition.
  • the first signal confers specificity to the immune response whereas the second signal serves to determine the nature, magnitude and duration of the response.
  • the immune system is tightly controlled by co- stimulatory and co- inhibitory ligands and receptors. These molecules provide the second signal for T cell activation and provide a balanced network of positive and negative signals to maximize immune responses against infection while limiting immunity to self (Wang, L. et al. (March 7, 2011) "VISTA, A Novel Mouse Ig Superfamily Ligand That Negatively Regulates T Cell Responses," J. Exp. Med. 10.1084/jem.20100619: l-16; Lepenies, B. et al. (2008) "The Role Of Negative Co stimulators During Parasitic Infections," Endocrine, Metabolic & Immune Disorders - Drug Targets 8:279-288).
  • CD28 is constitutively expressed on the surface of T cells (Gross, J., et al. (1992) "Identification And Distribution Of The Costimulatory Receptor CD28 In The Mouse," J. Immunol. 149:380-388), whereas CTLA4 expression is rapidly up-regulated receptor (Sharpe, A.H. et al. (2002) “The B7-CD28 Superfamily,” Nature Rev. Immunol. 2: 116-126), binding first initiates T cell proliferation (via CD28) and then inhibits it (via nascent expression of CTLA4), thereby dampening the effect when proliferation is no longer needed.
  • B7 Superfamily a set of related B7 molecules (the "B7 Superfamily") (Coyle, A.J. et al. (2001) "The Expanding B7
  • B7-H1 (PD-L1, CD274) is a particularly significant member of the B7 Superfamily as it is pivotally involved in shaping the immune response to tumors (Flies, D.B. et al. (2007) "The New B7s: Playing a Pivotal Role in Tumor Immunity " J. Immunother. 30(3):251-260; United States Patents Nos. 6,803,192; 7,794,710; United States Patent Application Publication Nos. 2005/0059051 ; 2009/0055944; 2009/0274666; 2009/0313687; PCT
  • B7-H1 is a 55kDa type 1 transmembrane protein. It has been speculated to play a major role in suppressing the immune system during particular events such as pregnancy, tissue allografts, autoimmune disease and other disease states such as hepatitis. Dormant tumor cells are believed to over-express B7-H1, which may explain how such cells are able to evade immune surveillance and persist for years or decades (Quesnel, B.
  • B7-H1 is broadly expressed in different human and mouse tissues, such as heart, placenta, muscle, fetal liver, spleen, lymph nodes, and thymus for both species, as well as liver, lung, and kidney in mouse only (Martin- Orozco, N. et al. (2007) "Inhibitory Co stimulation And Anti- x ⁇ or
  • PD-1 Programmed Death -1
  • B7-H1 and B7-DC are a receptor of B7-H1 and B7-DC.
  • PD-1 is a 50-55 kDa type I membrane protein member of the extended
  • CD28/CTLA4 family of T cell regulators Ishida, Y. et al. (1992) "Induced Expression Of PD-1, A Novel Member Of The Immunoglobulin Gene Superfamily, Upon Programmed Cell Death," EMBO J. 11 :3887-3895; United States Patent Application Publication No. 2007/0202100;
  • WO PD-1 is expressed on activated T cells, B cells, and monocytes (Agata, Y. et al. (1996) "Expression Of The PD-1 Antigen On The Surface Of Stimulated Mouse T And B Lymphocytes," Int. Immunol. 8(5):765-772; Yamazaki, T. et al. (2002) “Expression Of Programmed Death 1 Ligands By Murine T Cells AndAPC,” J. Immunol.
  • NK T cells natural killer T cells
  • the extracellular region of PD- 1 consists of a single
  • IgV domain immunoglobulin (Ig)V domain with 23% identity to the equivalent domain in CTLA4 (Martin-Orozco, N. et al. (2007) "Inhibitory Costimulation And Anti-tumor Immunity,” Semin. Cancer Biol. 17(4):288-298).
  • the extracellular IgV domain is followed by a transmembrane region and an intracellular tail.
  • the intracellular tail contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates TCR signals (Ishida, Y. et al. (1992) "Induced
  • B7-H1 (PD-L1) is a member of the B7 family of co- stimulatory molecules and is primarily expressed on immune cells such as B cells, dendritic cells, macrophages and T cells.
  • the binding of B7-H1 to its receptor, programmed death 1 (PD-1) expressed on activated T cells (and/or to its cognate B7 molecule, B7.1) delivers an inhibitory signal to T cells or "Inhibitory Co stimulation And Antitumor Immunity," Semin. Cancer Biol. 17(4):288-298) and functions as a cell death inducer (Ishida, Y. et al.
  • PD-1 has been shown to negatively regulate TCR signaling.
  • B7-H1 has been reported to decrease TCR-mediated
  • B7-H1 ligand results in the transmission of an inhibitory signal that strongly inhibits the proliferation of antigen-specific CD8 + T cells; at higher concentrations the interactions with PD- 1 do not inhibit T-cell proliferation but markedly reduce the production of multiple cytokines (Sharpe, A.H. et al. (2002) "The B7-CD28 Superfamily;' Nature Rev. Immunol. 2: 116-126).
  • T-cell proliferation and cytokine production by both resting and previously activated CD4 and CD8 T cells, and even naive T cells from umbilical-cord blood, are inhibited by soluble B7-Hl-Ig fusion proteins coupled to beads with an anti-CD3 mAb (Freeman, G.J. et al.
  • B7-H1 - PD-1 interactions lead to cell cycle arrest in G0-G1 but do not increase cell death (Latchman, Y. et al. (2001) "PD-L2 Is A Second Ligand For PD-1 And Inhibits T Cell Activation," Nature Immunol. 2:261- 268; Carter, L. et al. (2002) "PD-l. PD-L inhibitory pathway affects both antagonize the B7 - CD28 signal when antigenic stimulation is weak or limiting, and plays a key role in down-regulating T-cell responses.
  • B7-H1 and PD-1 The signal transduction mediated by B7-H1 and PD-1 is complex. Both molecules additionally bind to other proteins.
  • B7-H1 is capable of binding to B7-1 (CD80) (Butte, M.J. et al. (2008) “Interaction ofPD-Ll and 57-1," Molecular Immunol. 45:3567-3572);
  • PD-1 is capable of binding to B7-DC (PD-L2) (Lazar-Molnar, E. et al. (2008) "Crystal Structure Of The Complex Between Programmed Death-1 (PD-1) And Its Ligand PD-L2," Proc. Natl. Acad. Sci. (USA) 105(30): 10483-10488).
  • B7-1 interacts with CD28 to deliver a co-stimulatory signal for T-cell activation that is important in the early stages of immune response (Elloso, M.M. et al. (1999) "Expression and Contribution ofB7-l (CD80) and B7-2 (CD86) in the Early Immune Response to Leishmania major Infection," J. Immunol. 162:6708- 6715).
  • B7-DC is a strong stimulator of T cells, enhancing T cell proliferation and IFN- ⁇ production. However, it also exhibits an inhibitory effect on the immune response via its interaction with PD-1 (Ishiwata, K. et al.
  • B7-DC also is also believed to regulate respiratory immunity by binding to repulsive guidance molecule b (RGMb) (Xia, et al., "RGMb is a novel binding partner or PD-L2 and its engagement with PD-L2 promotes respiratory tolerance", J. Experimental Med., 211(5):943-959 (2014), WO 2014/022758).
  • RGMb repulsive guidance molecule b
  • PD- 1 function is able to restore many T cell functions (Rodriquez-Garcia, M.
  • B7-H1 and PD-1 in inhibiting T cell activation and proliferation has suggested that these biomolecules might serve as therapeutic targets for treatments of inflammation and cancer.
  • B7-H1 expression In contrast to normal tissues, which show minimal surface expression of B7-H1, B7-H1 expression has been found to be abundant on many murine and human cancers, and may be further up-regulated upon IFN- ⁇ stimulation.
  • B7- Hl has been noted to play an important role in tumor immune evasion. See Blank and Gajewski (2004) "Interaction ofPD-Ll on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications or tumor immunotherapy " Cancer Immunol Immunother.
  • PD- 1 expression is upregulated during chronic infections, such as viral infections (Golden-Mason, et al., Upregulation of PD-1 Expression on Circulating and Intrahepatic Hepatitis C Virus-Specific CD8+ T Cells Associated with Reversible Immune Dysfunction, J. Virol., 81(17):9249-9258 (2007)).
  • agents that modulate the interaction of PD-1 with B7-H1 have been suggested to have utility in up- or down-modulating the immune response (see, United States Patents Nos. 7,029,674; 7,488,802; United States Patent Application Publications Nos. 2007/0122378; 2009/0076250; 2009/0110667; 2009/0263865; 2009/0297518; PCT Publication No. WO 2006/133396).
  • the use of anti-PD-1 antibodies to treat infections and tumors and up-modulate an adaptive immune response has been proposed and demonstrated clinically (see, United States Patent Application Publication Nos. 2010/0040614; 2010/0028330; 2004/0241745; 2008/0311117;
  • the inflammatory milieu of the tumor microenvironment can cause the up-regulation of B7-H1 on both the surface of tumors (Zou, W et al. (2008) “Inhibitory B7 -Family Molecules In The Tumour Microenvironment," Nat. Rev. Immunol. 8(6):467-771) and the surfaces of CD68 + Tumor Associated Macrophages ("TAMs") (Kuang, D.M. et al. (2009) "Activated Monocytes In Peritumoral Stroma Of Hepatocellular Carcinoma Foster Immune Privilege And Disease Progression Through PD-L1," J. Exp. Med. 206(6): 1327-1337), further impairing anti-tumor T cell responses, and thereby correlating with poor prognosis and outcome (Gao, Q. et al. (2009) "Over expression OfPD-Ll Significantly Associates With Tumor
  • TAMs provide a link between inflammation and cancer.
  • Macrophages are immune system cells derived from activated blood monocytes. They are primarily recognized as participating in inflammatory responses induced by pathogens or tissue damage by acting to remove (i. e. , phagocytose) pathogens, dead cells, cellular debris, and various components of the extra-cellular matrix (ECM). Macrophages have been found to constitute an important constituent in the tumor microenvironment and to represent up to 50% of the tumor mass. TAMs may be tumor infiltrating (occasionally referred to as Tumor Infiltrating Macrophages, or TIMs) or on the periphery of the tumor, and the location may be relevant to patient prognosis, diagnosis and/or treatment.
  • TAMs may be tumor infiltrating (occasionally referred to as Tumor Infiltrating Macrophages, or TIMs) or on the periphery of the tumor, and the location may be relevant to patient prognosis, diagnosis and/or treatment.
  • B7-H1 protein is highly expressed by cancer cells, but limited to the macrophage lineage of cells in normal tissues (Dong, H. (2003) "B7-H1 Pathway And Its Role In The Evasion Of Tumor Immunity " J. Mol. Med. 81 :281-287), detection of its presence on a cell (such as by such cell's binding to anti-B7-Hl antibodies or fragments) is generally considered indicative and diagnostic of a cancer cell.
  • Antibodies that bind to B7-H1 have found particular utility in the diagnosis of cancer (see, United States Provisional Patent Application No. 61/477,414, herein incorporated by reference).
  • B7-H4 is another member of the B7 family that is a negative regulator of immune cell responses.
  • the B7-H4 protein possesses 282 amino acid residues, which have been categorized as comprising an amino terminal extracellular domain, a large hydrophobic transmembrane domain and a very short intracellular domain (consisting of only 2 amino acid residues).
  • B7-H4 possesses a pair of Ig-like regions in its extracellular domain.
  • the B7-H4 protein has an overall structure of a type I transmembrane protein. The protein has minimal (about 25%) homology with other B7 family members (Zang, X. et al. (2003) B7x: A Widely amino acid identity, suggesting an important evolutionarily conserved function.
  • B7-H4 The receptor for B7-H4 has not been cloned.
  • B7-H4 has been shown not to bind to known CD28 family members such as CD28, CTLA-4, ICOS, and PD- 1 (Sica, et al., Immunity, 18:849-861 (2003)), and these are therefore not potential receptors for B7-H4.
  • Functional studies using B7-H4 transfectants and B7-H4-Ig fusion proteins demonstrate that B7-H4 delivers a signal that inhibits TCR-mediated CD4+ and CD8+ T cell proliferation, cell-cycle progression and IL-2 production.
  • B7-1 costimulation cannot overcome B7-H4-Ig-induced inhibition.
  • B7-H4 knock-out mice develop autoimmunity.
  • the broad and inducible expression of B7-H4 together with functional studies, suggests that B7-H4 serves to downregulate immune responses in peripheral tissues.
  • B7-H4 mRNA is widely expressed. Its expression has been found in the brain, heart, kidney, liver, lung, ovary, pancreas, placenta, prostate, skeletal muscle, skin, small intestine, spleen, stomach, testis, thymus, thymus, and uterus (Sica, G.L. et al. (2003) "57-H4, A Molecule Of The B7 Family, Negatively Regulates T Cell Immunity " Immunityl8:849-861 ; Zang, X. et al. (2003) B7x: A Widely Expressed B7 Family Member That Inhibits T Cell Activation " Proc. Natl. Acad. Sci.
  • B7-H4 A Molecule Of The B7 Family, Negatively Regulates T Cell Immunity," Immunityl8:849-861).
  • the finding of such a wide distribution of B7-H4 expression suggests that the function of B7-H4 is quite distinct from that of other inhibitory B7 molecules (see, Zang, X. et al. (2003) B7x: A Widely Expressed B7 Family Member That Inhibits T Cell Activation;' Proc. Natl. Acad. Sci. (USA) 100: 10388-10392).
  • B7-H4 protein expression has been found in microenvironments of numerous tumor types, for example, human ovarian cancers (Choi, I.H. et al. (2003) "Genomic Organization And Expression Analysis 0/B7-H4, An Immune Inhibitory Molecule Of The B7 Family " J. Immunol. 171:4650-4654; Kryczek, I. et al. (2006) "B7-H4 Expression Identifies A Novel Suppressive Macrophage Population In Human Ovarian Carcinoma," J. Exp. Med. 203(4):871-881; Bignotti, E. et al.
  • B7-H4 has also been shown to be over-expressed in TAMs, including those present in ovarian tumors (Kryczek, I. et al. (2006) “B7-H4 Expression Identifies A Novel Suppressive Macrophage Population In Human Ovarian Carcinoma," J. Exp. Med. 203(4):871-881; Kryczek, I. et al. (2007) “Relationship Between B7-H4, Regulatory T Cells, And Patient Outcome In Human Ovarian Carcinoma," Cancer Res.
  • Tregs Regulatory T cells
  • ⁇ 7- ⁇ 4 induce upregulation of ⁇ 7- ⁇ 4 on TAMs via IL-6 and IL-10; this is thought to be one of the mechanisms by which Tregs contribute to immune suppression.
  • ⁇ 7- ⁇ 4 expression has also been observed in tubule epithelial cells of diseased kidneys (Chen, Y., Kidney Int., 70(12):2092-9 (2006) Epub 2006 Oct 18.)
  • TAMs expressing ⁇ 7- ⁇ 4 have been found to suppress tumor-associated antigen-specific T cell immunity (Kryczek, I. et al. (2006) "B7-H4 Expression Identifies A Novel Suppressive Macrophage Population In Human Ovarian Carcinoma," J. Exp. Med. 203(4):871-881).
  • the intensity of ⁇ 7- ⁇ 4 expression in TAMs correlates significantly with Treg cell numbers in the tumor.
  • ⁇ 7- ⁇ 4 expressed on TAMs is associated with poor patient outcome (Kryczek, I. et al. (2006) "B7-H4 Expression Identifies A Novel Suppressive Macrophage Population In Human Ovarian
  • TAMs spontaneously produce chemokine CCL22 that mediates Treg cell trafficking into the tumor, and Treg cell-induced ⁇ 7- ⁇ 4 expression on antigen-presenting cells (APC), including TAMs themselves (Kryczek, I. et al. (2006) "Cutting Edge: Induction OfB7-H4 On APCs Through IL-10: Novel Suppressive Mode For Regulatory T Cells,” J. Immunol. 177(1) :40- 44).
  • Cancer cells acquire a characteristic set of functional capabilities during their development, albeit through various mechanisms. Such capabilities include evading apoptosis, self-sufficiency in growth signals, and insensitivity to anti-growth signals, tissue invasion/metastasis, and limitless explicative potential and sustained angiogenesis.
  • the term "cancer cell” is meant to encompass both pre-malignant and malignant cancer cells.
  • cancer refers to a benign tumor, which has remained localized.
  • cancer refers to a malignant tumor, which has invaded and destroyed neighboring body structures and spread to distant sites.
  • tumor antigens such as Her2/neu, CEA, PSA, Bladder tumor antigen, thyroglobulin, alpha- fetoprotein, CA125, CA19.9, CA15.3, have been used as targets for anticancer therapies
  • MAPKs mitogen-activated protein kinases
  • the Raf-MEK-ERK cascade is a signal transduction pathway which relays extracellular signals from the cell membrane to the nucleus via an ordered series of consecutive phosphorylation events (Madhunapantula,
  • Raf is a family of protein kinases which acts to phosphorylate and thereby activate the MAP/ERK family of kinases (MEKs) (Kyriakis, J.M. et al. (1992) "Raf-1 Activates MAP Kinase- Kinase,” Nature 358:417-421; Dent, P. et al.
  • V600E valine to glutamic acid at codon 600
  • the mutated protein exhibits more a kinase activity that is more than 10-fold higher than normal BRAF (Davies, H. et al. (2002) “Mutations Of The BRAF Gene In Human Cancer," Nature 417:949-954; Hong, D.S. et al. (Epub 21 Feb 2012) "BRAF(V600) Inhibitor GSK2118436 Targeted Inhibition of Mutant BRAF in Cancer Patients Does Not Impair Overall Immune Competency,” Clin. Cancer Res. 18:2326-2335).
  • Such abnormally high activation of the MAP kinase pathway can inhibit cellular growth in a wide variety of normal and cancer cells by promoting cellular senescence (Michaloglou, C. et al. (2005) "BRAFE600-Associated Senescence -Like Cell Cycle Arrest Of Human Naevi,” Nature 436:720-724).
  • MEKs The MAP/ERK family of kinases (MEKs), in turn, activate an extracellular signal-regulated kinase (ERK)
  • ERK extracellular signal-regulated kinase
  • ERK exhibits proliferative effects when activated (Boulton, T.G. et al. (1990) "An Insulin-Stimulated Protein In Response To Insulin And NGF ,” Cell 65:663-675; Rossomando, AJ. et al. (1989) "Evidence That pp42, A Major Tyrosine Kinase Target Protein, Is A Mitogen- Activated Serine/Threonine Protein Kinase " Proc. Natl. Acad. Sci. (U.S.A.) 86:6940-6943; Payne, D.M. et al.
  • MAP Kinase MAP Kinase
  • the primary cytoplasmic target of ERK is p90RSK, also known as the ribosomal protein S6 kinase, but a wide array of other targets are known to exist.
  • the Raf-MEK-ERK signal transduction cascade is primarily activated in response to various extracellular growth factors which are able to initiate intracellular signaling. This mitogenic signal most often occurs at the level of a ligand-receptor interaction, followed by downstream signaling, which ultimately causes altered regulation of the genes responsible for oncogenesis (Lee, J.T. Jr. et al. (2002) "The Raf/MEK/ERK Signal
  • BRAF mutations are found in a wide range of cancers, a substantial proportion of cases have been found to additionally involve mutations in the RAS oncogene (for example, malignant melanoma, colorectal cancer and borderline ovarian cancers (Vogelstein, B. et al. (1988) "Genetic Alterations During Color ectal-Tumour Development " N. Engl. J. Med. 319:525-532; van't Veer, L.J. et al. (1989) "N-ras Mutations In Human Cutaneous Melanoma From Sun-Exposed Body Sites," Mol. Cell. Biol. 9:3114-3116; Caduff, R.F. et al.
  • regulated kinase (ERK)-MAP kinase pathway can be achieved by mutation at various levels in the pathway and that the pathway is activated in a substantial proportion of cases in these cancer types (Davies, H. et al. (2002) ' ⁇ ' ⁇ Mutations Of The BRA I ' Gene In Human Cancer," Nature 417:949-954).
  • therapies targeting mutant V600E B-Raf activity or other components of the MAP kinase cascade have potential as agents for halting the progression of malignant tumors by slowing tumor growth, preventing angiogenesis, inhibiting invasion and metastasis, inducing tumor cell death, or promoting tumor differentiation (Tuveson, D.A. et al. (2003) "BRAF As A Potential Therapeutic Target In Melanoma And Other Malignancies," Cancer Cell 4:95-98; Gaggioli, C. et al. (2007) “Tumor-Derived Fibronectin Is Involved In Melanoma Cell Invasion And Regulated By V600E B-Raf Signaling Pathway," J. Invest. Dermatol.
  • Melanoma is the most dangerous type of skin cancer and is the leading cause of death from skin disease.
  • the prognosis of patients with metastatic melanoma is particularly poor and is not influenced by systemic therapy with cytotoxic drugs (Arkenau, H.T. et al. (2011) “Targeting BRAF For Patients With Melanoma " Brit. J. Cancer 104:392-398). Only 5% of patients with visceral metastases survive for 2 years (Balch, CM. et al. (2001) "Prognostic Factors Analysis of 17,600 Melanoma Patients:
  • BRAF inhibitors such as vemurafenib and dabrafenib
  • vemurafenib and dabrafenib can result in the rapid onset of tumor response in many patients
  • intrinsic and/or acquired resistance means these are often temporary, with a median time to progression of less than 7 months (Ascierto, P.A. et al. (2012) “Sequencing Of BRAF Inhibitors And Ipilimumab In Patients With Metastatic Melanoma: A Possible Algorithm For Clinical Use," J.
  • the RAS-RAF-MEK-ERK pathway is deregulated in over 90% of malignant melanomas, (as well as in many other tumor types).
  • Targeting MEK and RAF (BRAF V600 mutants) as key kinases of this pathway is currently being evaluated in clinical trials.
  • the up-regulation of counteracting signaling cascades ⁇ e.g. , alternative kinase pathways and/or key immunomodulatory molecules (such as B7-H1, IDO, ICOS, PD-1, etc)) as a direct response to MEK or BRAF inhibition is also believed to play a role in the low response to MEK targeting drugs and resistance/evasion to BRAF inhibitors.
  • Such up-regulation results in resistance to treatment and in the re-emergence of the tumor (progression of disease).
  • the present disclosure relates to improved methods for characterizing tumors and/or the tumor microenvironment.
  • the disclosure express cell surface molecules, such as B7-H1, B7-H4 and PD-1, and/or that are capable of physiospecifically or immunospecifically binding to B7-H1, B7-H4 or PD-1, and to distinguish between tumor cells that express such biomarkers and non-tumor cells present within the tumor and/or tumor microenvironment.
  • the disclosure concerns the uses of such methods in the diagnosis, prognosis, selection of patients, and the treatment of cancer and other diseases.
  • Tumor specific T-cell function is regulated by a myriad of positive and negative co-stimulatory pathways that regulate the immune response by maintaining tolerance and controlling the balance between immunity and immune suppression. Regulation occurs via checkpoint receptors and their ligands expressed on cells throughout the tumor microenvironment such as: the tumors themselves, cytotoxic T cells, regulatory T cells, myeloid derived suppressor cells, dendritic cells and/or macrophages among others.
  • a first aspect of the present disclosure derives, in part, from the recognition that the presence of either (or both) TILs and IFN-gamma production disrupts co-stimulatory pathways (such as those involving, for example, PD-1 and B7-H4).
  • co-stimulatory pathways such as those involving, for example, PD-1 and B7-H4.
  • B7-H1+ immunohistochemical stains of tumor biopsies may reflect the fact that the tumor cells are B7-H1+, or it may reflect the fact that B7-H1+ CD68+ TAMs are present within the tumor microenvironment. As such, tumor biopsies responses and/or treatments by overcoming any initial suppressive tumor microenvironment (if present).
  • one aspect of the methods of the present disclosure relate to an assessment of the distinct cellular patterns of B7-H1 expression within a tumor to determine whether detected B7-H1 is being expressed by the tumor cells or by non-tumor cells (such as, for example, B7-H1+ CD68+ TAMs) that have infiltrated into the tumor.
  • the disclosure thus more specifically relates to methods sufficient to accomplish the dual (or differential) detection of the cells of the tumor microenvironment (so as to assess their expression of B7-H1 and other biomarkers indicative of non-tumor cells).
  • dual or differential verification provides clarification on which key cellular subsets within the tumor microenvironment are important therapeutic targets or predictive biomarkers for patient response to therapies targeting the immune checkpoint pathways.
  • B7-H1 expression may occur on the tumor, infiltrating macrophages, or both. Therefore, additional biomarkers can be used to differentiate which cells, tumor or non-tumor, are expressing the B7-H1 within the tumor microenvironment. If there is evidence that B7-H1 is expressed on tumor infiltrating macrophages, B7-H1 negative tumors may be targeted with PD- 1/B7-H1 targeted agents as if they are B7-H1 positive biopsies for diagnosis and/or treatment of the tumor.
  • a lower expression of B7-H1 on TAMs provides an additional or alternative immunosuppressive B7-H1 target for therapeutic intervention to overcome compared to an absence of B7-H1 positive tumors, or alternatively when B7-H1 is broadly expressed across the entire tumor.
  • B7-H4 expression may also occur on either the tumor, infiltrating macrophages, or both. Therefore, additional biomarkers can be used to differentiate which cells, tumor or non-tumor, are expressing the B7-H4 within the tumor microenvironment. If there is evidence that B7-H4 is expressed on tumor infiltrating macrophages, B7-H4 negative tumors may be macrophages, such as CD14, CD68, CD163 and TLR2, FoxP3 etc, and biomarkers of other tumor infiltrating cells. Biomarkers suitable for use in accordance with the methods of the present disclosure are known in the art (see, e.g. , Kunisch, E. et al.
  • the present disclosure contemplates the concurrent or sequential analysis of: (1) B7-H4, B7-H1 or PD-1 expression and (2) the expression of one, two, three or more additional biomarkers, especially biomarkers that are characteristic of non-tumor cells within tumors and/or the tumor
  • Antibodies that are immunospecific for biomarkers are known in the art (see citations noted above with respect to such biomarkers), or may be readily obtained using methods known in the art. Although antibodies (or their respective antigen-binding fragments) are the preferred binding molecules of the present disclosure, the disclosure further contemplates the use of protein receptors or receptor ligands as binding molecules.
  • PD-1 protein or a B7-Hl-binding fragment thereof
  • B7-H1 protein or a PD-l-binding fragment thereof
  • B7-DC protein or a PD-l-binding fragment thereof
  • fusion proteins possessing all or one or more contiguous fragments of such molecules (for example PD-1, B7-H4 or B7-H1) in the characterization of the cells of a tumor and/or tumor microenvironment.
  • a fusion protein comprises all or one or more fragments of both B7-H1 and PD-1 and binds to both molecules.
  • a fusion protein CD14, CD68, CD163, TLR2, etc.
  • such a fusion protein comprises all or one or more fragments of B7-H1 and a molecule (including an antibody or an antigen-binding fragment thereof) that binds a cell marker ⁇ e.g. , CD8, melanin, or a macrophage marker (e.g., CD14, CD68, CD163, TLR2, etc.) (see, e.g. , U.S. Patent No. 4,676,980).
  • the present disclosure also relates to improved methods for selecting patients who would be amenable for B7-H4 and/or PD-1 pathway targeted therapies and combination therapies, and for treating such patients.
  • the disclosure also pertains to improved PD- 1 targeted therapies and
  • combination therapies for treating patients who have failed treatment with BRAF/MEK inhibitors or other inhibitors of the RAS-RAF-MEK-ERK pathway.
  • the disclosure further pertains to improved PD- 1 targeted therapies and combination therapies to overcome resistance caused by "tumor dormancy" and to prevent the selection/outgrowth of rapidly, progressing, resistant tumors in the presence of various small molecule inhibitors.
  • the present disclosure additionally provides a PD-1 targeted therapy which involves the administration of an immunomodulatory molecule such as a PD-l-binding fusion protein/antibody (e.g., an anti-PD-1 antibody, a B7-DC-Ig, a B7-Hl-Ig, etc.) with a BRAF inhibitor ("BRAFi”) or other small molecule as an initial treatment regimen in such selected
  • an immunomodulatory molecule such as a PD-l-binding fusion protein/antibody (e.g., an anti-PD-1 antibody, a B7-DC-Ig, a B7-Hl-Ig, etc.) with a BRAF inhibitor ("BRAFi”) or other small molecule as an initial treatment regimen in such selected
  • the disclosure particularly provides a B7-DC-Ig that binds PD-1
  • B7-H1 T cells (chronically stimulated / exhausted T cells) but is substantially less capable or substantially incapable of binding to PD-1 + B7-
  • Hl + cells normal activated T cells
  • Figure 1 illustrates the scoring of B7-H1 expression via
  • Figure 2 shows the extent of correlations between B7-H1 expression on tumors and PD-1+ TILs from individual patients with a variety of cancers.
  • B7-H1 and PD-1 were detected in tumor biopsies via IHC.
  • Figure 4 shows necrotic tissue that picks up the brown DAB stain used for B7-H1 detection non-specifically along with the presence of B7- H1+ CD68+ tumor associated macrophages.
  • FIG. 5 shows that single stain (B7-H1 stain only)
  • Figure 6 shows an example where the tumor is B7-H1+ and the surrounding macrophages are B7-H1-.
  • the dual CD68/B7-H1 stain confirms that the few tumor cells are B7-H1+.
  • the disclosed examples show that B7- Hl is expressed only on the tumor, on the tumor and macrophages, or only on the macrophages in the presence of a B7-H1 negative tumor.
  • Figure 7 shows a sustained reduction in the percentage of PD-1 (HI) CD4+ and PD-1 (HI) CD8+ T cells remaining in the periphery from a melanoma BRAFm patient following therapy with a PD- 1 binding agent.
  • Figure 8 shows the H&E stains from three fresh biopsy specimens taken from a BRAFm melanoma patient who had failed BRAFi/MEKi therapy and then subsequently received treatment with a PD-1 binding agent.
  • the pre-treatment biopsy was performed prior to therapy, the first post treatment biopsy was performed on Cycle 1, Day 15, following 1 dose of the PD-1 binding molecule.
  • the second post treatment biopsy (C2D15) was taken on Cycle 2, Day 15 following three doses of the PD-1 binding molecule.
  • This biopsy contains fibrous tissue with pockets of lymphocyte infiltrates. The presence of tumor cells was confirmed with S100 stain.
  • Figure 9 shows the results of immunohistochemical staining for B7- Hl, PD-1, CD8, CD4 and FoxP3. of biopsy samples of Figure 8, along with an archival specimen taken from the same patient prior to BRAFi/MEKi therapy.
  • FIG 10 shows that a sustained increase in TILs was observed following treatment with a PD-1 -binding molecule for tumors that had Figure 11, Panels A-D show multiple tumor biopsies from a BRAF mutant melanoma cancer patient.
  • B7-H1 expression Prior to BRAFi/MEKi therapy (Panel A) B7-H1 expression was scored as 1; after such therapy but prior to therapy with a PD-1 binding molecule (Panel B), B7-H1 expression was scored as 3.
  • Post-treatment (Panel C; Panel D), B7-H1 expression remained scored as 3 and as 2.
  • B7-H1 expression was detected on remaining tumor cells, shed membrane and/or lymphocytes.
  • Figures 12A-12C are photoimages of a biopsy of a tumor taken from a BRAF mutant melanoma patient stained with B7-H1, PD-1 and CD8. The images reveal that there is a heterogeneous distribution of cells expressing B7-H1, CD8 and PD-1 markers across tumor tissue samples ( Figure 12A), not all CD8+ T cells express PD-1 ( Figure 12A), expression of tumor cells expressing B7-H1 tumor cells are located in the same area as CD8+ T cells ( Figure 12A-12B) and the B7-H1 membranous expression is entirely on tumor cells in this biopsy ( Figure 12C).
  • Figure 13 shows that high baseline LDH levels, or levels that rapidly increase above the upper level of normal (ULN) is prognostic of patients that will not successfully respond to PD-1 -targeted immunotherapy.
  • Figure 14 shows that the baseline absolute lymphocyte count (ALC) is a prognostic biomarker of successful response to PD-l-targeted immunotherapy.
  • ALC baseline absolute lymphocyte count
  • Figure 15 shows the correlation between clinical outcome and baseline TIL levels.
  • Figures 16A-16B show the correlation between clinical outcome and polyfunctional T cell populations (CD8+ ( Figure 16A) and CD4+ ( Figure 16B)).
  • Figure 17 summarizes the preferred prognostic biomarker criteria of the present disclosure for patient selection for PD-1 targeted immunotherapy.
  • Figure 19C shows that the tumor cells were rejected following re-challenge.
  • Panels A-H show the results of immunophenotype analysis conducted on Day 15 and Day 24 post- inoculation on mice having subcutaneous syngeneic CT26 colon carcinoma after administration of murine B7-DC IgG fusion.
  • FIG 21 Panels A-B shows the results of CT scans of a melanoma patient in the 30 mg/kg dose-escalation cohort exhibiting a Partial Response (PR).
  • the CT scans (of the lung) were performed prior to Cycle 1 ( Figure 21, Panel A) and at the end of Cycle 4 ( Figure 21, Panel B).
  • FIG 22 Panels A-B, shows the results of CT scans of a melanoma patient in the 30 mg/kg dose-escalation cohort exhibiting sustained (>20 months) Stable Disease (SD).
  • the CT scans (of the neck) were performed prior to Cycle 1 ( Figure 22, Panel A) and at the end of Cycle 6 ( Figure 22, Panel B).
  • FIG 23 Panels A-B, shows the results of CT scans of a melanoma patient in the 30 mg/kg dose-escalation cohort exhibiting Mixed Response (MR) meaning that reduction in tumor volumes were observed for some lesions while increased tumor volumes were observed at other lesions.
  • MR Mixed Response
  • Figures 24A-24B show the effect of the human B7-DC-Ig fusion on the levels of absolute lymphocyte, T cell, CD4 + T cell , CD8 + T cell , and
  • Figures 25A-25E show the changes in peripheral blood and the tumor microenvironment after treatment with human B7-DC-Ig Fusion molecules.
  • Figure 25A changes in the number of polyfunctional CD4 + T cells/ ml of blood
  • Figure 25B changes in the number of polyfunctional CD8 + T cells/ specimens
  • Figure 25E changes in TBX21 and FOXP3 gene expression (normalized to the expression of housekeeping genes) in paired tumor biopsy specimens.
  • Figure 26 shows changes in tumor CXCL9 gene expression in patients who left the trial after fewer than 4 cycles (black circles), patients who remained on the trial for 4 or more ("4+") (cycles (gray squares), and a clinical responder patient (gray triangles).
  • Figure 27 shows the correlation between tumor CXCL9 gene expression and CD8 TIL density in biopsy specimens (pretreatment, gray circle' post treatment, black triangle).
  • Figures 28 A-28E show the numbers of lymphocytes /ml of blood (Figure 28A), LDH fold over the upper limit of normal (Figure 28B), expression of tumor B7-H1 (Figure 28C), average number of CD8+ TIL cells per hpf ( Figure 28D) and average number of PD-1+ TIL cells per hpf ( Figure 28E) for Clinical Responders of treatment with human B7-DC-Ig Fusion molecules.
  • Figures 29A-29C show IHC images of a biopsy specimen from a melanoma metastasis on neck stained for B7-H1 (Figure 29A), CD8 ( Figure 29B) or PD-1 ( Figure 29C). White circles indicate cells that were counted as positive for the indicated marker.
  • Figures 30A-30B show changes in the ratio of CD8+ TIL cells to PD- 1+ TIL cells of paired tumor biopsy specimens from the 10-30 mg/kg cohorts, pre-treatment vs. post-treatment with a B7-DC Ig fusion molecule (Figure 30A) or across three treatment cycles (Figure 30B).
  • Figure 31 show IHC staining of B7-H1 (Panels A and
  • Figures 32A-32B show the normalized gene expression of a series of biomarkers in patients receiving human B7-DC-Ig Fusion therapy (black triangle - clinical responder; square - patients who stayed on trial for 4+ cycles; gray circle - patients who came off the clinical trial more rapidly due Fusion therapy.
  • Figure 34 shows the correlation between bDNA and IHC analyses of the gene expression of CXCL9 in patients receiving human B7-DC-Ig Fusion therapy.
  • Figures 35A-35C show the changes in gene expression of biomarkers in a clinical responder patient (patient 0402) receiving human B7-DC-Ig Fusion therapy over the course of the trial.
  • Figure 36 shows the changes in gene expression of biomarkers in a patient who remained in a human B7-DC-Ig Fusion therapy clinical trial 4+ cycles (patient 0506).
  • Figures 37A-37B show the changes in gene expression of biomarkers in a patient who remained in a human B7-DC-Ig Fusion therapy clinical trial 4+ cycles (patient 0609).
  • Figures 38A-38C show the effect of the administration of human B7- DC-Ig Fusion molecules on the number of polyfunctional CD4 T cells
  • Figures 39A and 39B are micrographs of PD-L1 (B7-H1) and B7-H4 (CD68) in a set of serial tissue sections of a melanoma under low (39 A) and high (39B) magnification.
  • Figures 40A and 40B are micrographs of PD-L1 (B7-H1) and B7-H4 (CD68) in a set of serial tissue sections of a renal cell carcinoma under low (40A) and high (40B) magnification.
  • PD-1 Programmed Death -1
  • PD-1 is a receptor of B7-H1 and B7-DC.
  • PD-1 is a 50-55 kDa type I membrane protein member of the extended CD28/CTLA4 family of T cell regulators (Ishida, Y. et al. (1992) "Induced Expression Of PD-1, A Novel Member Of The Immunoglobulin Gene Superfamily, Upon Programmed Cell Death," EMBO J. 11 :3887-3895; 7,101,550; 7,488,802; 7,635,757; 7,722,868; PCT Publication No. WO 01/14557).
  • amino acid sequence of human PD-1 is (SEQ ID NO:l):
  • amino acid sequence of human B7-H1 is (SEQ ID NO:2):
  • amino acid sequence of human B7-DC is (SEQ ID NO:3):
  • B7-H4 is member of the B7 family that is a negative regulator of T cell responses (U.S. Published Application Nos. 2012/0177645 and 2012/0276095).
  • amino acid sequence of human B7-H4 is (SEQ ID NO:4):
  • amino acid sequence of another human B7-H4 is (SEQ ID NO: 1
  • a “non-tumor cell” is a normal cell (which may be quiescent or activated) that is located within a tumor microenvironment, including but not limited to Tumor Infiltrating Lymphocytes (TILs), leucocytes, macrophages, and/or other cells of the immune system, and/or stromal cells, and/or fibroblasts (e.g., cancer or tumor associated fibroblasts).
  • TILs Tumor Infiltrating Lymphocytes
  • leucocytes e.g., macrophages, and/or other cells of the immune system
  • stromal cells e.g., fibroblasts
  • fibroblasts e.g., cancer or tumor associated fibroblasts.
  • the term "cell(s) of a tumor” is employed to refer to tumor cells and non- tumor cells located within a tumor or a tumor environment.
  • the subject e.g. , patient
  • the tumors to be characterized in accordance with the present disclosure may be
  • tumor cells include, but are not limited to, tumor cells of the following cancers:
  • leukemias including, but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblasts, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and
  • myelodysplastic syndrome chronic leukemias such as but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as, but not limited to, Hodgkin's disease, non-Hodgkin's disease; multiple myelomas such as, but not limited to, smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma; Waldenstrom's macroglobulinemia;
  • monoclonal gammopathy of undetermined significance benign monoclonal gammopathy; heavy chain disease; bone and connective tissue sarcomas such as, but not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma
  • breast cancer including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget' s disease, and inflammatory breast cancer; adrenal cancer, including but not limited to, pheochromocytom and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer, including but not limited to, insulinoma, gastrinoma, glucagonoma,
  • esophageal cancers including, but not limited to, squamous cancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; stomach cancers including, but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma,
  • liposarcoma, fibrosarcoma, and carcinosarcoma colon cancers; rectal cancers; liver cancers including, but not limited to, hepatocellular carcinoma and hepatoblastoma, gallbladder cancers including, but not limited to, adenocarcinoma; cholangiocarcinomas including, but not limited to, cancer; testicular cancers including, but not limited to, germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sac tumor), prostate cancers including, but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers including, but not limited to, squamous cell carcinoma; basal cancers;
  • salivary gland cancers including, but not limited to, adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; pharynx cancers including, but not limited to, squamous cell cancer, and verrucous; skin cancers including, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acral lentiginous melanoma; kidney cancers including, but not limited to, renal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, transitional cell cancer (renal pelvis and/ or uterer); Wilms' tumor; bladder cancers including, but not limited to, transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma.
  • cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, and gastic (for a review of such disorders, see Fishman et ah , 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia and Murphy et al. , 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books U.S.A., Inc., United States of America).
  • the term "characterizing" is intended to refer to assessing a patient, tissue sample or cell for the expression of a biomarker and its presentation on the surface of or within a cell. In accordance with the principles of the present disclosure, such characterization is mediated using molecules that physiospecifically bind, or that immunospecifically bind, to such expressed and presented molecules. "physiospecifically binding" to one another. A molecule may be capable of physiospecifically binding to more than one other molecule. A molecule is said to be able to "immunospecifically bind" a second molecule if such binding exhibits the specificity and affinity of an antibody to its cognate antigen.
  • Antibodies are said to be capable of "immunospecifically binding" to a target region or conformation ("epitope") of an antigen (and in particular, the antigens: B7-H1 or PD-1) if such binding involves the antigen recognition site of the immunoglobulin molecule.
  • An antibody that immunospecifically binds to a particular antigen may bind to other antigens with lower affinity if the other antigen has some sequence or conformational similarity that is recognized by the antigen recognition site as determined by, e.g. , immunoassays, BIACORE® assays, or other assays known in the art, but would not bind to a totally unrelated antigen.
  • antibodies will not cross-react with other antigens.
  • Antibodies may also bind to other molecules in a way that is not immunospecific, such as to FcR receptors, by virtue of binding domains in other regions/domains of the molecule that do not involve the antigen recognition site, such as the Fc region.
  • binding molecules will be "homogeneic,” (i.e. , molecules of the same species as that of the tumor being characterized, such as the use of human, chimeric or humanized antibodies for the characterization of the cells of a human tumor, or the use of human PD-1 protein to detect human B7-H1 on the surface of tumor or non-tumor cells).
  • binding molecules may be "heterogeneic,” (i.e. , molecules of a species that differs from that of the tumor being characterized, such as the use of a murine monoclonal antibody for the characterization of a human tumor).
  • biomarker is intended to denote a molecule whose expression and presentation on the surface of a cell is characteristic of a particular cell type, or an attribute of a cell or tissue sample that is characteristic of a particular cell or tissue type.
  • B7-H1 is Also of particular concern to the present disclosure are biomarkers that are prognostic for the selection of patients for subsequent treatment with PD- 1 targeted therapy.
  • the preferred “prognostic biomarkers” of the present disclosure include:
  • Peripheral PD-1 HI Levels The level of PD- 1 HI cells is a prognostic biomarker of immune function and response to PD-1 -targeted immunotherapy (PD-1 HI cells are discussed in: Onabajo, O.O. et al. (2013) "Rhesus Macaque Lymph Node PD-l(Hi)CD4( +) T Cells Express High Levels 0/CXCR5 And IL-21 And Display A CCR7(Lo)ICOS(+ )Bcl6(+ ) T- Follicular Helper (Tfh) Cell Phenotype," PLoS One. 8(3):e59758;
  • Lactate dehydrogenase is released into the serum from dying cells, and is a marker of rapid disease progression in cancer, particularly melanoma (Brown, J.E. et al. (Epub 2012 Sep 4) "Serum Lactate Dehydrogenase Is Prognostic For Survival In Patients With Bone Metastases From Breast Cancer: A Retrospective Analysis In Bisphosphonate-Treated Patients," Clin. Cancer Res.
  • ALC Level Absolute lymphocyte counts (ALC) and the rate of decline of ALC over time in the peripheral blood can be markers for the ability to mount an immune responsive (immune competency) (Lad, D.P. et al. (Epub 2012 Oct 16) "Regulatory T-Cells In B-Cell Chronic Lymphocytic Leukemia: Their Role In Disease Progression And Autoimmune Cytopenias," Leuk. Lymphoma. doi: 10.3109/10428194.2012.728287; Decker, T. et al. (Epub 2012 Jul 4) "Increased Number Of Regulatory T Cells (T-Regs) In The Peripheral Blood Of Patients With Her-2/Neu-Positive Early Breast Cancer,” J. Cancer Res. Clin.
  • TILs tumor infiltrating lymphocytes
  • a "PD-1 targeted therapy” is a therapy that involves the administration of molecules that physiospecifically or
  • immunospecifically bind PD-1 or any of its ligands e.g. , B7-H1, B7-DC, etc.
  • PD-1 immunospecifically binds PD-1 or any of its ligands (e.g. , B7-H1, B7-DC, etc.). More preferably, such molecules physiospecifically bind PD-1 and comprise, for example, anti-PD-1 antibodies, anti-PD-1 antibody antigen- binding fragments, and B7-DC (or B7-H1) fusion proteins (such as a B7-DC- Ig fusion or a B7-Hl-Ig fusion).
  • B7-DC or B7-H1 fusion proteins
  • PD-1 targeted therapies in which the mechanism of action is dependent on blocking the interaction between the ligand (B7-H1 or B7-DC) and the receptor (PD-1) are denoted as "ligand dependent.”
  • Blocking or neutralizing anti-PD- 1 antibodies are examples of molecules with ligand dependent activity.
  • PD-1 targeted therapies that are able to bind PD-1+ cells and modulate PD-1 levels or cellular activity in the absence of PD-1 ligands are denoted as having "ligand independent activities.”
  • Agonistic anti-PD-1 antibodies and B7-DC fusion proteins (such as a B7-DC-Ig) are examples of molecules with ligand independent activity whereby the ability to modulate PD-1 + cells directly has been clearly demonstrated.
  • Ligand dependent and ligand independent activities are not mutually exclusive and a single PD- 1 targeted therapy may demonstrate both activities.
  • Such molecules can be produced by screening hybridoma lines for those that produce antibody that are immunospecific for human PD-1, and then optionally screening amongst such lines for those exhibiting modulating activity (e.g. , neutralizing activity, agonizing activity, internalizing activity, altered signal transducing activity, etc.).
  • modulating activity e.g. , neutralizing activity, agonizing activity, internalizing activity, altered signal transducing activity, etc.
  • the disclosure provides for the use of PD-1 ligands that physiospecifically bind (also known as Nivolumab or BMS-936558), MK3475 (also referred to as lambrolizumab and pembrolizumab), and CT-011 (Pardoll, D.M. (April 2012) "The Blockade Of Immune Checkpoints In Cancer Immunotherapy," Nature Reviews Cancer 12:252-264).
  • B7-H4 targeted therapy is a therapy that involves the administration of molecules that physiospecifically or
  • B7-H4 targeted therapies in which the mechanism of action is dependent on blocking the interaction between the ligand (B7-H4) and a receptor thereof are denoted as "ligand dependent.” Blocking or neutralizing anti-B7-H4 antibodies are examples of molecules with ligand dependent activity.
  • B7-H4 targeted therapies that are able to bind B7-H4 receptor+ cells and modulate B7-H4 receptor levels or cellular activity in the absence of B7-H4 are denoted as having "ligand independent activities.”
  • Antagonistic anti-B7-H4 receptor antibodies and soluble, antagonistic B7-H4 proteins (such the extracellular domain of B7-H4) that can bind to B7-H4 receptors without activating signal transduction through the receptor are examples of molecules with ligand independent activity.
  • Ligand dependent and ligand independent activities are not mutually exclusive and a single B7- H4 targeted therapy may demonstrate both activities.
  • Such molecules can be produced by screening hybridoma lines for those that produce antibody that are immunospecific for human B7-H4 or a receptor thereof, and then optionally screening amongst such lines for those exhibiting modulating activity (e.g. , neutralizing activity, agonizing activity, internalizing activity, altered signal transducing activity, etc.).
  • modulating activity e.g. , neutralizing activity, agonizing activity, internalizing activity, altered signal transducing activity, etc.
  • the disclosure provides for the use of B7-H4 ligands that physiospecifically bind to human B7-H4 receptors.
  • Exemplary molecules are known in the art. See, for example, WO 2013/025779 which provides anti-B7-H4 antibodies and WO 2008/083239 which provides B7- recognition site.
  • variable region is intended to distinguish such domain of the immunoglobulin from domains that are broadly shared by antibodies (such as an antibody Fc domain).
  • the variable region comprises a "hypervariable region” whose residues are responsible for antigen binding.
  • the hypervariable region comprises amino acid residues from a "Complementarity Determining Region” or "CDR" (i.e.
  • antibody includes monoclonal antibodies, multi- specific antibodies, human antibodies, humanized antibodies, synthetic antibodies, chimeric antibodies, camelized antibodies (See e.g., Muyldermans, S. et al. (2001) "Recognition Of Antigens By Single-Domain Antibody Fragments: The Superfluous luxury Of Paired Domains," Trends Biochem. Sci. 26:230-235; Nuttall, S.D. et al. (2000) “Immunoglobulin VH Domains And Beyond: Design And Selection Of Single-Domain Binding And Targeting Reagents," Cur. Pharm. Biotech. 1:253-263; Reichmann, L. et al. (1999) "Single domain antibodies:
  • single-chain Fvs see, e.g., see anti-idiotypic (anti-Id) antibodies (including, e.g. , anti-Id and anti-anti-Id antibodies to antibodies of the disclosure).
  • anti-Id antibodies include immunoglobulin molecules of any type (e.g. , IgG, IgE, IgM, IgD, IgA and IgY), class (e.g. , Igd, IgG 2 , IgG 3 , IgG 4 , IgA] and IgA 2 ) or subclass.
  • the term "antigen binding fragment" of an antibody refers to one or more portions of an antibody that contain three light chain CDRs and three corresponding heavy chain CDRs and optionally the framework residues that comprise the antibody's "variable region” antigen recognition site, and exhibit an ability to immunospecifically bind antigen.
  • Such fragments include Fab, F(ab') 2 , Fv, single chain (ScFv),and mutants thereof, naturally occurring variants, and fusion proteins comprising the antibody' s "variable region" antigen recognition site and a heterologous protein (e.g. , a toxin, an antigen recognition site for a different antigen, an enzyme, a receptor or receptor ligand, etc.).
  • fragment refers to a peptide or polypeptide comprising an amino acid sequence of at least 5 contiguous amino acid residues, at least 10 contiguous amino acid residues, at least 15 contiguous amino acid residues, at least 20 contiguous amino acid residues, at least 25 contiguous amino acid residues, at least 40 contiguous amino acid residues, at least 50 contiguous amino acid residues, at least 60 contiguous amino residues, at least 70 contiguous amino acid residues, at least 80 contiguous amino acid residues, at least 90 contiguous amino acid residues, at least 100 contiguous amino acid residues, at least 125 contiguous amino acid residues, at least 150 contiguous amino acid residues, at least 175 contiguous amino acid residues, at least 200 contiguous amino acid residues, or at least 250 contiguous amino acid residues.
  • a humanized or chimeric antibody of the disclosure may comprise substantially all of at least one, and typically two, variable domains in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin (i. e. , donor antibody) and all or substantially all of the framework regions are those of a human immunoglobulin consensus may be selected with respect to the proposed function of the antibody, in particular the effector function which may be required.
  • a non-human immunoglobulin i. e. , donor antibody
  • all or substantially all of the framework regions are those of a human immunoglobulin consensus
  • the constant domains of the antibodies of the disclosure are (or comprise) human IgA, IgD, IgE, IgG or IgM domains.
  • human IgG constant domains, especially of the IgGl and IgG3 isotypes are used, when the humanized antibodies of the disclosure is intended for therapeutic uses and antibody effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement- dependent cytotoxicity (CDC) activity are needed.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement- dependent cytotoxicity
  • PD-1 is highly expressed on T cells as well as rare peripheral T cell lymphomas such as Angioimmunoblastic T-cell lymphoma (AITL).
  • Anti-PD-1 antibodies with ADCC or CDC activity are particularly relevant as therapeutic agents for treating such cancers.
  • IgG2 and IgG4 isotypes are used when the antibody of the disclosure is intended for therapeutic purposes and antibody effector function is not required. For example, if you want to increase the activity of T cells by targeting PD-1 on the surface of T cells, then effector functions that would kill the T cell are undesirable.
  • the disclosure encompasses Fc constant domains comprising one or more amino acid modifications which alter antibody effector functions such as those disclosed in U.S. Patent Application Publication Nos. 2005/0037000 and 2005/0064514.
  • the therapeutic antibodies used in the methods of the present disclosure may be monospecific.
  • bispecific antibodies, trispecific antibodies or antibodies of greater multispecificity that exhibit specificity to one, two or more targets in addition to B7-H1, B7-H4 or PD-1.
  • such antibodies may bind to multiple cell antigens or cellular molecules (e.g., CD4, CD8, CD25, CTLA4, melanin, or a macrophage marker (e.g. , CD14, CD68, CD163, TLR2, etc.).
  • Such bispecific antibodies, trispecific antibodies or antibodies of greater multispecificity may bind, for example, to both B7-H1 and PD-1.
  • Antibodies or fragments thereof with increased in vivo half-lives can multifunctional linker either through site-specific conjugation of the PEG to the N- or C- terminus of said antibodies or antibody fragments or via epsilon-amino groups present on lysine residues.
  • Linear or branched polymer derivatization that results in minimal loss of biological activity will be used.
  • the degree of conjugation will be closely monitored by SDS- PAGE and mass spectrometry to ensure proper conjugation of PEG molecules to the antibodies.
  • Unreacted PEG can be separated from antibody-PEG conjugates by, e.g. , size exclusion or ion-exchange chromatography.
  • the antibodies of the disclosure may also be modified by the methods and coupling agents described by Davis et al. (See U.S. Patent No. 4,179,337) in order to provide compositions that can be injected into the mammalian circulatory system with substantially no immunogenic response.
  • the present disclosure also encompasses antibodies (and more preferably, humanized antibodies) and antigen-binding fragments thereof that are recombinantly fused or chemically conjugated (including both covalently and non-covalently conjugations) to a heterologous molecule (i.e. , an unrelated molecule).
  • the fusion does not necessarily need to be direct, but may occur through linker sequences.
  • the Fc portion of the fusion the fusion protein may be varied by isotype or subclass, may be a chimeric or hybrid, and/or may be modified, for example to improve effector functions, control of half-life, tissue accessibility, augment biophysical characteristics such as stability, and improve efficiency of production (and less costly).
  • the Fc region is the native IgGl, IgG2, or IgG4 Fc region.
  • the Fc region is a hybrid, for example a chimeric consisting of IgG2/IgG4 Fc constant regions.
  • Modifications to the Fc region include, but are not limited to, IgG4 modified to prevent binding to changing expression host), and IgGl with altered pH-dependent binding to FcRn.
  • the Fc region may include the entire hinge region, or less than the entire hinge region.
  • the marker amino acid sequence is a hexa-histidine peptide, the hemagglutinin "HA” tag, which corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et ah , 1984 Cell, 37:767) and the "flag" tag (Knappik et al , 1994 Biotechniques, 17(4):754-761).
  • the term "combination therapy” refers to a treatment of a disease or a method for achieving a desired physiological change, such as increased or decreased response of the immune system to an antigen or immunogen, such as an increase or decrease in the number or activity of one or more cells, or cell types, that are involved in such response, wherein said treatment or method comprises administering to an animal, such as a mammal, especially a human being, a sufficient amount of two or more chemical agents or components of said therapy to effectively treat a disease or to produce said physiological change, wherein said chemical agents or components are administered together, such as part of the same composition, or administered separately and independently at the same time or at different times (i.e., administration of each agent or component is separated by a finite period of time from one or more of the agents or components). In some embodiments, administration of said one or more agents or components in combination achieves a result greater than that of any of said agents or components when administered alone or in isolation.
  • the disclosure pertains to improved methods for characterizing tumors so as to assess the extent to which the tumor cells and/or tumor infiltrating cells or tumor associated cells express cell surface molecules, such as B7-H1, PD-1 and B7-H4, and to distinguish between tumor cells that express such biomarkers and non-tumor cells present within the tumor and/or within the tumor microenvironment.
  • cell surface molecules such as B7-H1, PD-1 and B7-H4
  • the disclosure concerns the uses of such methods in the diagnosis and the treatment of cancer and other diseases.
  • a method for characterizing a cell of a tumor includes determining whether a cell of a tumor expresses B7-H1; and determining whether the cell of the tumor that expresses B7-H1 is a tumor cell or a non-tumor cell.
  • a method for characterizing a cell of a tumor includes determining whether a cell of a tumor expresses B7-H4; and determining whether the cell of the tumor that express B7-H4 is a tumor cell or a non-tumor cell.
  • the methods can include, for example, characterizing cells of a tumor of said patient by determining whether the cells of the tumor express B7-H1 or B7-H4; and determining whether the cells of the tumor that express B7-H1 or B7-H4 are tumor cells or non-tumor cells.
  • the methods can include, for example, characterizing cells of a tumor of the patient during the course of the therapy or after the completion thereof, wherein said characterization can include determining whether the cells of the tumor express B7-H1 or B7-H4; and determining whether said cells of said tumor that express B7-H1 or B7- H4 are tumor cells or non-tumor cells.
  • microenvironment have changed and whether or not cells expressing markers are tumor cells or non-tumor cells.
  • the methods typically include detecting B7-H1, PD-1, and/or B7- H4 alone or in combination with one or more biomarkers of non-tumor cells. Suitable methods of detection are known in the art and discussed above. For example, some of the disclosed methods include a step of contacting the cell of the tumor with: (A) a molecule that immunospecifically or
  • the contacting (A) and (B) are conducted concurrently. In some embodiments, the contacting (A) and (B) are conducted sequentially.
  • the molecule that immunospecifically or physiospecifically binds B7-H1 is an anti-B7-Hl antibody or an antigen- binding fragment thereof. In another embodiment the molecule that immunospecifically or physiospecifically binds B7-H1 includes PD-1 or a B7-Hl-binding portion thereof.
  • Some of the methods include, for example, contacting said cell of the tumor with: (A) a molecule that immunospecifically or physiospecifically binds B7-H4; and (B) a molecule that immunospecifically binds to a biomarker that is characteristic of a non-tumor cell.
  • the contacting (A) and (B) are conducted concurrently.
  • the contacting (A) and (B) are conducted sequentially.
  • B7-H4 physiospecifically binds B7-H4 is an anti-B7-H4 antibody or an antigen- binding fragment thereof.
  • the disclosed methods include contacting the cell of the tumor with more than one molecule, each of which
  • CD3 can be used to differentiate between lymphocytes that expression B7-H1 and those that do not. It will also be appreciated that these are markers that are characteristic of immune cells and can be expressed on neoplastic cells in leukemia / lymphoma. Therefore, in some embodiments, these markers are used to identify non-tumor cells in cancer samples from non-hematological cancers. In preferred embodiments, these are biomarkers of non-tumor cells present in solid tumors.
  • the molecule that immunospecifically or physiospecifically binds B7-H1, PD-1, B7-H4, and biomarkers of non-tumor cells to detect the B7-H1, PD-1, B7-H4, or biomarker of non-tumor cells is an antibody or antigen-binding fragment thereof.
  • the antibody is detectably-labeled.
  • a antibody the immunospecifically or physiospecifically binds B7-H1, PD-1, B7-H4, or biomarker of non-tumor cells is detected using a second antibody that immunospecifically or physiospecifically binds to the first antibody.
  • the second antibody can be detectably-labeled.
  • detection of the molecule, such as an antibody is carried out by immunohistochemistry or immunocytochemistry.
  • the detectable label can be a fluorophore.
  • the method of detection is an in vitro method.
  • the in vitro method comprises immunohistochemical staining, in situ hybridization; or flow cytometry.
  • the method of detection is an in vivo method.
  • the in vivo method comprises computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), and sonography.
  • CT computed tomography
  • PET positron emission tomography
  • MRI magnetic resonance imaging
  • sonography sonography
  • tumor is a solid tumor.
  • tumor is a tumor of an adrenal cancer, a bladder cancer, a bone and connective tissue sarcoma, a brain tumor, a breast cancer, a colon or rectal cancer, an esophageal cancer, cancer, a stomach cancer, a testicular or penile cancer, a thyroid cancer, or a vaginal, ovarian, uterine, or cervical cancer, or a gastric cancer.
  • the non-tumor cell is a macrophage, lymphocyte, leukocyte, stromal cell, or cancer associated fibroblast.
  • B7-H1 expression may also occur on either the tumor, infiltrating macrophages, or both. If there is evidence that B7-H1 is expressed on tumor infiltrating macrophages, subjects with B7-H1 negative tumors can be selected for treatment with PD-1/B7-H1 targeted agents as if they are B7-H1 positive biopsies for diagnosis and/or treatment of the tumor.
  • a lower expression of B7-H1 on TAMs provides an additional or alternative immunosuppressive B7-H1 target for therapeutic intervention to overcome compared to an absence of B7-H1 positive tumors, or alternatively when B7- Hl is broadly expressed across the entire tumor.
  • subjects can be selected for treatment with a PD-1 therapy if the tumor cells, non-tumor cells (particularly TAMs), or both tumor and non-tumor cells of the tumor are found to express B7-H1.
  • subjects that have B7- Hl positive tumor cells, B7-H1 positive TAMs, or both are treated with a PD-1 therapy that blocks PD-1 dependent signaling, but is not cytotoxic to cells expressing B7-H1.
  • subjects that have B7-H1 positive tumor cells, and preferably B7-H1 negative TAMs are treated with a PD-1 therapy that is cytotoxic to cells expressing B7-H1.
  • B7-H4 expression may also occur on either the tumor, infiltrating macrophages, or both. Therefore, additional biomarkers can be used to differentiate which cells, tumor or non-tumor, are expressing the B7-H4 within the tumor microenvironment. If there is evidence that B7-H4 is expressed on tumor infiltrating macrophages, B7-H4 negative tumors may be targeted with B7-H4 targeted agents as if they are B7-H4 positive biopsies for diagnosis and/or treatment of the tumor. For example, subjects can be selected for treatment with a B7-H4 therapy if the tumor cells, non-tumor cells (particularly TAMs), or both tumor and non-tumor cells of the tumor are found to express B7-H4.
  • subjects that have B7- cells expressing B7-H4 are treated with a B7-H4 therapy that is cytotoxic to cells expressing B7-H4.
  • subjects that have B7-H4 negative tumor cells and B7-H4 positive TAMs are treated with a B7-H4 therapy that blocks B7-H4 dependent signaling but is not cytotoxic to cells expressing B7-H4.
  • the present disclosure relates to improved methods for selecting patients who would be amenable for PD- 1 targeted therapies and combination therapies.
  • the disclosure pertains to improved PD- 1 targeted therapies and combination therapies for treating patients who have failed treatment with BRAF/MEK inhibitors or other inhibitors of the RAS-RAF-MEK-ERK pathway.
  • the disclosure further pertains to improved PD- 1 targeted therapies and combination therapies to overcome resistance caused by "tumor dormancy" and to prevent the selection/outgrowth of rapidly, progressing, resistant tumors in the presence of various small molecule inhibitors.
  • prognostic markers capable of providing improved patient selection criteria for PD-1 targeted therapy or other immunotherapies.
  • PD- 1 targeted therapy In order for patients to respond to immunotherapy, such as PD- 1 targeted therapy, they should typically demonstrate a threshold level of immune competency (i.e., a level of immune competency sufficient to allow the immune system to mount a response when an immune stimulatory molecule is administered).
  • a threshold level of immune competency i.e., a level of immune competency sufficient to allow the immune system to mount a response when an immune stimulatory molecule is administered.
  • a number of such prognostic markers have been identified that can be used for patient selection (i. e. , for the identification of "immune responders" or for defining inclusion/exclusion criteria).
  • PD-1 is up-regulated following antigen exposure via TCR engagement and activation of the transcription factor NFAT (Oestreich et al. (2008) “NFATcl Regulates PD-1 Expression Upon T Cell Activation,” J. Immunol. 184(l):476-487). As shown herein, the population of CD4 or
  • CD8 cells that are PD-l ni T cells can be reduced following treatment with PD- 1 targeted therapy in a dose-dependent manner, and reductions are can be sustained through at least the first cycle of treatment.
  • peripheral PD- 1 T cells is a prognostic biomarker for immune
  • the ability to maintain a sustained decrease in PD-1 levels in the periphery is thus a prognostic marker for response to PD-1 targeted therapy.
  • Lactate dehydrogenase is released into the serum from dying cells and is a marker of rapid disease progression in cancer, particularly melanoma.
  • High baseline LDH or rapidly increasing LDH is a biomarker for rising antigen exposure, which leads to increased T cell exhaustion.
  • High baseline LDH is also associated with up-regulation of PD-1 expression. Rapid T cell exhaustion and PD-1 expression may counteract the activity of a PD-1 targeting therapy.
  • cancer patients selected for immunotherapy can have low baseline LDH levels (or be enrolled for treatment before LDH levels reach high levels).
  • LDH levels suitable for immunotherapy treatment are those generally that are ⁇ 2-fold greater than the ULN, and/or which are not increasing rapidly.
  • a level of lactate dehydrogenase that is more than should be monitored to make sure they are stable, or more preferably, decreasing.
  • Patients who exhibit rapid increases in LDH levels following the start of treatment i. e. , within the first couple of months) may be considered for alternative therapy.
  • Absolute lymphocyte counts (ALC) in the peripheral blood are a marker for the ability to mount an immune responsive (immune
  • patients that demonstrate the ability to respond to PD-1 targeting therapy have high ALC counts (> 1000 cells/ ' ⁇ ), and high ALC counts correlated with improved immune function following PD- 1 targeted therapy, as indicated by high intracellular cytokine markers (IFNy, TNFa and IL2) and/or the expression of immune effector genes (TNFRSF9, TNFRSF4, ICOS, KLRG1, CXCL10, CCR2, CXCL9, granzymeA and granzymeB).
  • a rapid decline in ALC over a short period of time is an indicator that the subject may respond poorly to PD-1 targeted therapy, and may require a combination therapy, for example a therapy including a PD- 1 targeted therapy and a second agent that boosts the immune system (e.g., IL-2).
  • a rapid decline in in absolute lymphocyte count over a short period of time can be, for example, a persistent decline of >40 of the ALC count over the course of 2 treatment cycles.
  • each treatment cycle is about 1 month (e.g., 2 treatment cycles can equal two months).
  • a persistent decline excludes acute drops that can be observed immediately or shortly after dosing, which subsequently rebound.
  • Patients demonstrating a low ALC may be treated with an agent to boost lymphocyte counts prior to immune therapy. Suitable pre-treatment introduced into the patient by adoptive cell therapy (ACT) prior to immune therapy. ALCs should be monitored with treatment as a metric for improved immune function and responsiveness. No increase in ALCs with treatment over time may indicate that the patient is not responding to immune therapy and not a good candidate for such therapy.
  • a baseline absolute lymphocyte count that is less than approximately 1000 cells/ ⁇ L can be predictive of a patient's enhanced suitability for treatment with a PD-1 targeted combination therapy, particularly where the combination therapy causes an increase in ALC levels.
  • Fresh tumor biopsies taken at baseline can be used to measure the number of tumor infiltrating lymphocytes (TILs) in a tumor.
  • Patients that demonstrate a high number of TILs e.g. , greater than 100 per high powered microscope field (hpf)
  • hpf high powered microscope field
  • a baseline tumor infiltrating lymphocyte count that is less than approximately 100 cells/hpf is predictive of a patient's enhanced suitability for treatment with a PD-1 targeted combination therapy.
  • TILs can be identified by immunohistochemistry of tumor sections that is capable of differentiating lymphocytes from tumor cells (e.g. , staining sections for CD8 or PD-1).
  • Post therapy tumor biopsies can be used to monitor TILs in response to immune therapy, and an increase in TILs is representative of a response to immune therapy.
  • the methods relate to selecting patients who would be amenable for PD-1 and/or B7-H4 targeted therapies response to the tumor. Accordingly, prognostic markers/patient selection criteria for PD-1 and/or B7-H4 targeted therapy are provided.
  • PD- 1 targeted therapy for the rescue of patients who have failed treatment with BRAF/MEK inhibitors or other inhibitors of the RAS-RAF-MEK-ERK pathway are provided.
  • Such PD-1 targeted therapy can overcome treatment resistance caused by "tumor dormancy" and prevent the selection/outgrowth of rapidly, progressing, resistant tumors in the presence of various small molecule inhibitors.
  • this can involve unique monotherapy approaches following treatment failure and/or combinatorial approaches that are more potent and allow for lower concentrations of the combination drug being used (for example, combination therapy including a PD-1 targeted therapy in combination with a BRAF /MEK (or other kinase) inhibitors to enhance overall tumor responses and efficacy, particularly PD- 1 targeted therapy with ligand independent activity).
  • combination therapy including a PD-1 targeted therapy in combination with a BRAF /MEK (or other kinase) inhibitors to enhance overall tumor responses and efficacy, particularly PD- 1 targeted therapy with ligand independent activity.
  • improved PD- 1 targeted therapies and combination therapies for treating patients who have failed treatment (and preventing treatment failure that is frequently observed) with BRAF/MEK inhibitors or other inhibitors of the RAS-RAF-MEK-ERK pathway are also provided and discussed in more detail below.
  • Improved PD-1 targeted therapies and combination therapies to overcome treatment resistance caused by "tumor dormancy" and to prevent the selection/outgrowth of rapidly, progressing, resistant tumors in the presence of various small molecule inhibitors are also provided and discussed in more detail below.
  • the disclosure includes solutions to the problem of identifying and/or selecting immune competent patients most likely to respond to PD-1 and/or B7-H4 targeted therapy and to the problem of monitoring the response of such patients over time using immune competency prognostic markers. Furthermore, the disclosure includes solutions to the problem of providing rescue and combination treatments to overcome/prevent tumor resistance to cancer therapy (particularly cancer the efficacy for RAS-RAF-MEK-ERK pathway inhibitors (and other agents that induce homeostatic proliferation of immune cells) as well as to enhance the immunomodulatory effects of PD-1/B7-H4 targeted molecules (fusion proteins and antibodies etc.).
  • the disclosures addresses these problems by combining existing therapeutic approaches with PD-1 and/or B7-H4 targeted therapies (and other therapeutics that target key-co-stimulatory pathway molecules that may be up-regulated following treatment with such inhibitors).
  • a PD-1 targeted therapy includes the administration of an immunomodulatory molecule such as a PD- 1 -binding fusion protein/antibody (e.g. , an anti-PD-1 antibody, a B7-DC-Ig, a B7-Hl-Ig, etc.) with a BRAF inhibitor ("BRAFi”) or other small molecule up-front (i.e. , as an initial treatment regimen), and particularly as long as:
  • an immunomodulatory molecule such as a PD- 1 -binding fusion protein/antibody (e.g. , an anti-PD-1 antibody, a B7-DC-Ig, a B7-Hl-Ig, etc.) with a BRAF inhibitor ("BRAFi”) or other small molecule up-front (i.e. , as an initial treatment regimen), and particularly as long as:
  • an immunomodulatory molecule such as a PD- 1 -binding fusion protein/antibody (e.g. , an anti-PD-1 antibody, a B
  • the small molecules do not impair T cell/immune responses;
  • the treatment is used in patients with appropriate mutations for target molecules (e.g., BRAF mutants and PD-1 positive).
  • target molecules e.g., BRAF mutants and PD-1 positive.
  • target molecules e.g., BRAF mutants and PD-1 positive.
  • the small molecule(s) may enhance T cell responses leading to further synergy/additive effects with the upfront combination, using the correct staging.
  • the present disclosure is thus also directed to the solution of the problem of enhancing immune responses through up-front combination therapies.
  • the present disclosure thus derives in part, from the discovery that in patients refractory to treatment with BRAF/MEK inhibitors or other inhibitors of the RAS-RAF-MEK-ERK pathway, tumors that are refractory to treatment with such inhibitors or with other inhibitors of the RAS-RAF- MEK-ERK pathway can be effectively treated by targeting key
  • Such treatment can involve monotherapy approaches (i. e. , treatment with a single drug) following treatment failure and/or embodiment, agents that target PD-1 are employed to rescue patients who have failed prior MEK/BRAF inhibitor treatment and/or prior ipilimumab (anti-CTLA-4 antibody) treatment.
  • monotherapy approaches i. e. , treatment with a single drug
  • agents that target PD-1 are employed to rescue patients who have failed prior MEK/BRAF inhibitor treatment and/or prior ipilimumab (anti-CTLA-4 antibody) treatment.
  • combination or rescue treatments utilizing PD- 1 targeted therapies in combination with (or following) drug treatments targeting the RAS-RAF-MEK-ERK pathway
  • a method for determining whether a cancer patient suffers from a cancer having enhanced suitability for treatment with a PD-1 targeted monotherapy or a PD-1 targeted combination therapy includes evaluating tissue or fluid of the patient to ascertain the level of a prognostic biomarker correlative of immune system responsiveness.
  • the method can include providing the patient with the PD- 1 targeted
  • the evaluating includes removing the tissue or fluid from the patient, and/or wherein the evaluation of the tissue or fluid of the patient includes immunohistochemical staining, in situ hybridization; gene expression analysis (e.g., bDNA, qRT-PCR, or microarray analysis), or flow cytometry (including, for example, FACS assays that assess cell surface expression and/or FACS assays that assess intracellular expression).
  • gene expression analysis e.g., bDNA, qRT-PCR, or microarray analysis
  • flow cytometry including, for example, FACS assays that assess cell surface expression and/or FACS assays that assess intracellular expression.
  • the prognostic marker is the baseline:
  • lymphocytes lymphocytes
  • the methods include evaluating the level of at least two of the prognostic biomarkers, or three, four or more of the prognostic biomarkers.
  • At least one of the prognostic biomarkers is the level of peripheral CD4 + or CD8 + cells that are PD-1 HI cells, and wherein:
  • PD- 1 target therapy includes administering the subject a B7-DC-Ig fusion protein.
  • At least one of the prognostic biomarkers is lactate dehydrogenase, and wherein:
  • a level of lactate dehydrogenase that is within, or less than two-fold greater than, the upper level of normal (ULN) is predictive of the patient's enhanced suitability for treatment with a PD-1 targeted monotherapy or combination therapy;
  • a level of lactate dehydrogenase that is more than two-fold greater than the upper level of normal (ULN) is predictive of the patient's reduced suitability for treatment with a PD-1 targeted monotherapy or combination therapy.
  • the tumor in such embodiments is a melanoma.
  • A a baseline absolute lymphocyte count that is equal to or greater than approximately 950 e ⁇ / ⁇ L ⁇ is predictive of the patient's enhanced suitability for treatment with a PD-1 targeted monotherapy;
  • a baseline absolute lymphocyte count that is less than said baseline absolute lymphocyte count is predictive of the patient's enhanced suitability for treatment with a PD-1 targeted monotherapy or combination therapy.
  • the absolute lymphocyte count is determined using an intracellular cytokine lymphocyte marker selected from the group consisting of: IFNy, TNFa and IL2.
  • At least one of the prognostic biomarkers is a baseline tumor infiltrating lymphocyte count, and wherein:
  • a baseline tumor infiltrating lymphocyte count that is equal to or greater than approximately 50-100 cells per high powered microscope field is predictive of the patient's enhanced suitability for treatment with immunotherapy, such as a PD- 1 targeted monotherapy or combination therapy;
  • a baseline tumor infiltrating lymphocyte count that is less than the baseline tumor infiltrating lymphocyte count of approximately 50-100 cells per high powered microscope field is predictive of the patient' s enhanced suitability for
  • the prognostic biomarker is gene expression of CD8A, FCGR3A, CTLA4, PDl, FASLG, CCL3, CXCL9, CXCL10, or GZMA in a tumor biopsy specimen.
  • Suitable immunotherapies including PD-1 therapies, and particularly PD-1 combination therapies are discussed in more detail below. However, in some particular embodiments,
  • an anti-PD-1 antibody includes administration of an anti-PD-1 antibody, a PD-1- binding fragment of an antibody, or a B7-DC-Ig fusion molecule, and/or
  • (B) includes the administration of an agent that targets a co- stimulatory pathway molecule that is up-regulated following treatment with a RAS-RAF-MEK-ERK inhibitor, or
  • (C) includes administration of cyclophosphamide
  • (D) includes the administration of a BRAFi or other small molecule, as an initial treatment regimen.
  • Methods of determining patient suitability for participation in a trial for the safety and/or efficacy of a PD-1 targeted cancer therapy are also provided.
  • the method can include determining whether tissue or fluid of a candidate patient for the trial possesses:
  • tumor cells of a subject are analyzed for expression of both B7-H1 and B7-H4 according to one or more of the methods disclosed herein. If the tumor cells of the subject express both B7- HI and B7-H4 the subject can be selected for B7-H4 targeted therapy alone or in combination with PD- 1 targeted therapy and/or administration of a second therapeutic agent such as cyclophosphamide.
  • a second therapeutic agent such as cyclophosphamide.
  • tumor is a solid tumor.
  • tumor is a tumor of an adrenal cancer, a bladder cancer, a bone and connective tissue sarcoma, a brain tumor, a breast cancer, a colon or rectal cancer, an esophageal cancer, an eye cancer, a kidney cancer, a leukemia, a lymphoma, a multiple myeloma, a liver cancer, a lung cancer, a pancreatic cancer, a pharyngeal cancer, a pituitary cancer, an oral cancer, a salivary gland cancer, a skin cancer, a stomach cancer, a testicular or penile cancer, a thyroid cancer, or a vaginal, ovarian, uterine, or cervical cancer, or a gastric cancer.
  • PD-1 targeted therapy such as a molecule that binds PD-1 (e.g. , soluble B7- DC fused to an Ig (B7-DC-Ig, or soluble B7-H1 fused to an Ig), should include these markers of immune competency.
  • Patients that demonstrate all three criteria i.e. , ALC >1000); CD8 TILs >100/hpf; and LDH (within ULN)) are particularly suitable for such PD-1 targeted therapy.
  • the PD- 1 targeted therapy can be combined with not demonstrate one or more of the immune competency markers are better suited to combination therapy that combines PD- 1 targeted therapy with an immune stimulator capable of improving one or more immune competency markers, such as IL2 or GMCSF.
  • B7-H1 expression by tumors is associated with immune evasion by the tumor. Furthermore, ⁇ -interferon (IFNy) expression by TILs in the tumor microenvironment up-regulates B7-H1 expression by tumor cells. Therefore, B7-H1 expression in tumor biopsies has been used as a selection criterion for PD-1 targeted therapy wherein B7-H1 expression must be present for a PD-1 targeted therapy to function, particularly as it relates to therapies that block PD-1 binding to its ligands.
  • one aspect of the present disclosure relates to the recognition that B7-H1 expression by tumor cells represents an active and evolving immune response rather than a required pre-disposition for PD-1 targeted therapy.
  • B7-H1 expression in the tumor is co-localized with infiltrating TILs (as determined by CD8 or PD-1 staining), with localized expression of IFNy by TILs leading to B7-H1 expression. Therefore, co-localization of CD8 TILs and B7-H1 in the tumor represents an "immune front," which is necessary for response to immune therapy.
  • B7-H1 expression and TILs in the tumor microenvironment, it is desired to stain multiple serial tumor sections, since the expression of markers and the infiltration of TILs can be highly heterogenous within the tumor. Furthermore, when studying B7-H1 associated macrophages (TAMs). Expression of B7-H1 on TAMs (or other cell types) can be differentiated using cell surface markers that are specific for different cell types. For example, B7-H1 expression on TAMs can be determined by dual staining for B7-H1 in conjunction with a TAM- specific marker such as CD68.
  • TAMs B7-H1 associated macrophages
  • any of the methods described herein can include one or more steps of detecting PD-1, B7-H1, B7-H4, any of the prognostic biomarkers discussed herein, or any combination thereof.
  • B7-Hl-binding molecules, B7-H4 binding molecules or PD-1 -binding molecules can used for the in vitro or in vivo analysis of B7-H1, B7-H4 or PD-1 expression, respectively, by tumor and/or non-tumor cells in conjunction with agents that specifically detect other cell biomarkers in order to differentiate and characterize specific cells types.
  • the prognostic biomarkers are assessed immunohistochemically by staining or using FACS, etc. using one or a plurality of binding molecules specific for the prognostic biomarker of
  • peripheral PD-1 levels e.g. , peripheral PD-1 levels, LDH release, baseline ALC levels, baseline TIL levels, etc.
  • biomarker-specific molecule e.g. , a soluble molecule that binds to ALC or TIL cells or that is specific for LDH or PD-1, or a fusion molecule thereof
  • detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radioactive materials, positron emitting metals, and nonradioactive paramagnetic metal ions.
  • the detectable substance may be coupled or conjugated either directly to the biomarker- specific molecule or secondary antibody or indirectly, through an intermediate (such as, for example, a linker known in the art) using techniques known in the art. See, for example, U.S. Patent No.
  • 4,741,900 for antibody to detectable substances including, but not limited to, various enzymes, enzymes including, but not limited to, horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; prosthetic group complexes such as, but not limited to, streptavidin/biotin and avidin/biotin; fluorescent materials such as, but not limited to, umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; luminescent material such as, but not limited to, luminol; bioluminescent materials such as, but not limited to, luciferase, luciferin, and aequorin; radioactive material such as, but not limited to, bismuth ( 213 Bi), carbon ( 14 C), chromium ( 51 Cr), cobalt ( 57
  • the molecules may be attached to solid supports, which are particularly useful for immunoassays of the target antigen.
  • solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene.
  • the characterization of the cellular expression of the desired biomarkers will be accomplished in vitro using an antibody (or antigen binding fragment thereof) to human B7-H1, B7-H4 or PD-1 in conjunction with antibodies that bind to one or more additional biomarkers.
  • an antibody or antigen binding fragment thereof
  • the evaluation of the biomarker(s) will be accomplished using histochemical stains, fluorescence in situ
  • FISH fluorescent in situ hybridization
  • CISH chromogenic in situ hybridization
  • SISH silver-enhanced in situ hybridization
  • Pleural Neoplasia Arch. Pathol. Lab. Med. 132(7): 1062-1072; Erratum in: Arch. Pathol. Lab Med. (2008) 132(9): 1384; Olsen, J. et al. (2008) "Acute Leukemia Immunohistochemistry: A Systematic Diagnostic Approach " Arch. Pathol. Lab. Med. 132(3):462-475; Hoei-Hansen, C.E. et al. (2007) "Current Approaches For Detection Of Carcinoma In Situ Testis,” Int. J. Androl.
  • the evaluation of the biomarker(s) will be accomplished in vitro using an antibody (or an antigen binding fragment thereof) that, for the evaluation of peripheral PD-l/LDH, immunospecifically or physiospecifically binds to LDH or PD-1 ; for the evaluation of ALC
  • One aspect of the disclosure relates to the use of antibodies and fragments, and particularly such antibodies and fragments that bind to human B7-H1, B7-H4 or PD-1 in conjunction with antibodies that bind to one or more additional biomarkers, as reagents for IHC analysis in cells in vivo.
  • the size of the subject and the imaging system used will determine the quantity of imaging moiety needed to produce diagnostic images. In vivo tumor imaging is described in S.W. Burchiel et al. , "Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments.” (Chapter 13 in Tumor Imaging: The Radiochemical Detection of Cancer, S.W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. (1982).
  • the time interval following the administration for permitting the labeled molecule to preferentially concentrate at sites in the subject and for unbound labeled molecule to be cleared to background level is 6 to 48 hours or 6 to 24 hours or 6 to 12 hours.
  • the infection for example, one month after initial diagnosis, six months after initial diagnosis, one year after initial diagnosis, etc.
  • Presence of the labeled molecule can be detected in the subject using methods known in the art in vivo scanning. These methods depend upon the type of label used. Skilled artisans will be able to determine the appropriate method for detecting a particular label. Methods and devices that may be used in the diagnostic methods of the disclosure include, but are not limited to, computed tomography (CT), whole body scan such as position emission tomography (PET), magnetic resonance imaging (MRI), and sonography.
  • CT computed tomography
  • PET position emission tomography
  • MRI magnetic resonance imaging
  • sonography sonography
  • the molecule is labeled with a radioisotope and is detected in the patient using a radiation responsive surgical instrument (Thurston et ah, U.S. Patent No. 5,441,050).
  • the molecule is labeled with a fluorescent compound and is detected in the patient using a fluorescence responsive scanning instrument.
  • the molecule is labeled with a positron emitting metal and is detected in the patient using positron emission-tomography.
  • the molecule is labeled with a paramagnetic label and is detected in a patient using magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • Methods of administering the molecules of the disclosure for in vivo diagnostic use include, but are not limited to, parenteral administration (e.g. , intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous), epidural, and mucosal (e.g. , intranasal and oral routes).
  • parenteral administration e.g. , intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous
  • epidural e.g. , epidural and mucosal
  • mucosal e.g. , intranasal and oral routes.
  • the antibodies of the disclosure are administered
  • compositions may be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g. , oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. See, e.g. , U.S. Patent Nos. 6,019,968; 5,985, 20;
  • carrier refers to a diluent, excipient, or vehicle.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the time interval following the administration for permitting the labeled molecule to preferentially concentrate at sites in the subject and for unbound labeled molecule to be cleared to background level is 6 to 48 hours or 6 to 24 hours or 6 to 12 hours. In another embodiment the time interval following administration is 5 to 20 days or 5 to 10 days.
  • monitoring of a disease, disorder or infection is carried out by repeating the method for diagnosing the disease, disorder or infection, for example, one month after initial diagnosis, six months after initial diagnosis, one year after initial diagnosis, etc.
  • Presence of the labeled molecule can be detected in the subject using methods known in the art in vivo scanning. These methods depend upon the type of label used. Skilled artisans will be able to determine the appropriate method for detecting a particular label. Methods and devices that may be used include, but are not limited to, computed tomography (CT), whole body scan such as position emission tomography (PET), magnetic resonance (Thurston et ah , U.S. Patent No. 5,441,050).
  • CT computed tomography
  • PET position emission tomography
  • PET magnetic resonance
  • the molecule is labeled with a fluorescent compound and is detected in the patient using a fluorescence responsive scanning instrument.
  • the molecule is labeled with a positron emitting metal and is detected in the patient using positron emission-tomography.
  • the molecule is labeled with a paramagnetic label and is detected in a patient using magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • Methods of administering the molecules of the disclosure for in vivo diagnostic use include, but are not limited to, parenteral administration (e.g. , intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous), epidural, and mucosal (e.g. , intranasal and oral routes).
  • parenteral administration e.g. , intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous
  • epidural e.g. , epidural and mucosal
  • mucosal e.g. , intranasal and oral routes.
  • the antibodies of the disclosure are administered
  • compositions may be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g. , oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. See, e.g., U.S. Patent Nos. 6,019,968; 5,985, 20;
  • carrier refers to a diluent, excipient, or vehicle.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • any of the disclosed methods of detection, diagnosis, or selection can be linked to a method of treatment.
  • the methods typically include administered a subject a PD-1 targeted therapy or a B7-H4 targeted therapy.
  • the PD-1 targeted therapy or B7-H4 targeted therapy is co-administered in combination with a second therapeutic agent.
  • the methods include the use of PD- 1 targeted therapies and combination therapies that include such PD- 1 targeted therapies in the treatment of individuals who have been selected based on an evaluation of any one, two or, more preferably, all of the above- described prognostic markers.
  • prognostic markers can be used as inclusion criteria for a clinical trial involving PD-1 targeting agents.
  • targeting PD-1 can rescue melanoma patients (including ocular melanoma patients) who have failed MEK/BRAF treatment and/or ipilimumab treatment prior therapies.
  • the administration of a PD- 1 targeted therapy can rescue patients suffering from other tumors involving the RAS-RAF-MEK-ERK pathway. Exemplary combinations are discussed in more detail below.
  • Suitable PD-1 targeted therapies include anti-PD-1 antibodies, anti-PD-1 antibody antigen-binding fragments, and fusion proteins such as a B7-DC-Ig or B7-Hl-Ig.
  • An analysis of real-time data from patient samples indicates that one may identify those patients at high risk of rapid disease progression upon relapse with a BRAF inhibitor (and possibly other therapies) who might not have time to subsequently complete PD-1 targeted therapy (or any other proposed immunomodulatory therapy) because they are immune
  • the present disclosure additionally provides a PD-1 targeted therapy in which immune responses of a patient are enhanced through the administration of up-front combination therapies that involve an immunomodulatory molecule, such as a PD-1 -binding fusion
  • protein/antibody e.g. , an anti-PD-1 antibody, a B7-DC-Ig, a B7-Hl-Ig, etc.
  • BRAFi or other small molecule, up-front (i.e. , as an initial treatment regimen), and particularly as long as:
  • the treatment is used in patients with appropriate mutations for target molecules (e.g., BRAF mutants and PD-1 positive).
  • target molecules e.g., BRAF mutants and PD-1 positive.
  • Such an approach is a synergistic/additive effect strategy that may be cell responses leading to further synergy/additive effects with the upfront combination, using the correct staging.
  • BRAF- mutation positive patients i.e. , patients having a mutation in their BRAF gene, and particularly the V600E and V600K BRAF mutations
  • PD- 1 targeted therapies such as those described above
  • Braf inhibitor/chemotherapy are also provided.
  • Benefits of such treatments include limiting the outgrowth of resistant tumor cell types, thereby prolonging the efficacy of treatment, improving response and survival. It is particularly desirable for such combination therapy to be provided early in the progression of the disease, since the early
  • administration of the combined therapy enhances the immune response repertoire and generates a diverse response to the tumor, thereby minimizing its ability to escape treatment via such mutation, selection, etc.
  • Tumor dormancy Long term tumor dormancy can occur when residual cancer cells develop strategies to escape cell death and exist in equilibrium with the immune system of the host (Quesnel, B. "Tumor Dormancy: Long-Term Survival in a Hostile Environment," In: SYSTEMS BIOLOGY OF TUMOR DORMANCY, ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY (H. Enderling et al., Eds.), Springer Science+Business Media, NY; Chapter 9, pp. 181-200; Quesnel, B. (2008) “Tumor Dormancy And Immunoescape," APMIS 116(7-8):685-94; Quesnel, B.
  • Dormant tumor cells frequently express immune checkpoint markers such as B7-H1 (and B7.1) that inhibit effector T cell function by inducing T cell exhaustion, and can be under selective pressure from maintenance treatments involving the administration of cytotoxic drugs or small molecule kinase inhibitors.
  • Continuous drug treatment of tumors containing such cells selects for the growth of drug-resistant cells that are also resistant to autologous immune responses. Accordingly, after variable lengths of time the dormancy ends, and the cancer cells resume their growth, resulting in disease progression. This may be the result of the development of nonspecific resistance mechanisms, such as deregulation of the JAK/STAT and mTORC2/AKT pathways.
  • the resistance mechanisms that have been selected may result in more aggressive tumor sub-clones and in tumor relapses that are more difficult to treat.
  • immunotherapy such as PD- 1 targeted immunotherapy
  • targeted cancer therapy in providing such combined treatment early in the cancer treatment regime.
  • the addition of such immunotherapy will enhance immune responses and will act to prevent the establishment of an immune equilibrium capable of protecting dormant tumor cells.
  • Such prevention of immune equilibrium is particularly beneficial where the immunotherapy has ligand independent activity and is able to modulate T cell activity directly.
  • preventing immune equilibrium will limit the ability of the tumor cells to survive and develop resistance and the outgrowth of more aggressive tumor cell populations, thus enhancing the efficacy of cytotoxic drugs or small molecule kinase inhibitors.
  • combination therapies including a PD- 1 targeted immunotherapy and a cancer targeted therapy are provided.
  • such combinations are administered at a time and dosage effective to reduce, D.
  • Other Combination Therapies including a PD- 1 targeted immunotherapy and a cancer targeted therapy are provided.
  • PD-1 or B7-H4 targeted therapies can be combined with: (1) agents/drugs that effect tumor proliferation, growth and/or progression by direct effects on the tumor, or (2) agents/drugs that induce homeostatic proliferation on infiltrating and circulating immune cells that are directed against the tumor.
  • agents/drugs that effect tumor proliferation, growth and/or progression by direct effects on the tumor or (2) agents/drugs that induce homeostatic proliferation on infiltrating and circulating immune cells that are directed against the tumor.
  • the latter approach (2) is based upon the recognition that immune enhancing agents such as PD-1 targeted therapeutics may best be able to reverse tolerance under conditions of homeostatic proliferation.
  • PD-1 or B7-H4 targeted therapy particularly therapies with ligand independent activity, include combination with radiation therapy, anti-CTLA4 (ipilimumab) and anti-tumor vaccines.
  • CTLA4 anti-CTLA4
  • anti-tumor vaccines anti-tumor vaccines.
  • a preferred combination and trial for PD- 1 targeted therapy employs a differentiated approach sufficient to allow for rapid accrual in the competitive space.
  • patients with a high unmet medical need where PD- 1 pathway plays an important role are targeted, with a focus on different indications from those met by anti-PD-1 antibodies (for example: ovarian cancer (especially ovarian cancer that is platinum sensitive, (“NSCLC”), head and neck cancer, melanoma; and in combination with low dose cyclophosphamide therapy (“CTX").
  • NSCLC platinum sensitive,
  • CTX low dose cyclophosphamide therapy
  • a second preferred combination and trial for PD- 1 targeted therapy employs the first-line standard of care ("SOC") used in early tumor development in combination with chemotherapeutic agents having immunostimulatory activity.
  • SOC first-line standard of care
  • Such an approach is particularly desirable in the treatment of ovarian cancer (e.g. , in combination with
  • carboplatin/paclitaxel triple negative breast cancer (e.g. in combination with paclitaxel, docetaxel or doxorubicin), NSCLC (e.g. , in combination with carboplatin/paclitaxel).
  • Differential staining between B7-H1 or B7-H4 (and other co- stimulatory proteins etc.) expression on tumors versus TAMs or other immune cells will enhance the understanding of how mechanisms of immune suppression and clinical response are related, and how patients may be treated.
  • Differential staining to verify the presence of TILs, B7-H1+ TAMs and/or B7-H1+ tumors (as well as other co-stimulatory markers such as B7- H4 etc.) provides clarification on which key cellular subsets within the tumor microenvironment may be beneficial therapeutic targets, which are predictive biomarkers for patient response to therapies targeting the immune checkpoint pathways. Such an approach will aid in optimizing treatment regimens, combination approaches and patient selection for the next generation of immunomodulatory therapies, as well as other treatments that affect the tumor microenvironment.
  • tumors expressing B7-H1 are thought to respond best to an anti-PD- 1 therapeutic.
  • alternative therapies that mitigate the suppressive effect of TAMs may be more appropriate.
  • Staining for additional markers of suppression on TAMs e.g. B7-H4, LAG3 etc.
  • may suggest the administration of other immunomodulatory drugs e.g. anti-B7-
  • the distinct cellular patterns of B7-H1 expression may be elucidated to further refine the predictive value of this biomarker in clinical trials that target the PD-1 pathway and that are using the B7-H1 as a primary or sole selection marker. For example, a patient thought to be B7- H1+ may be responding but the tumor itself may actually be B7-H1-.
  • a patient is excluded based on a lack of B7-H1 staining, such excluded patient might be a potentially responsive patient.
  • a patient is selected for treatment where B7-H1+ staining is from a non-tumor cell, such a patient may not respond to a treatment that is specific for the PD- 1 pathway, such as an anti-B7-Hl, B7-DC-Ig or anti-PD- 1.
  • a treatment that is specific for the PD- 1 pathway such as an anti-B7-Hl, B7-DC-Ig or anti-PD- 1.
  • staining is limited to small areas of the tumor sample.
  • B7-H1 is not heterogeneously expressed throughout the tumor and B7-H1 staining across the tumor can also be highly variable; some areas of the tumor or some tumor sections may be B7-H1+, whereas other areas may be B7-H1- or necrotic. Therefore, it may be important to stain multiple sections or tumors to fully assess the B7-H1 (or B7-H4) status of a patient' s tumor(s) and use additional markers in combination to assess whether such staining relates to tumor or non-tumor cells. Also, staining for B7-H1 can be highly correlated CD8 (and PD-1) i.e.
  • CD8 may be used as a correlative readout.
  • CD8 may provide a better assessment of T cell infiltration and potential response, and ii) it is useful to use both stains to get a good sense of the proportion of tumor infiltrating lymphocytes that are PD- 1 high and thus potentially exhausted, and thus whether a patient may respond to an immunomodulatory treatment. It may also be beneficial to monitor other markers, such as those for TAMs, in order to monitor response to therapy. For example, B7-H1 staining of tumor cells may stay high, but a reduction in TAMs may indicate an immune response, and such tumors may benefit from treatments that enhance T cell activity (e.g., IL-2).
  • IL-2 enhance T cell activity
  • Elevated levels of IFN-gamma in tumors and within the tumor correlate with enhanced expression of B7-H1 on tumor cells or within the tumor microenvironment (perhaps a negative feedback, regulatory mechanism).
  • Changes in B7-H1 expression levels may occur following specific chemotherapeutic and biologic therapies, or other therapeutic interventions (e.g. radiation, cryoablation, surgical resection of the tumor etc.) that can also trigger changes that enhance IFN-gamma and induce B7- Hl expression.
  • enhanced IFN-gamma levels can be stimulated by a variety of factors, including tumor necrosis, chemotherapeutic tx, radiation, etc. It is precisely these patients who may benefit most from therapies targeting immune checkpoint pathways, such as B7-H1/PD-1.
  • the present disclosure is also directed to a method for selecting patients for anti-cancer therapy based on characterization of the tumor or tumor microenvironment.
  • cancer patient tumor samples are characterized following treatment with following specific
  • chemotherapeutic and biologic therapies or other therapeutic interventions (e.g. radiation, cryoablation, surgical resection of the tumor etc.) that can trigger changes in B7-H1 expression as indicated above.
  • therapeutic interventions e.g. radiation, cryoablation, surgical resection of the tumor etc.
  • expression of B7-H1 in melanoma patients has been shown following Brafi treatment, and thus may be responsive to therapies targeting the B7-H1/PD-1 pathway. Therefore, treatment with therapies targeting the B7-H1/PD-1 pathway may be a good option for patients that fail to respond to other therapies, including but not limited to, Braf and MEK inhibitors.
  • the disclosure provides a diagnostic kit comprising one or more containers containing a reagent capable of detecting a prognostic biomarker.
  • the kit may also comprise one or more containers containing ingredient(s) for facilitating the characterization of tumor and/or non-tumor cells.
  • Optionally associated with such container(s) can be instruction protocols and/or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human provided by way of illustration and are not intended to be limiting of the present disclosure unless specified.
  • FIG. 1 illustrates the scoring of B7-H1 expression using a scaled score that ranges from 0 (negative) to 3 (intense positive stain).
  • melanoma tumors contain expressed melanin and thus stain darkly irrespective of their B7-H1 staining.
  • Melanin is cytoplasmic and highly blobby/granular. In optimal samples, such staining may be distinguished from the sharp, intense peripheral staining associated with B7-H1 expression.
  • biopsy samples from melanoma tumors may have been subjected to sub-optimal fixation and processing since B7-H1 stains are acceptable after 48 hrs of formalin fixation, but are optimal only after 144 hr of formalin fixation.
  • the DAB chromagen can be picked up non-specifically at the edge of a diffuse stain in a granular pattern. Additionally, such necrotic tissue contains many macrophages (not necessarily TAMs), which express B7-H1 ( Figure 4).
  • Tumor-associated B7-H1+CD68+ macrophages have been observed to be present within tumors ( Figure 4).
  • Such macrophages can have membraneous or cytoplasmic B7-H1 expression (e.g. lung biopsies can reveal large numbers of infiltrating macrophages that accumulate brown pigment).
  • Macrophages that express B7-H1 and do not express CD68 can be distinguished by their small nuclei as opposed to tumors with large pleomorphic nuclei.
  • B7H1+ tumor with CD68+/B7H1- TAMs nearby As illustrated in Figure 5, Left Panel, immunohistochemical analysis appears to show the presence of B7-H1+ tumor cells. However, the same biopsy sample, when stained using a dual CD68/B7-H1 stain shows that the tumor is B7-H1- and that the detected expression of B7-H1 actually reflects the presence of CD68+ B7- H1+ macrophages (Figure 5, Right Panel).
  • Figure 6 shows an example in which a few interspersed melanoma tumor cells express B7-H1. The expression of B7-H1 on the tumor has been confirmed by the dual CD68/B7- Hl stain. Thus, B7-H1 expression may occur on either the tumor, infiltrating macrophages, or both.
  • FIG. 7 illustrates this recognition by showing the sustained expression in the tumor and the periphery (Sfanos et al. (2009) "Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+," Prostate 69(15): 1694-1703; and Shi et al. (2011) “PD-1 and PD-L1 upregulation promotes CD8( + ) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients,” 128(4):887-896;
  • peripheral changes mimic the changes that are occurring in the tumor microenvironment.
  • Figures 8-11 show the H&E stains from three fresh biopsies of a metastatic neck lymph node taken from the patient while receiving treatment with a PD-1 binding agent.
  • the pre-treatment biopsy was performed on prior to therapy, the first post treatment biopsy was performed on Cycle 1, Day 15 (C1D15) following 1 dose of the PD-1 binding molecule.
  • the second post treatment biopsy was taken on Cycle 2, Day 15 (C2D15) following three doses of the PD- 1 binding molecule. Each cycle was a month long.
  • This biopsy contains mostly fibrotic/necrotic tumor tissue with distinct pockets of lymphocyte infiltrates at the edges. The presence of tumor cells was confirmed with S100 stain.
  • the biopsies, along with an archival specimen that was taken prior to the patient' s treatment with the BRAFi/MEKi were evaluated via immunohistochemical staining for B7-H1, PD-1, CD8, CD4 and FoxP3 ( Figure 9 and Figure 11 (Panels A-D)).
  • TILs An increase in TILs was observed following BRAFi/MEKi therapy, which was sustained following treatment with a PD-l-binding molecule (Figure 10; the PD-1 IHC stain may be detecting PD-1 (HI) and PD-l(LO) T cells; for the C2D15 biopsy, the reduction in tumor volume results in a higher TIL:tumor ratio).
  • Panels A-D show multiple tumor biopsies from a cancer patient.
  • B7-H1 expression Prior to BRAFi/MEKi therapy (Panel A) B7-H1 expression was scored as 1 ; after such therapy but prior to therapy with a PD- 1 binding molecule (Panel B), B7-H1 expression was scored as 3.
  • Post-treatment confirms the occurrence of change in B7-H1 expression within the tumor microenvironment as a consequence of the cancer therapy.
  • FIG. 12A is a photo image of tumor cells expressing B7-H1 in a biopsy taken from a BRAF mutant melanoma patient who has failed BRAFi therapy.
  • Changes in B7-H1 expression levels may occur following specific chemotherapeutic and biologic therapies, or other therapeutic interventions (e.g. radiation, cryoablation, surgical resection of the tumor etc.) that can also trigger changes that enhance IFN-gamma and induce B7- Hl expression.
  • B7-H1 is not heterogeneously expressed throughout the tumor, but is co-localized in the area with CD8+ TILs, which may be PD-1+ or PD-1- or change PD-1 expression over time ( Figure 12A-12B).
  • CD8+ TILs which may be PD-1+ or PD-1- or change PD-1 expression over time ( Figure 12A-12B).
  • Figure 12A not all CD8 T+ cells are staining for PD-1.
  • CD8 may be used as a correlative readout of B7-H1 expression, as CD8+ T cells infiltrate into areas in which B7-H1 is expressed.
  • Figure 12B shows areas of necrosis in the tumor.
  • Figure 12C shows that B7-H1 is expressed on the membrane of the tumor cells.
  • Figure 13 shows the LDH levels observed in such patients following 1 cycle of treatment. Levels were obtained at the start of cycle 1 (i.e. , baseline) and prior to the start of cycle 2. Patients who exhibited disease progression ("PD") typically showed increased LDH release, whereas patients who exhibited an immune response or a clinical response typically showed decreased LDH release (cycle 1 compared to cycle 2). As stated above, high baseline LDH and/or rapidly increasing LDH is a biomarker for rising antigen exposure and up-regulation of PD-1 expression. Figure 13 the upper level of normal (ULN) is prognostic of patients that will not successfully respond to PD-1 -targeted immunotherapy.
  • UPN upper level of normal
  • One aspect of the present disclosure reflects the recognition that a correlation aspect between of the level of LDH release and the level of PD- 1 HI cells, such that a synergistic prognostic benefit is obtained by evaluating both such prognostic markers.
  • patient 0403 had the highest baseline LDH levels
  • patient 0604 had the most rapidly increasing LDH levels
  • patient 0606 had the second highest LDH level at CI DO and the highest at C2D0.
  • immunotherapeutics are insufficient to overcome the signals promoting up- regulation of PD-1.
  • Figure 15 shows that the baseline TIL level is a prognostic biomarker of successful response to PD-1 -targeted immunotherapy.
  • FIGS. 16A and 16B show that polyfunctional T cell populations (CD8+ ( Figure 16A) and CD4+ ( Figure 16B)) increased in immune responder patients, but decreased in progressive disease patients.
  • Figures 16A-16B show that a change in polyfunctional T cell populations is a prognostic biomarker of successful response to PD-1 -targeted immunotherapy.
  • bDNA analysis was used to measure the changes in effector markers and exhaustion markers in the T cell populations of the above patients.
  • the measured effector markers were: TNFRSF9, TNFRSF4, ICOS, KLRG1, CCR2, CXCL9, CXCL10, granzymeA (GzmA) and granzymeB (GzmB).
  • the measured markers of T cell exhaustion were: PD1, CTLA4, FasL, CCL3, CD40L, LAG3, CD244 and CD160.
  • Figure 17 summarizes the preferred prognostic biomarker criteria of the present disclosure for patient selection for PD-1 targeted immunotherapy.
  • Figure 18A-18B show a tumor biopsy stain showing the immune front of a patient.
  • Figure 18A shows a tumor biopsy stain of patient 0505 (CR), fresh pre-treatment BRAFm, with TILs. The left panel shows staining for B7-H1; the right panel shows staining for CD8.
  • Figure 18A-18B also shows areas of necrosis as well as the variability of B7-H1 staining across the tumor microenvironment relative to the staining of CD8 (i.e. , areas that are B7-H1 positive, areas that are necrotic, and areas that are B7-H1 negative).
  • a murine B7-DC Ig fusion molecule was found to promote the survival, tumor eradication, and long-term anti-tumor immune memory of B ALB/c (immune competent) mice using a subcutaneous syngeneic CT26 colon carcinoma model.
  • Mice received a low-dose treatment with CTX on Day 10 followed by the murine B7-DC Ig fusion twice weekly for four weeks, starting on Day 11. The tumor was found to have been eradicated in 60% of mice treated (at 15 mg/kg).
  • Figure 19B shows the effect of the murine B7-DC Ig fusion on tumor volume. Following inoculation of tumor cells in naive mice, tumors grew in almost all cases. To evaluate long-term immune memory in mice that eradicated tumor following treatment with CTX + murine B7-DC Ig, these mice were re-challenged with CT26 cells. In almost all cases, the CT26 cells were rejected following re-challenge, demonstrating long-term immune antitumor immune (Figure 19C).
  • the enrolled patients had the following demographics: mean age 56, range 27-80; 26 males (59%) /18 females (41%); 43 Caucasian / European heritage (98%) and 1 African American / African heritage (2%); ECOG performance status of 1 (28 patients, 64%) or 0 (16 patients, 36%).
  • SAE serious adverse events
  • AE Grade 3 adverse events
  • the B7-DC Ig was found to have a sustained serum half-life of approximately 10 days, with a tumor volume was demonstrated in CT scans of the lung performed prior to Cycle 1 ( Figure 21, Panel A) vs. at the end of Cycle 4 ( Figure 21, Panel B). An overall reduction of 48.4% in tumor burden was observed at the end of Cycle 4.
  • FIG. 22 Panels A-B, shows evidence of Sustained Disease in a melanoma patient in the 10 mg/kg dose-escalation cohort.
  • a reduction of tumor volume was demonstrated in CT scans of the neck performed prior to Cycle 1 ( Figure 22, Panel A) vs. end of Cycle 6 ( Figure 22, Panel B). This lesion was initially palpable and was observed to begin regressing following the first dose of B7-DC Ig.
  • Figures 23A-23B show evidence of a Mixed Response (MR) in a melanoma patient in the Expansion cohort.
  • MR Mixed Response
  • Figures 25A-25E show data for all patients meeting these criteria. Patients who came off trial more rapidly for progressive disease evaluated. Increased counts of GzmB effector / EMRA cells were observed in the peripheral blood of all (7/7) patients evaluated. Paired tumor biopsy specimens for gene expression analysis were available for 3 patients in the 10-30 mg/kg cohorts who remained on the trial for at least 4 cycles.
  • Candidate biomarkers were evaluated for all patients in the 10-30 mg/kg dose cohorts. All patients in these cohorts who had completed 4 or more treatment cycles had relatively normal ALC and serum LDH levels at baseline. Confirmed clinical responders (PR / SD > 6 months) also had an inflammatory tumor microenvironment at baseline, as evidenced by a high average number of CD8 + and PD-1 + TIL cells per high-powered field (hpf) plus membranous B7-H1 expression on tumor cells in areas of high TIL density. As shown in Figures 28A-28E, patients who were Clinical
  • the gene expression analysis corroborates the IHC results; this biopsy specimen had the highest levels of CD8A, FCGR3A, CTLA4, PDl, FASLG, CCL3, CXCL9, CXCLIO, and GZMA expression of the evaluated pre-treatment biopsy specimens.
  • IHC analysis of paired tumor biopsy specimens from the 10-30 mg/kg cohorts shows increased ratio of CD8 + TIL to PD-1 + TIL in 9/14 cases, including 5/5 evaluated patients who remained on the trial for 4 or more cycles ( Figures 30A-30B), a further increase in average number of CD8 + TIL/hpf (from 1068 to 1522) in patient 20-0402 (SD in Cycle 20) and the emergence of an "immune front" in patient 10-0506 (B7-H1 score increased from 0 to 3, and average number of CD8 + TIL/hpf increased 11.8- fold (from 8 to 94) (Figure 31, Panels A-D).
  • the results show that the human B7-DC-Ig fusion had an acceptable safety profile, with no evidence of pneumonitis or GI toxicities.
  • Initial evidence of clinical activity PR, long-term SD, and MR's
  • MR's MR's
  • Improvements in immune function were consistently observed in the periphery and tumor microenvironment in patients in the 10-30 mg/kg cohorts who were able to remain on the trial for 4 or more treatment cycles.
  • Baseline ALC and LDH stratify all patients who remained on trial for 4+ cycles (including clinical responders) vs. patients who came off trial in ⁇ 4 cycles due to rapid disease progression.
  • Baseline tumor B7-H1 expression, CD8 TIL levels, and PD-1 TIL levels (“immune front") stratify confirmed clinical responders vs. other patients who remained on trial for 4+ cycles (including MR).
  • the expression of 19 exhaustion/effector genes and 17 lymphocyte phenotype genes were evaluated by branched DNA (bDNA) analysis using tumor biopsy specimens from 16 patients participating in the clinical trial of Example 3; paired specimens from 8 patients have been analyzed.
  • the assay is based on the direct quantification of 3- 80 different RNA target using magnetic beads for multiplexing the RNA targets and branched DNA (bDNA) signal amplification technology (Zhang, A. et al. (2005) "Small Interfering RNA And Gene Expression Analysis Using A Multiplex Branched DNA Assay Without RNA Purification " J. Biomol. Screen. 10(6):549-556; Zheng, Z. et al.
  • Increases in these markers are consistent with data showing an increase in the relative population effector/memory T cells (which express most of these markers) versus naive T cells in Cohort 4-6 patients who have stayed on trial 4+ cycles. Reduction across both exhaustion and effector molecules were observed to correlate with rapidly progressing disease. This is consistent with data showing an increase in the relative population naive T cells (which do not express most of these markers) versus effector/memory T cells with progression.
  • B7-H1 is upregulated, and PD-1 is down-regulated, in patients who came off trial in ⁇ 4 cycles due to progressive disease vs. patients who completed 4+ cycles.
  • Pre-treatment biopsy specimens from the different patients were compared and evaluated for potential patient selection biomarkers ( Figures 32A-32B).
  • the pre-dose biopsy specimen from a confirmed clinical responder (patient 0402) black triangle
  • patient 0402 had significantly higher CD8 + TIL and PD-1 + TIL levels than other fresh pre-dose biopsies evaluated to date, either for patients who stayed on trial for 4+ cycles (square)or patients who came off trial more rapidly(gray circle).
  • patient 0402 had the highest levels of CD8A (CD8a), FCGR3A (FcyRIIIa, CD16), CTLA4, PD-1, FASL, CCL3, CXCL9, CXCL10, and GZMA gene expression.
  • the pre-treatment biopsy specimen from a confirmed clinical responder (patient 0402) exhibited very high expression of many immune markers in the tumor. Post-treatment biopsy specimens from this patient exhibited stable, strong expression of many immune markers from CI DO to C2D15, as well as evidence for improved T cell function following treatment. The myeloid populations also appeared to change.
  • the patient exhibited an increase in TBX21 (Tbet, Thl master transcription factor) while FOXP3 expression was stable, indicating an improved ratio of Thl to Treg cells in the tumor microenvironment.
  • the patient also exhibited an increased expression of CD40L relative to other markers (CD40L is expressed on effector/memory T cells and plays a central role in promoting DC maturation and migration).
  • the patient also exhibited decreased expression of the T cell suppressive molecules, LAG3 and 2B4, relative to other markers as well as an increase in CCR2 expression (CCR2 is expressed in the tumor microenvironment on monocytes, macrophages and Treg), but without a concomitant increase in FOXP3 or CD68 expression.
  • Pre-treatment biopsy specimens from patients who remained on study 4+ cycles (patients 0506 and 0609) exhibited low-level expression of most immune markers. Overall, changes in gene expression suggested improved function following treatment. Specifically, such patients exhibited a pronounced increase in CXCL9. CXCL10 also increased in patient 0506, while increased recruitment of CD8 T cells was evidenced by an increase in CD8A gene expression observed in patient 0609 (2.3 -fold increase in normalized gene expression, largest fold-increase in phenotyping panel) and increased CD8+ TIL (average # / hpf increased from 8 to 94) in patient 0506.
  • CXCL9 and CXCL10 which recruit effector T cells to the tumor, were among the most strongly down-regulated genes in 6/7 paired biopsies;
  • Lytic molecules GzmA and GzmB were among the most 3.
  • Inhibitory molecules were among the most strongly up- regulated genes; specifically CD160 (3/7 paired biopsies), CTLA4 (3/7 paired biopsies) and 2B4 (2/7 paired biopsies).
  • CD160 3/7 paired biopsies
  • CTLA4 3/7 paired biopsies
  • 2B4 2/7 paired biopsies.
  • the most up-regulated and down-regulated genes were typically myeloid-associated rather than T-cell associated.
  • RORC Thl7 master transcription factor
  • IRF4 which can be expressed by some T cell subsets as well as other populations.
  • Baseline CXCL9 expression correlated with levels of CD8 + TIL cells.
  • Two patients (patients 0506 and 0609) who had low baseline TIL levels exhibited large increases in tumor-CXCL9 expression following treatment. Increased CD8 infiltration was observed in IHC for patient 0506 (avg #/hpf increased from 8 to 94) and by bDNA for 0609 (2.3 -fold increase).
  • patients with rapidly progressing disease were found to have stable or declining levels of CXCL9 and CD8A expression in tumor biopsies.
  • the B7-DC Ig fusion was found to have an acceptable safety profile, with no evidence of pneumonitis or GI toxicities.
  • Initial evidence of clinical activity PR, long-term SD, and MR's
  • a dose-dependent reduction in PD- 1 HI T cells was found to occur following B7-DC Ig fusion treatment.
  • Baseline ALC and LDH stratify all patients who remained on the trial for 4+ cycles (including clinical responders) vs. patients who came off trial in ⁇ 4 cycles due to rapid disease progression.
  • Baseline tumor B7-H1 expression, CD8 TIL levels, and PD-1 TIL levels (“immune front") stratify confirmed clinical responders vs. other patients who remained on the trial for 4+ cycles (including MR).
  • Improvements in immune function are consistently observed in the periphery and tumor microenvironment, in patients in 10-30 mg/kg cohorts who were able to remain on trial for 4+ treatment cycles.
  • the treatment resulted in expanded populations of polyfunctional and lytic T cells in peripheral blood, enhanced levels of CXCL9 gene expression (as determined by tumor biopsies), and increased ratio of CD8+ to PD-1 + lymphocytes in the tumor least 4 treatment cycles days (Cohort 4-6). This is consistent with enhanced immune function in these patients.
  • the IHC and bDNA analyses of pre- treatment biopsy specimens provided similar results for CD8, CD4, and PD- 1, thus validating their use in screening patient candidates.
  • CXCL9 and/or CXCL10 which recruit effector T cells to the tumor, were strongly down-regulated in 6/7 cases;
  • Inhibitory molecules 2B4, CD 160, and/or CTLA4 were received 10-30 mg/kg of a B7-DC-Ig Fusion molecule and were able to stay in the clinical trial for at least 4 cycles. In contrast, evidence of increased immune suppression was observed in patients who came off study more rapidly due to disease progression.
  • T cells secreting IFN- ⁇ , TNF-a, and IL-2
  • dual functional T cells secreting IFN- ⁇ and TNF-a
  • monofunctional IFN- ⁇ " T cells were found to be stable or declining in 4 of 5 patients (20-0403, 30-0601, 20-0604, 20-0606 and 20-0607) who stayed on the clinical trial for fewer than 4 cycles (due to disease progression).
  • the unstimulated cells also showed higher levels of GzmB than
  • GzmB expression was therefore evaluated using unstimulated cell samples. GzmB expression on CD8 T cells was high or increasing in natients who remained on trial for 4+ cvcles. Tvnicallv GzmB. which is treatment in patients 0406, 0501, and 0506; this is generally a very small population but may play an important role in anti-tumor immune response (Quezada, S.A. et al. (2010) "Tumor-Reactive CD4(+) T Cells Develop Cytotoxic Activity And Eradicate Large Established Melanoma After Transfer Into Lymphopenic Hosts," J. Exp. Med. 207(3):637-650). Increases in GzmB cells often occurred at much later timepoints in some patients.
  • the absolute numbers of key effector cell populations were calculated using absolute CD8 counts.
  • the number of cells per mL of blood for these populations was calculated pre- treatment and at each post-treatment timepoint; the highest post-treatment rapidly typically had declining absolute numbers of the key effector cell populations at all post-dose timepoints.
  • the flow cytometry analysis of PBMC specimens from 10-30 mg/kg cohorts thus shows increased numbers of polyfunctional (IFN- ⁇ " TNF-a + IL-2 + ) CD4 + and CD8 + T cells and increased numbers of effector and EMRA T cells producing the lytic marker Granzyme B in patients who stayed on trial for 4 or more cycles, including clinical responders (20-0505 evaluable for GzmB only).
  • results show that consistent evidence of improved immune function was seen in patients who received 10-30 mg/kg of a human B7-DC-Ig Fusion molecule and completed at least 4 cycles of therapy.
  • Such evidence included the findings that patients exhibited increases in the frequency of:
  • TNF-a + IL-2 + T cells cells that have been shown to correlate with protective immunity during infection and following vaccination
  • peripheral T cell function was generally not observed in PBMC specimens from patients that received ⁇ 10 mg/kg of the human B7-DC-Ig Fusion molecule or in PBMC specimens from patients who came off the clinical trial more rapidly due to disease progression (patients 0403, 0601, 0603, 0604, and 0607).
  • immunostainers and detected using DAB (3, 3'-diaminobenzidine) HRP substrate were generally not observed in PBMC specimens from patients that received ⁇ 10 mg/kg of the human B7-DC-Ig Fusion molecule or in PBMC specimens from patients who came off the clinical trial more rapidly due to disease progression (patients 0403, 0601, 0603, 0604, and 0607).
  • Figure 39A-39B and 40A-40B are micrographs showing that PD-Ll (B7-H1) and B7-H4 (CD68) are co-expressed in tissue sections of a melanoma.
  • Figures 40A-40B are micrographs showing that PD-Ll (B7-H1) and B7-H4 (CD68) are co- expressed in tissue sections of a renal cell carcinoma.

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Abstract

La présente invention concerne des méthodes améliorées de sélection de patients qui pourraient être soumis à des thérapies et polythérapies ciblant les voies de PD-1 et B7-H4, et permettant de traiter ces patients. En particulier, l'invention concerne des thérapies et polythérapies améliorées ciblant PD-1 et permettant de traiter des patients qui n'ont pu être traités avec des inhibiteurs de BRAF/MEK ou d'autres inhibiteurs de la voie de RAS-RAF-MEK-ERK. L'invention concerne en outre des thérapies et polythérapies améliorées ciblant PD-1 et permettant de vaincre la résistance due à la « dormance tumorale » et d'empêcher la sélection/l'excroissance de tumeurs résistantes à évolution rapide en présence de divers inhibiteurs à petite molécule. De plus, la présente invention concerne une thérapie ciblant PD-1 qui implique l'administration d'une molécule immunomodulatrice, telle qu'une protéine de fusion/un anticorps se liant à PD-1 (par exemple, un anticorps anti-PD-1, une B7-DC-Ig, une B7-H1-Ig, etc.), avec un inhibiteur de BRAF (« BRAFi ») ou une autre petite molécule, en tant que régime initial de traitement pour ces patients sélectionnés.
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Publication number Priority date Publication date Assignee Title
WO2016071890A1 (fr) * 2014-11-07 2016-05-12 Immunid Méthode théranostique pour optimiser le choix du bloqueur de point de contrôle immunitaire à administrer à un patient atteint de cancer
WO2016094377A1 (fr) 2014-12-09 2016-06-16 Merck Sharp & Dohme Corp. Système et procédés pour dériver des marqueurs biologiques de signature génique de réponse à des antagonistes de pd-1
WO2016196298A1 (fr) * 2015-05-29 2016-12-08 Genentech, Inc. Méthodes diagnostiques et thérapeutiques pour le cancer
WO2017065000A1 (fr) * 2015-10-15 2017-04-20 国立大学法人京都大学 Biomarqueur destiné à prévoir un exemple aux effets remarquables d'inhibiteur de voie d'apoptose – 1 (pd-1)
WO2017085307A1 (fr) * 2015-11-22 2017-05-26 Ventana Medical Systems, Inc. Méthodes d'identification de cellules immunitaires dans un tissu tumoral positif pd-l1
WO2017201036A1 (fr) * 2016-05-17 2017-11-23 Genentech, Inc. Signatures génétiques stromales destinées au diagnostic et à l'utilisation en immunothérapie
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US9885721B2 (en) 2014-05-29 2018-02-06 Spring Bioscience Corporation PD-L1 antibodies and uses thereof
US9920123B2 (en) 2008-12-09 2018-03-20 Genentech, Inc. Anti-PD-L1 antibodies, compositions and articles of manufacture
US9938345B2 (en) 2014-01-23 2018-04-10 Regeneron Pharmaceuticals, Inc. Human antibodies to PD-L1
US9987500B2 (en) 2014-01-23 2018-06-05 Regeneron Pharmaceuticals, Inc. Human antibodies to PD-1
EP3265825A4 (fr) * 2015-03-06 2018-08-08 Dana-Farber Cancer Institute, Inc. Biomarqueurs pd-l2 prédictifs de réponses d'inhibiteurs de la voie pd-1 dans les cancers oesophagogastriques
CN109416925A (zh) * 2016-05-05 2019-03-01 南托米克斯有限责任公司 检查点失效和使检查点失效的方法
WO2019164870A1 (fr) * 2018-02-20 2019-08-29 Medimmune, Llc Expression d'arnm de signature pour l'identification de patients sensibles au traitement par anticorps anti-pd-l1
US10457725B2 (en) 2016-05-13 2019-10-29 Regeneron Pharmaceuticals, Inc. Methods of treating skin cancer by administering a PD-1 inhibitor
US10513558B2 (en) 2015-07-13 2019-12-24 Cytomx Therapeutics, Inc. Anti-PD1 antibodies, activatable anti-PD1 antibodies, and methods of use thereof
US10620211B2 (en) 2015-02-03 2020-04-14 Ventana Medical Systems, Inc. Histochemical assay for evaluating expression of programmed death ligand 1 (PD-L1)
CN111094977A (zh) * 2017-07-13 2020-05-01 古斯塔夫·鲁西研究所 监测抗pd-1/pd-l1治疗的肿瘤患者中肿瘤淋巴细胞浸润和预后的基于影像组学的成像工具
US10736940B2 (en) 2013-12-19 2020-08-11 Immutep S.A.S. Combined preparations for the treatment of cancer
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US10874713B2 (en) 2015-01-09 2020-12-29 Immutep S.A.S. Combined preparations for the treatment of cancer or infection
WO2021092171A1 (fr) * 2019-11-06 2021-05-14 Genentech, Inc. Méthodes diagnostiques et thérapeutiques pour le traitement de cancers hématologiques
EP3707164A4 (fr) * 2017-11-07 2021-11-24 Memorial Sloan-Kettering Cancer Center Inhibition de ctla-4 et/ou pd-1 pour la régulation de lymphocytes t
WO2022003554A1 (fr) * 2020-07-01 2022-01-06 Pfizer Inc. Biomarqueurs destinés à une thérapie par antagoniste de liaison à l'axe pd-1
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US11299544B2 (en) 2013-03-15 2022-04-12 Genentech, Inc. Biomarkers and methods of treating PD-1 and PD-L1 related conditions
RU2777945C2 (ru) * 2015-01-09 2022-08-12 Иммутеп С.А.С. Комбинированные препараты для лечения рака или инфекции
CN114902048A (zh) * 2020-02-18 2022-08-12 创新生物有限公司 伴随诊断用生物标志物组合物及包含其的伴随诊断用试剂盒
WO2022235482A1 (fr) * 2021-05-03 2022-11-10 Rutgers, The State University Of New Jersey Immunothérapie pour une maladie intestinale inflammatoire et/ou un cancer
US11530269B2 (en) 2014-07-11 2022-12-20 Ventana Medical Systems, Inc. Anti-PD-L1 antibodies and diagnostic uses thereof
US11603407B2 (en) 2017-04-06 2023-03-14 Regeneron Pharmaceuticals, Inc. Stable antibody formulation
WO2024102620A3 (fr) * 2022-11-09 2024-06-13 Tempest Therapeutics, Inc. Composés de triazolone et leurs utilisations
US12054557B2 (en) 2015-12-22 2024-08-06 Regeneron Pharmaceuticals, Inc. Combination of anti-PD-1 antibodies and bispecific anti-CD20/anti-CD3 antibodies to treat cancer

Citations (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4179337A (en) 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
US4485045A (en) 1981-07-06 1984-11-27 Research Corporation Synthetic phosphatidyl cholines useful in forming liposomes
US4544545A (en) 1983-06-20 1985-10-01 Trustees University Of Massachusetts Liposomes containing modified cholesterol for organ targeting
US4676980A (en) 1985-09-23 1987-06-30 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Target specific cross-linked heteroantibodies
US4741900A (en) 1982-11-16 1988-05-03 Cytogen Corporation Antibody-metal ion complexes
US4880078A (en) 1987-06-29 1989-11-14 Honda Giken Kogyo Kabushiki Kaisha Exhaust muffler
WO1992019244A2 (fr) 1991-05-01 1992-11-12 Henry M. Jackson Foundation For The Advancement Of Military Medicine Procede de traitement des maladies respiratoires infectieuses
WO1994004678A1 (fr) 1992-08-21 1994-03-03 Casterman Cecile Immunoglobulines exemptes de chaines legeres
WO1994025591A1 (fr) 1993-04-29 1994-11-10 Unilever N.V. PRODUCTION D'ANTICORPS OU DE FRAGMENTS FONCTIONNALISES D'ANTICORPS, DERIVES DES IMMUNOGLOBULINES A CHAINE LOURDE DE $i(CAMELIDAE)
US5441050A (en) 1992-12-18 1995-08-15 Neoprobe Corporation Radiation responsive surgical instrument
WO1997032572A2 (fr) 1996-03-04 1997-09-12 The Penn State Research Foundation Materiaux et procedes permettant d'accroitre la penetration intracellulaire
WO1997044013A1 (fr) 1996-05-24 1997-11-27 Massachusetts Institute Of Technology Particules legeres aerodynamiques pour la diffusion de medicaments dans l'appareil respiratoire
WO1998031346A1 (fr) 1997-01-16 1998-07-23 Massachusetts Institute Of Technology Preparation de particules pour inhalation
US5855913A (en) 1997-01-16 1999-01-05 Massachusetts Instite Of Technology Particles incorporating surfactants for pulmonary drug delivery
US5934272A (en) 1993-01-29 1999-08-10 Aradigm Corporation Device and method of creating aerosolized mist of respiratory drug
US5985309A (en) 1996-05-24 1999-11-16 Massachusetts Institute Of Technology Preparation of particles for inhalation
US6005079A (en) 1992-08-21 1999-12-21 Vrije Universiteit Brussels Immunoglobulins devoid of light chains
WO1999066903A2 (fr) 1998-06-24 1999-12-29 Advanced Inhalation Research, Inc. Grandes particules poreuses emises par un inhalateur
US6019968A (en) 1995-04-14 2000-02-01 Inhale Therapeutic Systems, Inc. Dispersible antibody compositions and methods for their preparation and use
WO2001014557A1 (fr) 1999-08-23 2001-03-01 Dana-Farber Cancer Institute, Inc. Pd-1, recepteur de b7-4, et son utilisation
WO2001039722A2 (fr) 1999-11-30 2001-06-07 Mayo Foundation For Medical Education And Research Nouvelle molecule immunoregulatrice b7-h1,
WO2002086083A2 (fr) 2001-04-20 2002-10-31 Mayo Foundation For Medical Education And Research Procedes d'amelioration de la capacite de reaction de cellules t
WO2004056875A1 (fr) 2002-12-23 2004-07-08 Wyeth Anticorps anti pd-1 et utilisations
US6803192B1 (en) 1999-11-30 2004-10-12 Mayo Foundation For Medical Education And Research B7-H1, a novel immunoregulatory molecule
US20040241745A1 (en) 2001-07-31 2004-12-02 Tasuku Honjo Substance specific to pd-1
US20050037000A1 (en) 2003-01-09 2005-02-17 Macrogenics, Inc. Identification and engineering of antibodies with variant Fc regions and methods of using same
US20050064514A1 (en) 2003-01-09 2005-03-24 Macrogenics, Inc. Identification and engineering of antibodies with variant Fc regions and methods of using same
US7029674B2 (en) 2001-04-02 2006-04-18 Wyeth Methods for downmodulating immune cells using an antibody to PD-1
WO2006133396A2 (fr) 2005-06-08 2006-12-14 Dana-Farber Cancer Institute Methodes et compositions pour le traitement d'infections persistantes
WO2008083239A2 (fr) 2006-12-27 2008-07-10 The Johns Hopkins University Compositions et procédés pour la stimulation d'une réaction immunitaire
WO2008083174A2 (fr) 2006-12-27 2008-07-10 Emory University Compositions et procédés pour le traitement d'infections et de tumeurs
US20090055944A1 (en) 2005-07-01 2009-02-26 Medarex, Inc. Human monoclonal antibodies to be programmed death ligand 1 (pd-l1)
US20090110667A1 (en) 2007-10-01 2009-04-30 Children's Hospital And Reginonal Medical Center Detection and treatment of autoimmune disorders
US7563869B2 (en) 2003-01-23 2009-07-21 Ono Pharmaceutical Co., Ltd. Substance specific to human PD-1
US20090217401A1 (en) 2005-05-09 2009-08-27 Medarex, Inc Human Monoclonal Antibodies To Programmed Death 1(PD-1) And Methods For Treating Cancer Using Anti-PD-1 Antibodies Alone or in Combination with Other Immunotherapeutics
US7595048B2 (en) 2002-07-03 2009-09-29 Ono Pharmaceutical Co., Ltd. Method for treatment of cancer by inhibiting the immunosuppressive signal induced by PD-1
US20090313687A1 (en) 2004-10-15 2009-12-17 Nicolas Popp One time password
US7635757B2 (en) 1999-08-23 2009-12-22 Dana-Farber Cancer Institute, Inc. B7-4 Antibodies and uses therefor
WO2010027423A2 (fr) 2008-08-25 2010-03-11 Amplimmune, Inc. Compositions d'antagonistes de pd-1 et methodes d'utilisation associees
EP2172219A1 (fr) * 2008-10-02 2010-04-07 SNU R&DB Foundation Agent thérapeutique cancéreux comprenant an iNKT-ligand et un anticorps anti-PD-1 ou un anticorps anti-PD-L1
US7722868B2 (en) 2001-11-13 2010-05-25 Dana-Farber Cancer Institute, Inc. Agents that modulate the interaction of B7-1 polypeptide with PD-L1 and methods of use thereof
US20120177645A1 (en) 2009-08-31 2012-07-12 Solomon Langermann Methods and compositions for the inhibition of transplant rejection
WO2012145493A1 (fr) * 2011-04-20 2012-10-26 Amplimmune, Inc. Anticorps et autres molécules qui se lient à b7-h1 et à pd-1
WO2013025779A1 (fr) 2011-08-15 2013-02-21 Amplimmune, Inc. Anticorps anti-b7-h4 et leurs utilisations
WO2014022758A1 (fr) 2012-08-03 2014-02-06 Dana-Farber Cancer Institute, Inc. Anticorps de liaison double à agent unique anti-pd-l1 et pd-l2 et procédés d'utilisation

Patent Citations (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4179337A (en) 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
US4485045A (en) 1981-07-06 1984-11-27 Research Corporation Synthetic phosphatidyl cholines useful in forming liposomes
US4741900A (en) 1982-11-16 1988-05-03 Cytogen Corporation Antibody-metal ion complexes
US4544545A (en) 1983-06-20 1985-10-01 Trustees University Of Massachusetts Liposomes containing modified cholesterol for organ targeting
US4676980A (en) 1985-09-23 1987-06-30 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Target specific cross-linked heteroantibodies
US4880078A (en) 1987-06-29 1989-11-14 Honda Giken Kogyo Kabushiki Kaisha Exhaust muffler
WO1992019244A2 (fr) 1991-05-01 1992-11-12 Henry M. Jackson Foundation For The Advancement Of Military Medicine Procede de traitement des maladies respiratoires infectieuses
US5290540A (en) 1991-05-01 1994-03-01 Henry M. Jackson Foundation For The Advancement Of Military Medicine Method for treating infectious respiratory diseases
WO1994004678A1 (fr) 1992-08-21 1994-03-03 Casterman Cecile Immunoglobulines exemptes de chaines legeres
US6005079A (en) 1992-08-21 1999-12-21 Vrije Universiteit Brussels Immunoglobulins devoid of light chains
US5441050A (en) 1992-12-18 1995-08-15 Neoprobe Corporation Radiation responsive surgical instrument
US5934272A (en) 1993-01-29 1999-08-10 Aradigm Corporation Device and method of creating aerosolized mist of respiratory drug
WO1994025591A1 (fr) 1993-04-29 1994-11-10 Unilever N.V. PRODUCTION D'ANTICORPS OU DE FRAGMENTS FONCTIONNALISES D'ANTICORPS, DERIVES DES IMMUNOGLOBULINES A CHAINE LOURDE DE $i(CAMELIDAE)
US6019968A (en) 1995-04-14 2000-02-01 Inhale Therapeutic Systems, Inc. Dispersible antibody compositions and methods for their preparation and use
WO1997032572A2 (fr) 1996-03-04 1997-09-12 The Penn State Research Foundation Materiaux et procedes permettant d'accroitre la penetration intracellulaire
US5985320A (en) 1996-03-04 1999-11-16 The Penn State Research Foundation Materials and methods for enhancing cellular internalization
WO1997044013A1 (fr) 1996-05-24 1997-11-27 Massachusetts Institute Of Technology Particules legeres aerodynamiques pour la diffusion de medicaments dans l'appareil respiratoire
US5874064A (en) 1996-05-24 1999-02-23 Massachusetts Institute Of Technology Aerodynamically light particles for pulmonary drug delivery
US5985309A (en) 1996-05-24 1999-11-16 Massachusetts Institute Of Technology Preparation of particles for inhalation
WO1998031346A1 (fr) 1997-01-16 1998-07-23 Massachusetts Institute Of Technology Preparation de particules pour inhalation
US5855913A (en) 1997-01-16 1999-01-05 Massachusetts Instite Of Technology Particles incorporating surfactants for pulmonary drug delivery
WO1999066903A2 (fr) 1998-06-24 1999-12-29 Advanced Inhalation Research, Inc. Grandes particules poreuses emises par un inhalateur
WO2001014557A1 (fr) 1999-08-23 2001-03-01 Dana-Farber Cancer Institute, Inc. Pd-1, recepteur de b7-4, et son utilisation
US7635757B2 (en) 1999-08-23 2009-12-22 Dana-Farber Cancer Institute, Inc. B7-4 Antibodies and uses therefor
US6808710B1 (en) 1999-08-23 2004-10-26 Genetics Institute, Inc. Downmodulating an immune response with multivalent antibodies to PD-1
US20070202100A1 (en) 1999-08-23 2007-08-30 Genetics Institute, Llc PD-1, a receptor for B7-4, and uses therefor
US7101550B2 (en) 1999-08-23 2006-09-05 Dana-Farber Cancer Institute, Inc. PD-1, a receptor for B7-4, and uses therefor
WO2001039722A2 (fr) 1999-11-30 2001-06-07 Mayo Foundation For Medical Education And Research Nouvelle molecule immunoregulatrice b7-h1,
US20090317368A1 (en) 1999-11-30 2009-12-24 Lieping Chen B7-h1, a novel immunoregulatory molecule
US6803192B1 (en) 1999-11-30 2004-10-12 Mayo Foundation For Medical Education And Research B7-H1, a novel immunoregulatory molecule
US20090274666A1 (en) 1999-11-30 2009-11-05 Lieping Chen B7-h1, a novel immunoregulatory molecule
US20050059051A1 (en) 1999-11-30 2005-03-17 Mayo Foundation For Medical Education And Research B7-H1, a novel immunoregulatory molecule
US7029674B2 (en) 2001-04-02 2006-04-18 Wyeth Methods for downmodulating immune cells using an antibody to PD-1
US7794710B2 (en) 2001-04-20 2010-09-14 Mayo Foundation For Medical Education And Research Methods of enhancing T cell responsiveness
WO2002086083A2 (fr) 2001-04-20 2002-10-31 Mayo Foundation For Medical Education And Research Procedes d'amelioration de la capacite de reaction de cellules t
US20090076250A1 (en) 2001-07-31 2009-03-19 Tasuku Honjo Substance that Specifically Recognizes PD-1
US20040241745A1 (en) 2001-07-31 2004-12-02 Tasuku Honjo Substance specific to pd-1
US7722868B2 (en) 2001-11-13 2010-05-25 Dana-Farber Cancer Institute, Inc. Agents that modulate the interaction of B7-1 polypeptide with PD-L1 and methods of use thereof
US20090297518A1 (en) 2002-07-03 2009-12-03 Tasuku Honjo Immunopotentiative composition
US7595048B2 (en) 2002-07-03 2009-09-29 Ono Pharmaceutical Co., Ltd. Method for treatment of cancer by inhibiting the immunosuppressive signal induced by PD-1
US7521051B2 (en) 2002-12-23 2009-04-21 Medimmune Limited Methods of upmodulating adaptive immune response using anti-PD-1 antibodies
US7488802B2 (en) 2002-12-23 2009-02-10 Wyeth Antibodies against PD-1
US20080311117A1 (en) 2002-12-23 2008-12-18 Mary Collins Antibodies against PD-1 and uses therefor
US20100028330A1 (en) 2002-12-23 2010-02-04 Medimmune Limited Methods of upmodulating adaptive immune response using anti-pd1 antibodies
WO2004056875A1 (fr) 2002-12-23 2004-07-08 Wyeth Anticorps anti pd-1 et utilisations
US20050064514A1 (en) 2003-01-09 2005-03-24 Macrogenics, Inc. Identification and engineering of antibodies with variant Fc regions and methods of using same
US20050037000A1 (en) 2003-01-09 2005-02-17 Macrogenics, Inc. Identification and engineering of antibodies with variant Fc regions and methods of using same
US7563869B2 (en) 2003-01-23 2009-07-21 Ono Pharmaceutical Co., Ltd. Substance specific to human PD-1
US20090263865A1 (en) 2003-01-23 2009-10-22 Tasuku Honjo Substance Specific to Human PD-1
US20090313687A1 (en) 2004-10-15 2009-12-17 Nicolas Popp One time password
US20090217401A1 (en) 2005-05-09 2009-08-27 Medarex, Inc Human Monoclonal Antibodies To Programmed Death 1(PD-1) And Methods For Treating Cancer Using Anti-PD-1 Antibodies Alone or in Combination with Other Immunotherapeutics
US20070122378A1 (en) 2005-06-08 2007-05-31 Gordon Freeman Methods and compositions for the treatment of persistent infections
WO2006133396A2 (fr) 2005-06-08 2006-12-14 Dana-Farber Cancer Institute Methodes et compositions pour le traitement d'infections persistantes
US20090055944A1 (en) 2005-07-01 2009-02-26 Medarex, Inc. Human monoclonal antibodies to be programmed death ligand 1 (pd-l1)
US20100040614A1 (en) 2006-12-27 2010-02-18 Rafi Ahmed Compositions and methods for the treatment of infections and tumors
WO2008083174A2 (fr) 2006-12-27 2008-07-10 Emory University Compositions et procédés pour le traitement d'infections et de tumeurs
WO2008083239A2 (fr) 2006-12-27 2008-07-10 The Johns Hopkins University Compositions et procédés pour la stimulation d'une réaction immunitaire
US20090110667A1 (en) 2007-10-01 2009-04-30 Children's Hospital And Reginonal Medical Center Detection and treatment of autoimmune disorders
WO2010027423A2 (fr) 2008-08-25 2010-03-11 Amplimmune, Inc. Compositions d'antagonistes de pd-1 et methodes d'utilisation associees
EP2172219A1 (fr) * 2008-10-02 2010-04-07 SNU R&DB Foundation Agent thérapeutique cancéreux comprenant an iNKT-ligand et un anticorps anti-PD-1 ou un anticorps anti-PD-L1
US20120177645A1 (en) 2009-08-31 2012-07-12 Solomon Langermann Methods and compositions for the inhibition of transplant rejection
US20120276095A1 (en) 2009-08-31 2012-11-01 Solomon Langermann B7-h4 fusion proteins and methods of use thereof
WO2012145493A1 (fr) * 2011-04-20 2012-10-26 Amplimmune, Inc. Anticorps et autres molécules qui se lient à b7-h1 et à pd-1
WO2013025779A1 (fr) 2011-08-15 2013-02-21 Amplimmune, Inc. Anticorps anti-b7-h4 et leurs utilisations
WO2014022758A1 (fr) 2012-08-03 2014-02-06 Dana-Farber Cancer Institute, Inc. Anticorps de liaison double à agent unique anti-pd-l1 et pd-l2 et procédés d'utilisation

Non-Patent Citations (263)

* Cited by examiner, † Cited by third party
Title
ADVANI, A. ET AL.: "A Prognostic Scoring System For Adult Patients Less Than 60 Years Of Age With Acute Lymphoblastic Leukemia In First Relapse,", LEUK. LYMPHOMA., vol. 50, no. 7, 2009, pages 1126 - 1131
AGARWAL, A. ET AL.: "The Role Of Positive Costimulatory Molecules In Transplantation And Tolerance,", CURR. OPIN. ORGAN TRANSPLANT., vol. 13, 2008, pages 366 - 372
AGARWALA, S.S. ET AL.: "LDH Correlation With Survival In Advanced Melanoma From Two Large, Randomised Trials (Oblimersen GM301 And EORTC 18951),", EUR. J. CANCER., vol. 45, no. 10, 2009, pages 1807 - 1814
AGATA, Y. ET AL.: "Expression Of The PD-1 Antigen On The Surface Of Stimulated Mouse T And B Lymphocytes,", INT. IMMUNOL., vol. 8, no. 5, 1996, pages 765 - 772
AL-LAZIKANI, B. ET AL.: "Combinatorial Drug Therapy For Cancer In The Post-Genomic Era,", NATURE BIOTECHNOL., vol. 30, 2012, pages 679 - 692
AL-LAZIKANI, B. ET AL.: "Unpicking the Combination Lock for Mutant BRAF and RAS Melanomas,", CANCER DISCOVERY, vol. 3, no. 1, 2013, pages 14 - 19
ANDRE, S. ET AL.: "Surveillance Of Antigen-Presenting Cells By CD4+ CD25+ Regulatory T Cells In Autoimmunity: Immunopathogenesis And Therapeutic Implications,", AMER. J. PATHOL., vol. 174, no. 5, 2009, pages 1575 - 1587
ARCH. PATHOL. LAB MED., vol. 132, no. 9, 2008, pages 1384
ARKENAU, H.T. ET AL.: "Prospective Validation Of A Prognostic Score To Improve Patient Selection For Oncology Phase I Trials,", J. CLIN. ONCOL., vol. 27, no. 16, 2009, pages 2692 - 2696
ARKENAU, H.T. ET AL.: "Targeting BRAF For Patients With Melanoma,", BRIT. J. CANCER, vol. 104, 2011, pages 392 - 398
ARMSTRONG, A.J. ET AL.: "Serum Lactate Dehydrogenase Predicts For Overall Survival Benefit In Patients With Metastatic Renal Cell Carcinoma Treated With Inhibition Of Mammalian Target Of Rapamycin,", J. CLIN. ONCOL., vol. 30, no. 27, 13 August 2012 (2012-08-13), pages 3402 - 3407
ASCIERTO, P.A. ET AL.: "Sequencing Of BRAF Inhibitors And Ipilimumab In Patients With Metastatic Melanoma: A Possible Algorithm For Clinical Use,", J. TRANSLATIONAL MED., vol. 10, no. 107, 2012, pages 1 - 8
ASCIERTO, P.A. ET AL.: "The Additional Facet Of Immunoscore: Immunoprofiling As A Possible Predictive Tool For Cancer Treatment,", J. TRANSL. MED., vol. 11, 2013, pages 54
ATZPODIEN, J. ET AL.: "Peripheral Blood Neutrophils As Independent Immunologic Predictor Of Response And Long-Term Survival Upon Immunotherapy In Metastatic Renal-Cell Carcinoma,", CANCER BIOTHER. RADIOPHARM., vol. 23, no. 1, 2008, pages 129 - 134
BALCH, C.M. ET AL.: "Prognostic Factors Analysis of 17,600 Melanoma Patients: Validation of the American Joint Committee on Cancer Melanoma Staging System,", J. CLIN. ONCOL., vol. 19, no. 16, 2001, pages 3622 - 3634
BALKWILL, F.R.: "The Chemokine System And Cancer,", J PATHOL., vol. 226, no. 2, 2011, pages 148 - 157
BEASLEY, M.B.: "Immunohistochemistry Of Pulmonary And Pleural Neoplasia,", ARCH. PATHOL. LAB. MED., vol. 132, no. 7, 2008, pages 1062 - 1072
BENJAMIN, D. ET AL.: "Human B-Cell TNF-Beta Microheterogeneity,", LYMPHOKINE CYTOKINE RES., vol. 11, no. 1, 1992, pages 45 - 54
BESWICK, E.J. ET AL.: "CD74 In Antigen Presentation, Inflammation, And Cancers Of The Gastrointestinal Tract,", WORLD J. GASTROENTEROL., vol. 15, no. 23, 2009, pages 2855 - 2861
BIGNOTTI, E. ET AL.: "Differential Gene Expression Profiles Between Tumor Biopsies And Short Term Primary Cultures Of Ovarian Serous Carcinomas: Identification Of Novel Molecular Biomarkers For Early Diagnosis And Therapy,", GYNECOL. ONCOL., vol. 103, 2006, pages 405 - 416
BLACKBURN, S.D. ET AL.: "Tissue-Specific Differences In PD-1 And PD-LI Expression During Chronic Viral Infection: Implications For CD8 T-Cell Exhaustion,", J. VIROL., vol. 84, no. 4, 2010, pages 2078 - 2089
BLANK, C. ET AL.: "Contribution Of The PD-L1/PD-1 Pathway To T-Cell Exhaustion: An Update On Implications For Chronic Infections And Tumor Evasion Cancer", IMMUNOL. IMMUNOTHER., vol. 56, no. 5, 29 December 2006 (2006-12-29), pages 739 - 745
BLANK; GAJEWSKI: "Interaction of PD-LI on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy,", CANCER IMMUNOL IMMUNOTHER, vol. 54, 2004, pages 307 - 314
BLATTMAN, J.N. ET AL.: "Impact Of Epitope Escape On PD-1 Expression And CD8 T-Cell Exhaustion During Chronic Infection,", J. VIROL., vol. 83, no. 9, 2009, pages 4386 - 4394
BLUM, K.A.: "Upcoming Diagnostic And Therapeutic Developments In Classical Hodgkin's Lymphoma,", HEMATOLOGY AMER. SOC. HEMATOL. EDUC. PROGRAM., 2010, pages 93 - 100
BOGEN, S.A. ET AL.: "Recent Trends And Advances In Immunodiagnostics Of Solid Tumors,", BIODRUGS, vol. 18, no. 6, 2004, pages 387 - 398
BOULTON, T.G. ET AL.: "An Insulin-Stimulated Protein Kinase Similar To Yeast Kinases Involved In Cell Cycle Control,", SCIENCE, vol. 249, 1990, pages 64 - 67
BOULTON, T.G. ET AL.: "ERKS: A Family Of Protein-SerinelThreonine Kinases That Are Activated And Tyrosine Phosphorylated In Response To Insulin And NGF,", CELL, vol. 65, 1991, pages 663 - 675
BRAHMER JULIE R ET AL: "Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.", JOURNAL OF CLINICAL ONCOLOGY : OFFICIAL JOURNAL OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY 1 JUL 2010, vol. 28, no. 19, 1 July 2010 (2010-07-01), pages 3167 - 3175, XP055124332, ISSN: 1527-7755 *
BROWN, J.A. ET AL.: "Blockade Of Programmed Death-I Ligands On Dendritic Cells Enhances T Cell Activation And Cytokine Production,", J. IMMUNOL., vol. 170, 2003, pages 1257 - 1266
BROWN, J.E. ET AL.: "Serum Lactate Dehydrogenase Is Prognostic For Survival In Patients With Bone Metastases From Breast Cancer: A Retrospective Analysis In Bisphosphonate-Treated Patients,", CLIN. CANCER RES., vol. 18, no. 22, 4 September 2012 (2012-09-04), pages 6348 - 6355
BROWN, K.E. ET AL.: "Role Of PD-1 In Regulating Acute Infections,", CURR. OPIN. IMMUNOL., vol. 22, no. 3, 2010, pages 397 - 401
BRUNETTO, A.T. ET AL.: "A Study Of The Pattern Of Hospital Admissions In A Specialist Phase I Oncology Trials Unit: Unplanned Admissions As An Early Indicator Of Patient Attrition,", EUR. J. CANCER., vol. 46, no. 15, 2010, pages 2739 - 2745
BURCHIEL ET AL.: "Tumor Imaging: The Radiochemical Detection of Cancer", 1982, MASSON PUBLISHING INC., article "Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments."
BUTTE, M.J. ET AL.: "Interaction of PD-LI and B7-1", MOLECULAR IMMUNOL., vol. 45, 2008, pages 3567 - 3572
BUTTE, M.J. ET AL.: "Interaction of PD-Ll and B7-1,", MOLECULAR IMMUNOL., vol. 45, 2008, pages 3567 - 3572
CADUFF, R.F. ET AL.: "Comparison Of Mutations Of Ki-RAS And p53 Immunoreactivity In Borderline And Malignant Epithelial Ovarian Tumours,", AM. J. SURG. PATHOL., vol. 23, 1999, pages 323 - 328
CAIRO, M.S. ET AL.: "Advanced Stage, Increased Lactate Dehydrogenase, And Primary Site, But Not Adolescent Age (> 15 Years), Are Associated With An Increased Risk Of Treatment Failure In Children And Adolescents With Mature B-Cell Non-Hodgkin's Lymphoma: Results Of The FAB LMB 96 Study,", J. CLIN. ONCOL., vol. 30, no. 4, 3 January 2012 (2012-01-03), pages 387 - 393
CARTER, L. ET AL.: "PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2,", EUR. J. IMMUNOL., vol. 32, no. 3, 2002, pages 634 - 643
CETIN, B. ET AL.: "Prognostic Factors For Overall Survival In Patients With Metastatic Colorectal Carcinoma Treated With Vascular Endothelial Growth Factor-Targeting Agents,", ASIAN PAC. J. CANCER PREV., vol. 13, no. 3, 2012, pages 1059 - 1063
CHAE, Y.S. ET AL.: "Absolute Lymphocyte Count At Day + 21 Predicts Survival In Patients With Early-Stage Diffuse Large B-Cell Lymphoma Treated With Rituximab, Cyclophosphamide,", ADRIAMYCIN, VINCRISTINE AND PREDNISONE,, 19 April 2012 (2012-04-19)
CHAU, N.G. ET AL.: "Early Mortality And Overall Survival In Oncology Phase I Trial Participants: Can We Improve Patient Selection?,", BMC CANCER, vol. 11, 2011, pages 426
CHEN, J. ET AL.: "Upregulation Of B7-H1 Expression Is Associated With Macrophage Infiltration In Hepatocellular Carcinomas,", CANCER IMMUNOL. IMMUNOTHER, vol. 61, no. 1, 2012, pages 101 - 108
CHEN, Y. ET AL.: "Expression of B7-H1 in Inflammatory Renal Tubular Epithelial Cells,", NEPHRON. EXP. NEPHROL., vol. 102, 2005, pages E81 - E92
CHEN, Y., KIDNEY INT., vol. 70, no. 12, 18 October 2006 (2006-10-18), pages 2092 - 9
CHOI, I.H. ET AL.: "Genomic Organization And Expression Analysis Of B7-H4, An Immune Inhibitory Molecule Of The B7 Family,", J. IMMUNOL., vol. 171, 2003, pages 4650 - 4654
CHOI, LH. ET AL.: "Genomic Organization And Expression Analysis Of B7-H4, An Immune Inhibitory Molecule Of The B7 Family,", J. IMMUNOL., vol. 171, 2003, pages 4650 - 4654
CHOTHIA, C. ET AL.: "Canonical Structures For The Hypervariable Regions Of Immunoglobulins,", J. MOL. BIOL., vol. 196, 1987, pages 901 - 917
COLLINS, M. ET AL.: "The B7 Family Of Immune-Regulatory Ligands,", GENOME BIOL., vol. 6, 2005, pages 223.1 - 223.7
COLLOT-TEIXEIRA, S. ET AL.: "CD36 And Macrophages In Atherosclerosis,", CARDIOVASC RES., vol. 75, no. 3, 1 August 2007 (2007-08-01), pages 468 - 477
CONROY, H. ET AL.: "Inflammation And Cancer: Macrophage Migration Inhibitory Factor (MIF)--The Potential Missing Link,", QJM, vol. 103, no. 11, 2010, pages 831 - 836
COYLE, A.J. ET AL.: "The Expanding B7 Superfamily: Increasing Complexity In Costimulatory Signals Regulating T Cell Function,", NATURE IMMUNOL., vol. 2, no. 3, 2001, pages 203 - 209
CREWS, C. ET AL.: "The Primary Structure Of MEK, A Protein Kinase That Phosphorylates The ERK Gene Product,", SCIENCE, vol. 258, 1992, pages 478 - 480
CROWE, S.M. ET AL.: "The Macrophage: The Intersection Between HIV Infection And Atherosclerosis,", J. LEUKOC. BIOL., vol. 87, no. 4, 2009, pages 589 - 598
DAVE, S.S. ET AL.: "Prediction Of Survival In Follicular Lymphoma Based On Molecular Features Of Tumor-Infiltrating Immune Cells,", N. ENGL. J. MED., vol. 351, 2004, pages 2159 - 2169
DAVIES, H. ET AL.: "Mutations Of The BRAF Gene In Human Cancer,", NATURE, vol. 417, 2002, pages 949 - 954
DE HAIJ, S. ET AL.: "Renal Tubular Epithelial Cells Modulate T-Cell Responses Via ICOS-L And B7-HI", KIDNEY INT., vol. 68, 2005, pages 2091 - 2102
DECKER, T. ET AL.: "Increased Number Of Regulatory T Cells (T-Regs) In The Peripheral Blood Of Patients With Her-2/Neu-Positive Early Breast Cancer,", J. CANCER RES. CLIN. ONCOL., vol. 138, no. 11, 4 July 2012 (2012-07-04), pages 1945 - 1950
DENT, P. ET AL.: "Activation Of Mitogen-Activated Protein Kinase Kinase By V-Raf In NIH 3T3 Cells And in vitro,", SCIENCE, vol. 257, 1992, pages 1404 - 1407
DONG, C. ET AL.: "Immune Regulation by Novel Costimulatory Molecules,", IMMUNOLOG. RES., vol. 28, no. 1, 2003, pages 39 - 48
DONG, H.: "B7-H] Pathway And Its Role In The Evasion Of Tumor Immunity,", J. MOL. MED., vol. 81, 2003, pages 281 - 287
DONSKOV, F.: "Immunomonitoring And Prognostic Relevance Of Neutrophils In Clinical Trials,", SEMIN. CANCER BIOL., 2013
DROESER, R. ET AL.: "Differential Pattern And Prognostic Significance Of CD4+, FOXP3+ And IL-1 7+ Tumor Infiltrating Lymphocytes In Ductal And Lobular Breast Cancers,", BMC CANCER, vol. 12, 2012, pages 134
DULOS JOHN ET AL: "PD-1 Blockade Augments Th1 and Th17 and Suppresses Th2 Responses in Peripheral Blood From Patients With Prostate and Advanced Melanoma Cancer", JOURNAL OF IMMUNOTHERAPY, LIPPINCOTT WILLIAMS & WILKINS, HAGERSTOWN, MD, US, vol. 35, no. 2, 1 February 2012 (2012-02-01), pages 169 - 178, XP008171910, ISSN: 1524-9557, DOI: 10.1097/CJI.0B013E318247A4E7 *
DURAISWAMY, J. ET AL.: "Phenotype, Function, And Gene Expression Profiles Of Programmed Death-1(Hi) CD8 T Cells In Healthy Human Adults,", J. IMMUNOL., vol. 186, no. 7, 2011, pages 4200 - 4212
ELLOSO, M.M.; 1999 ET AL.: "Expression and Contribution of B7-1 (CD80) and B7-2 (CD86) in the Early Immune Response to Leishmania major Infection,", J. IMMUNOL., vol. 162, pages 6708 - 6715
EPSTEIN ET AL., PROC. NATL. ACAD. SCI. USA, vol. 82, 1985, pages 3688
FARINHA, P. ET AL.: "Analysis Of Multiple Biomarkers Shows That Lymphoma-Associated Macrophage (LAM) Content Is An Independent Predictor Of Survival In Follicular Lymphoma (FL),", BLOOD, vol. 106, 2005, pages 2169 - 2174
FEDOR, H.L. ET AL.: "Practical Methods For Tissue Microarray Construction,''", METHODS MOLEC. MED., vol. 103, 2005, pages 89 - 101
FERGUSON, J. ET AL.: "Combination of MEK and SRC Inhibition Suppresses Melanoma Cell Growth And Invasion,''", ONCOGENE, vol. 32, no. 1, 2012, pages 86 - 96
FERGUSON, J. ET AL.: "Combination of MEK and SRC Inhibition Suppresses Melanoma Cell Growth And Invasion,", ONCOGENE, vol. 32, no. 1, 2012, pages 86 - 96
FISHMAN ET AL.: "Medicine", 1985, J.B. LIPPINCOTT CO.
FITZGERALD, D.J. ET AL.: "Treatment Of Hematologic Malignancies With Immunotoxins And Antibody-Drug Conjugates,", CANCER RES., vol. 71, no. 20, 2011, pages 6300 - 6309
FLIES, D.B. ET AL.: "The New B7s: Playing a Pivotal Role in Tumor Immunity,", J. IMMUNOTHER, vol. 30, no. 3, 2007, pages 251 - 260
FLIES, D.B. ET AL.: "The New B7s: Playing a Pivotal Role in Tumor Immunity,", J. IMMUNOTHER., vol. 30, no. 3, 2007, pages 251 - 260
FORD, J.W. ET AL.: "TREM And TREM-Like Receptors In Inflammation And Disease,", CURR. OPIN. IMMUNOL., vol. 21, no. 1, 2009, pages 38 - 46
FREEMAN, G.J. ET AL.: "Engagement Of The PD-1 Immunoinhibitory Receptor By A Novel B7 Family Member Leads To Negative Regulation Of Lymphocyte Activation,", J. EXP. MED., vol. 192, 2000, pages 1 - 9
FULIANG CHU ET AL: "Immunological Effects and Predictive Gene Signatures in Patients with Relapsed Follicular Lymphoma Treated with CT-011, a Humanized Anti-PD-1 Monoclonal Antibody", BLOOD, vol. 120, no. 21, 16 November 2012 (2012-11-16) - 11 December 2012 (2012-12-11), US, pages 162, XP055138386, ISSN: 0006-4971 *
GAGGIOLI, C. ET AL.: "Tumor-Derived Fibronectin Is Involved In Melanoma Cell Invasion And Regulated By V600E B-Raf Signaling Pathway,", J. INVEST. DERMATOL., vol. 127, 2007, pages 400 - 410
GAO, Q. ET AL.: "Overexpression Of PD-LI Significantly Associates With Tumor Aggressiveness And Postoperative Recurrence In Human Hepatocellular Carcinoma,", CLIN. CANCER RES., vol. 15, no. 3, 2009, pages 971 - 999
GEORGE, B. ET AL.: "Predictive And Prognostic Markers In Colorectal Cancer,", CURR. ONCOL. REP., vol. 13, no. 3, 2011, pages 206 - 215
GERLINGER, M. ET AL.: "Intratumor Heterogeneity And Branched Evolution Revealed By Multiregion Sequencing,", N. ENGL. J. MED., vol. 366, 2012, pages 883 - 892
GIBBINGS, D. ET AL.: "CD4 and CDB: an inside-out coreceptor model for innate immune cells,", J. LEUKOC. BIOL., vol. 86, no. 2, 2009, pages 251 - 259
GÖKMEN-POLAR, Y. ET AL.: "Biomarkers For Breast Cancer Stem Cells: The Challenges Ahead,", BIOMARK. MED., vol. 5, no. 5, 2011, pages 61 - 71
GOLD, J.S. ET AL.: "Combined Surgical And Molecular Therapy: The Gastrointestinal Stromal Tumor Model,", ANN. SURG., vol. 244, no. 2, 2006, pages 176 - 184
GOLDEN-MASON ET AL.: "Upregulation of PD-1 Expression on Circulating and Intrahepatic Hepatitis C Virus-Specific CD8+ T Cells Associated with Reversible Immune Dysfunction", J. VIROL., vol. 81, no. 17, 2007, pages 9249 - 9258
GONZALEZ-GARCIA, I. ET AL.: "Metapopulation Dynamics And Spatial Heterogeneity In Cancer,", PROC. NATL. ACAD. SCI. (USA, vol. 99, no. 20, 2002, pages 13085 - 13089
GREENWALD, R.J. ET AL.: "Ann. Rev. Immunol.", THE B7 FAMILY REVISITED,, vol. 23, 2005, pages 515 - 548
GREENWALD, R.J. ET AL.: "The B7 Family Revisited,", ANN. REV. IMMUNOL., vol. 23, 2005, pages 515 - 548
GRIEB, G. ET AL.: "Macrophage Migration Inhibitory Factor (MIF): A Promising Biomarker,", DRUG NEWS PERSPECT., vol. 23, no. 4, 2010, pages 257 - 264
GROSS, J. ET AL.: "Identification And Distribution Of The Costimulatory Receptor CD28 In The Mouse,", J. IMMUNOL., vol. 149, 1992, pages 380 - 388
HAMEL, K.M. ET AL.: "B7-H] Expression On Non-B And Non-T Cells Promotes Distinct Effects On T- And B-Cell Responses In Autoimmune Arthritis,", EUR. J. IMMUNOL., vol. 40, no. 11, 2010, pages 3117 - 3127
HAMID, O. ET AL.: "A Prospective Phase II Trial Exploring The Association Between Tumor Microenvironment Biomarkers And Clinical Activity Of Ipilimumab In Advanced Melanoma,", J. TRANSL. MED., vol. 9, 2011, pages 204
HASAN, A.: "Therapeutic Targeting O| B7-111 In Breast Cancer,", EXPERT OPIN. THER. TARGETS, vol. 15, no. 10, 2011, pages 1211 - 1225
HELD, M.A. ET AL.: "Genotype-Selective Combination Therapies For Melanoma Identified By High-Throughput Drug Screening,", CANCER DISCOVERY, vol. 3, 2013, pages 52 - 67
HENSEL, J.A. ET AL.: "Clinical Opportunities And Challenges In Targeting Tumour Dormancy,", NAT. REV. CLIN. ONCOL., vol. 10, no. 1, 27 November 2012 (2012-11-27), pages 41 - 5
HICKS, S.D. ET AL.: "Evaluation Of Cell Proliferation, Apoptosis, And DNA-Repair Genes As Potential Biomarkers For Ethanol-Induced CNS Alterations,", BMC NEUROSCI., vol. 13, no. 1, 2012, pages 1 - 13
HOEI-HANSEN, C.E. ET AL.: "Current Approaches For Detection Of Carcinoma In Situ Testis,", INT. J. ANDROL., vol. 30, no. 4, 2007, pages 398 - 405
HOLM, M. ET AL.: "PD-1 Predicts CD4 Loss Rate In Chronic HIV-1 Infection Better Than HIV RNA And CD38 But Not In Cryopreserved Samples,", CURR. HIV RES., vol. 6, no. 1, 2008, pages 49 - 58
HONG, D.S. ET AL.: "BRAF(V600) Inhibitor GSK2118436 Targeted Inhibition of Mutant BRAF in Cancer Patients Does Not Impair Overall Immune Competency,", CLIN. CANCER RES., vol. 18, 21 February 2012 (2012-02-21), pages 2326 - 2335
HOUGHTON, O ET AL.: "The Expression And Diagnostic Utility Of P63 In The Female Genital Tract,", ADV. ANAT. PATHOL., vol. 16, no. 5, 2009, pages 316 - 321
HUANG, R.R. ET AL.: "CTLA4 Blockade Induces Frequent Tumor Infiltration By Activated Lymphocytes Regardless Of Clinical Responses In Humans,", CLIN. CANCER RES., vol. 17, no. 12, 2011, pages 4101 - 4109
HWANG ET AL., PROC. NATL. ACAD. SCI. USA, vol. 77, 1980, pages 4030 - 4
ISHIDA, Y. ET AL.: "Induced Expression Of PD-1, A Novel Member Of The Immunoglobulin Gene Superfamily, Upon Programmed Cell Death,", EMBO J., vol. 11, 1992, pages 3887 - 3895
ISHIDA, Y. ET AL.: "Induced Expression Of PD-l, A Novel Member Of The Immunoglobulin Gene Superfamily, Upon Programmed Cell Death,", EMBO J., vol. 11, 1992, pages 3887 - 3895
ISHIWATA, K. ET AL.: "Costimulator Responses Induced by Nippostrongylus brasiliensis,", J. IMMUNOL, vol. 184, 10 January 2010 (2010-01-10), pages 2086 - 2094
JANELLE M. FAUCI ET AL: "A review of B7-H3 and B7-H4 immune molecules and their role in ovarian cancer", GYNECOLOGIC ONCOLOGY, vol. 127, no. 2, 1 November 2012 (2012-11-01), pages 420 - 425, XP055134637, ISSN: 0090-8258, DOI: 10.1016/j.ygyno.2012.08.017 *
JAOUDE, P.A.: "Biomarkers In The Diagnosis Of Aspiration Syndromes,", EXPERT REV. MOL. DIAGN., vol. 10, no. 3, 2010, pages 309 - 319
JI, R.R. ET AL.: "An Immune-Active Tumor Microenvironment Favors Clinical Response To Ipilimumab,", CANCER IMMUNOL. IMMUNOTHER, vol. 61, no. 7, 2012, pages 1019 - 1031
JOYCE, J.A. ET AL.: "Microenvironmental Regulation Of Metastasis,", NAT. REV. CANCER., vol. 9, no. 4, 2008, pages 239 - 252
JUDD, N.P. ET AL.: "Comparative Analysis Of Tumor-Infiltrating Lymphocytes In A Syngeneic Mouse Model Of Oral Cancer,", OTOLARYNGOL. HEAD NECK SURG, vol. 147, no. 3, 2012, pages 493 - 500
KABAT ET AL.: "Sequences of Proteins of Immunological Interest", 1991, PUBLIC HEALTH SERVICE, NATIONAL INSTITUTES OF HEALTH
KAJIMA, H. ET AL.: "Histopathology And Tumor Markers,", RINSHO BYORI., vol. 51, no. 12, December 2003 (2003-12-01), pages 1203 - 1215
KIM, Y.R. ET AL.: "Lymphopenia Is An Important Prognostic Factor In Peripheral T-Cell Lymphoma (NOS) Treated With Anthracycline-Containing Chemotherapy,", J. HEMATOL. ONCOL., vol. 4, 2011, pages 34
KLEIN, C.A. ET AL.: "Genetic Heterogeneity Of Single Disseminated Tumour Cells In Minimal Residual Cancer,", LANCET, vol. 360, no. 9334, 31 August 2002 (2002-08-31), pages 683 - 689
KNAPPIK ET AL., BIOTECHNIQUES, vol. 17, no. 4, 1994, pages 754 - 761
KOH, Y.W. ET AL.: "The Ratio Of The Absolute Lymphocyte Count To The Absolute Monocyte Count Is Associated With Prognosis In Hodgkin's Lymphoma: Correlation With Tumor-Associated Macrophages,", ONCOLOGIST, vol. 17, no. 6, 15 May 2012 (2012-05-15), pages 871 - 880
KORMAN, A.J. ET AL.: "Checkpoint Blockade in Cancer Immunotherapy,", ADV. IMMUNOL., vol. 90, 2007, pages 297 - 339
KORN, E.L. ET AL.: "Meta-Analysis Of Phase II Cooperative Group Trials In Metastatic Stage IV Melanoma To Determine Progression-Free And Overall Survival Benchmarks For Future Phase II Trials", J. CLIN. ONCOL., vol. 26, 2008, pages 527 - 534
KOSAKO, H. ET AL.: "Xenopus MAP Kinase Activator Is A SerinelThreoninelTyrosine Kinase Activated By Threonine Phosphorylation,", EMBO J., vol. 11, 1992, pages 2903 - 2908
KOWAL, K. ET AL.: "CD163 And Its Role In Inflammation,", FOLIA HISTOCHEM CYTOBIOL., vol. 49, no. 3, 2011, pages 365 - 374
KRAMBECK, A.E. ET AL.: "B7-H4 Expression In Renal Cell Carcinoma And Tumor Vasculature: Associations With Cancer Progression And Survival,", PROC. NATL. ACAD. SCI. (USA, vol. 103, 2006, pages 10391 - 10396
KRYCZEK, 1. ET AL.: "B7-H4 Expression Identifies A Novel Suppressive Macrophage Population In Human Ovarian Carcinoma,", J. EXP. MED., vol. 203, no. 4, 2006, pages 71 - 81
KRYCZEK, 1. ET AL.: "B7-H4 Expression Identifies A Novel Suppressive Macrophage Population In Human Ovarian Carcinoma,", J. EXP. MED., vol. 203, no. 4, 2006, pages 871 - 881
KRYCZEK, I. ET AL.: "B7-H4 Expression Identifies A Novel Suppressive Macrophage Population In Human Ovarian Carcinoma,", J. EXP. MED., vol. 203, no. 4, 2006, pages 871 - 881
KRYCZEK, I. ET AL.: "Cutting Edge: Induction Of B7-H4 On APCs Through IL-10: Novel Suppressive Mode For Regulatory T Cells,", J. IMMUNOL., vol. 177, no. 1, 2006, pages 40 - 44
KRYCZEK, I. ET AL.: "Relationship Between B7-H4, Regulatory T Cells, And Patient Outcome In Human Ovarian Carcinoma,", CANCER RES., vol. 67, no. 18, 2007, pages 8900 - 8905
KRYCZEK, J.I, J. IMMUNOL., vol. 177, no. 1, 2006, pages 40 - 44
KUANG, D.M. ET AL.: "Activated Monocytes In Peritumoral Stroma Of Hepatocellular Carcinoma Foster Immune Privilege And Disease Progression Through PD-L7,", J. EXP. MED., vol. 206, no. 6, 2009, pages 1327 - 1337
KUCZYK, M. ET AL.: "The Need For Microdissectional Tumor Cell Preparation During The Molecular Genetic Analysis Of Prostate Cancer,", WORLD J. UROL., vol. 17, no. 2, 1999, pages 115 - 122
KUNISCH, E. ET AL.: "Macrophage Specificity Of Three Anti-CD68 Monoclonal Antibodies (KPI, EBM11 And PGM1) Widely Used For Immunohistochemistry And Flow Cytometry,", ANN RHEUM DIS., vol. 63, no. 7, 2004, pages 774 - 784
KUWABARA, M. ET AL.: "Molecular Microheterogeneity Of Tumor Marker Substances And Its Significance Of Biological Recognition,", NIHON RINSHO., vol. 54, no. 6, 1996, pages 1580 - 1586
KYRIAKIS, J.M. ET AL.: "Raf Activates MAP Kinase-Kinase,", NATURE, vol. 358, 1992, pages 417 - 421
LAD, D.P. ET AL.: "Regulatory T-Cells In B-Cell Chronic Lymphocytic Leukemia: Their Role In Disease Progression And Autoimmune Cytopenias,", LEUK. LYMPHOMA, 16 October 2012 (2012-10-16)
LASH, G.E. ET AL.: "Multiplex Cytokine Analysis Technologies,", EXPERT REV. VACCINES, vol. 9, no. 10, 2010, pages 1231 - 1237
LATCHMAN, Y. ET AL.: "PD-L2 Is A Second Ligand For PD-1 And Inhibits T Cell Activation,", NAT. IMMUNOL, vol. 2, 2001, pages 261 - 268
LATCHMAN, Y. ET AL.: "PD-L2 Is A Second Ligand For PD-1 And Inhibits T Cell Activation,", NATURE IMMUNOL., vol. 2, 2001, pages 261 - 268
LÁZÁR-MOLNÁR, E. ET AL.: "Crystal Structure Of The Complex Between Programmed Death-I (PD-1) And Its Ligand PD-L2,", PROC. NATL. ACAD. SCI. (USA, vol. 105, no. 30, 2008, pages 10483 - 10488
LEE, J.T. JR. ET AL.: "The Raf/MEK/ERK Signal Transduction Cascade As A Target For Chemotherapeutic Intervention In Leukemia,", LEUKEMIA, vol. 16, 2002, pages 486 - 507
LEE, J.T. JR. ET AL.: "The RafIMEKIERK Signal Transduction Cascade As A Target For Chemotherapeutic Intervention In Leukemia,", LEUKEMIA, vol. 16, 2002, pages 486 - 507
LEE, J.-Y. ET AL.: "Remembering To Be Tolerant,", SCIENCE, vol. 335, 2012, pages 667 - 668
LEE, J.Y. ET AL.: "Remembering To Be Tolerant,", SCIENCE, vol. 335, 2013, pages 667 - 668
LENSCHOW, D.J. ET AL.: "CD28/B7 System of T Cell Costimulation,", ANN. REV. IMMUNOL., vol. 14, 1996, pages 233 - 258
LEPENIES, B. ET AL.: "The Role Of Negative Costimulators During Parasitic Infections,", ENDOCRINE, METABOLIC & IMMUNE DISORDERS - DRUG TARGETS, vol. 8, 2008, pages 279 - 288
LINDLEY, P.S. ET AL.: "The Clinical Utility Of Inhibiting CD28-Mediated Costimulation,", IMMUNOL. REV., vol. 229, 2009, pages 307 - 321
LINSLEY, P. ET AL.: "Intracellular Trafficking Of CTLA4 And Focal Localization Towards Sites Of TCR Engagement,", IMMUNITY, vol. 4, 1996, pages 535 - 543
LOKE, P. ET AL.: "Emerging Mechanisms Of Immune Regulation: The Extended B7 Family And Regulatory T Cells.", ARTHRITIS RES. THER., vol. 6, 2004, pages 208 - 214
LONG, G.V. ET AL.: "Clinicopathologic Correlates Of BRAF Mutation Status In 207 Consecutive Patients With Metastatic Melanoma,", J. CLIN. ONCOL, vol. 28, 2010, pages 15S
MADHUNAPANTULA, S.R.V. ET AL.: "Is B-Raf a Good Therapeutic Target for Melanoma and Other Malignancies?", CANCER RES, vol. 68, 2008, pages 5 - 8
MARTIN-OROZCO, N ET AL.: "Inhibitory Costimulation And Anti-tumor Immunity,", SEMIN. CANCER BIOL., vol. 17, no. 4, 2007, pages 288 - 298
MARTIN-OROZCO, N. ET AL.: "Inhibitory Costimulation And Anti-tumor Immunity,", SEMIN. CANCER BIOL., vol. 17, no. 4, 2007, pages 288 - 298
MAZANET, M.M. ET AL.: "B7-H] Is Expressed By Human Endothelial Cells And Suppresses T Cell Cytokine Synthesis,", J. IMMUNOL., vol. 169, 2002, pages 3581 - 3588
MCCUBREY, J.A. ET AL.: "Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascade Inhibitors: How Mutations Can Result in Therapy Resistance and How to Overcome Resistance", ONCOTARGET, vol. 3, 2012, pages 1068 - 1111
MICHALOGLOU, C. ET AL.: "BRAFE600-Associated Senescence-Like Cell Cycle Arrest Of Human Naevi,", NATURE, vol. 436, 2005, pages 720 - 724
MITROVIC, Z. ET AL.: "The Prognostic Significance Of Lymphopenia In Peripheral T-Cell And Natural KillerIT-Cell Lymphomas: A Study Of 826 Cases From The International Peripheral T-Cell Lymphoma Project,", AM. J. HEMATOL., vol. 87, no. 8, 10 April 2012 (2012-04-10), pages 790 - 794
MOCIKOVÁ H.: "Prognostic Significance Of Absolute Lymphocyte Count And Lymphocyte Subsets In Lymphomas,", PRAGUE MED. REP., vol. 111, no. 1, 2010, pages 1
MUELLER ET AL., MOL. IMMUN., vol. 34, no. 6, 1997, pages 441 - 452
MURPHY ET AL.: "Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery", 1997, PENGUIN BOOKS U.S.A., INC.
MUYLDERMANS, S. ET AL.: "Recognition Of Antigens By Single-Domain Antibody Fragments: The Superfluous Luxury Of Paired Domains,", TRENDS BIOCHEM. SCI., vol. 26, 2001, pages 230 - 235
MYKLEBUST, J.H. ET AL.: "High PD-1 Expression And Suppressed Cytokine Signaling Distinguish T Cells Infiltrating Follicular Lymphoma Tumors From Peripheral T Cells,", BLOOD, vol. 121, no. 8, 7 January 2013 (2013-01-07), pages 1367 - 1376
NISHIMURA, H. ET AL.: "Facilitation Of Beta Selection And Modification Of Positive Selection In The Thymus Of PD- -Deficient Mice,", J. EXP. MED., vol. 191, 2000, pages 891 - 898
NUTTALL, S.D. ET AL.: "Immunoglobulin VH Domains And Beyond: Design And Selection Of Single-Domain Binding And Targeting Reagents,", CUR. PHARM. BIOTECH., vol. 1, 2000, pages 253 - 263
OESTREICH ET AL.: "NFATcl Regulates PD-1 Expression Upon T Cell Activation,", J. IMMUNOL., vol. 181, 2008, pages 4832 - 4848
OKAZAKI, T. ET AL.: "PD-1 And PD-1 Ligands: From Discovery To Clinical Application,", INT. IMMUNOL., vol. 19, no. 7, 2007, pages 813 - 824
OKI, Y. ET AL.: "Low Absolute Lymphocyte Count Is A Poor Prognostic Marker In Patients With Diffuse Large B-Cell Lymphoma And Suggests Patients' Survival Benefit From Rituximab,", EUR. J. HAEMATOL., vol. 81, no. 6, 2008, pages 448 - 453
OLSEN, J. ET AL.: "Acute Leukemia Immunohistochemistry: A Systematic Diagnostic Approach,", ARCH. PATHOL. LAB. MED., vol. 132, no. 3, 2008, pages 462 - 475
ONABAJO, O.O. ET AL.: "Rhesus Macaque Lymph Node PD-1 (Hi)CD4(+) T Cells Express High Levels Of CXCRS And IL-21 And Display A CCR7(Lo)ICOS(+)Bcl6(+) T-Follicular Helper (Tfh) Cell Phenotype,", PLOS ONE, vol. 8, no. 3, 2013, pages E59758
PADMANABHAN, P. ET AL.: "Molecular Targeting Of Breast Cancer: Imaging And Therapy,", CURR. PHARM. BIOTECHNOL., vol. 12, no. 4, 2011, pages 528 - 538
PALMER, S. ET AL.: "Prognostic Importance Of TAnd NK-Cells In A Consecutive Series Of Newly Diagnosed Patients With Chronic Lymphocytic Leukaemia,", BR. J. HAEMATOL., vol. 141, no. 5, 2008, pages 607 - 614
PANER, G.P.: "Best Practice In Diagnostic Immunohistochemistry: Prostate Carcinoma And Its Mimics In Needle Core Biopsies,", ARCH. PATHOL. LAB. MED., vol. 132, no. 9, 2008, pages 1388 - 1396
PAOLO A ASCIERTO ET AL: "The additional facet of immunoscore: immunoprofiling as a possible predictive tool for cancer treatment", JOURNAL OF TRANSLATIONAL MEDICINE, BIOMED CENTRAL, LONDON, GB, vol. 11, no. 1, 3 March 2013 (2013-03-03), pages 54, XP021142097, ISSN: 1479-5876, DOI: 10.1186/1479-5876-11-54 *
PARAISO K.H. ET AL.: "Recovery Of Phospho-ERK Activity Allows Melanoma Cells To Escape From BRAF Inhibitor Therapy,", BR. J. CANCER, vol. 102, no. 12, 2010, pages 1724 - 1730
PARDOLL, D. ET AL.: "Immunotherapy Earns Its Spot In The Ranks Of Cancer Therapy,", J. EXP. MED., vol. 209, no. 2, 2012, pages 201 - 209
PARDOLL, D.M.; APRIL 2012: "The Blockade Of Immune Checkpoints In Cancer Immunotherapy,", NATURE REVIEWS CANCER, vol. 12, pages 252 - 264
PARK, B.J. ET AL.: "Dasatinib Synergizes With Both Cytotoxic And Signal Transduction Inhibitors In Heterogeneous Breast Cancer Cell Lines--Lessons For Design Of Combination Targeted Therapy,''", CANCER LETT., vol. 320, no. 1, 2 February 2012 (2012-02-02), pages 104 - 110
PATEL, T. ET AL.: "Cancer Stem Cells, Tumor Dormancy, And Metastasis,", FRONT. ENDOCRINOL. (LAUSANNE, vol. 3, 23 October 2012 (2012-10-23), pages 125
PAYNE, D.M. ET AL.: "Identification Of The Regulatory Phosphorylation Sites In pp42/Mitogen-Activated Protein Kinase (MAP Kinase),", EMBO J., vol. 10, 1991, pages 885 - 892
PENAULT-LLORCA, F. ET AL.: "Emerging Technologies For Assessing HER2 Amplification,", AMER. J. CLIN. PATHOL., vol. 132, no. 4, 2009, pages 539 - 548
PENG WEIYI ET AL: "PD-1 Blockade Enhances T-cell Migration to Tumors by Elevating IFN-gamma Inducible Chemokines", CANCER RESEARCH, vol. 72, no. 20, October 2012 (2012-10-01), pages 5209 - 5218, XP002729473 *
PETROFF, M.G. ET AL.: "B7 Family Molecules: Novel Immunomodulators At The Maternal-Fetal Interface,", PLACENTA, vol. 23, 2002, pages S95 - S101
PICCOLI, A.K. ET AL.: "Expression Of Complement Regulatory Proteins CD55, CD59, CD35, And CD46 In Rheumatoid Arthritis,", REV. BRAS. REUMATOL., vol. 51, no. 5, 2011, pages 503 - 510
PLATZ, A. ET AL.: "Human Cutaneous Melanoma; A Review Of NRAS And BRAF Mutation Frequencies In Relation To Histogenetic Subclass And Body Site,", MOL. ONCOL., vol. 1, 2008, pages 395 - 405
PLUCKTHUN: "The Pharmacology of Monoclonal Antibodies", vol. 113, 1994, SPRINGER-VERLAG, pages: 269 - 315
POLANSKI, M. ET AL.: "A List Of Candidate Cancer Biomarkers For Targeted Proteomics,", BIOMARKER INSIGHTS, vol. 2, 2006, pages 1 - 48
POLLARD, J.W.: "Trophic Macrophages In Development And Disease,", NAT. REV. IMMUNOL., vol. 9, 2009, pages 259 - 270
PORRATA, L.F. ET AL.: "Absolute Lymphocyte Count At The Time Of First Relapse Predicts Survival In Patients With Diffuse Large B-Cell Lymphoma,", AM. J. HEMATOL., vol. 84, no. 2, 2009, pages 93 - 97
PRASAD, D.V. ET AL.: "B7Sl, A Novel B7 Family Member That Negatively Regulates T Cell Activation,", IMMUNITY, vol. 18, 2003, pages 863 - 873
PRENDERGAST, A. ET AL.: "Factors Influencing T Cell Activation And Programmed Death 1 Expression In HIV-Infected Children,", AIDS RES. HUM. RETROVIRUSES, vol. 28, no. 5, 2012, pages 465 - 468
PRESTA, CUR. OPIN. IMMUN., vol. 20, 2008, pages 460 - 470
QUESNEL, B. ET AL.: "SYSTEMS BIOLOGY OF TUMOR DORMANCY, ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY", SPRINGER SCIENCE+BUSINESS MEDIA, article "Tumor Dormancy: Long-Term Survival in a Hostile Environment,''", pages: 181 - 200
QUESNEL, B. ET AL.: "SYSTEMS BIOLOGY OF TUMOR DORMANCY, ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY", vol. 734, 2013, SPRINGER SCIENCE+BUSINESS MEDIA, article "Tumor Dormancy: Long-Term Survival in a Hostile Environment,", pages: 181 - 200
QUESNEL, B.: "Cancer Vaccines And Tumor Dormancy: A Long-Term Struggle Between Host Antitumor Immunity And Persistent Cancer Cells?,", EXPERT REV VACCINES, vol. 5, no. 6, 2006, pages 773 - 781
QUESNEL, B.: "Dormant Tumor Cells As A Therapeutic Target?,", CANCER LETT., vol. 267, no. 1, 2008, pages 10 - 17
QUESNEL, B.: "Tumor Dormancy And Immunoescape,", APMIS, vol. 116, no. 7-8, 2008, pages 685 - 94
QUEZADA, S.A. ET AL.: "Tumor-Reactive CD4(+) T Cells Develop Cytotoxic Activity And Eradicate Large Established Melanoma After Transfer Into Lymphopenic Hosts,", J. EXP. MED., vol. 207, no. 3, 2010, pages 637 - 650
REICHMANN, L. ET AL.: "Single domain antibodies: comparison of camel VH and camelised human VH domains", J. IMMUNOL. METHODS, vol. 231, no. 1-2, 1999, pages 25 - 38
RODRÍQUEZ-GARCÍA, M. ET AL.: "Expression Of PD-LI And PD-L2 On Human Macrophages Is Up-Regulated By HIV-1 And Differentially Modulated By IL-10,", J. LEUKOCYTE BIOL., vol. 89, 19 November 2010 (2010-11-19)
ROMANO, F. ET AL.: "Preoperative IL-2 Immunotherapy Enhances Tumor Infiltrating Lymphocytes (TILs) In Gastric Cancer Patients,", HEPATOGASTROENTEROLOGY, vol. 53, no. 70, 2006, pages 634 - 638
ROSSOMANDO, A.J. ET AL.: "Evidence Thatpp42, A Major Tyrosine Kinase Target Protein, Is A Mitogen-Activated SerineIThreonine Protein Kinase,", PROC. NATL. ACAD. SCI. (U.S.A., vol. 86, 1989, pages 6940 - 6943
S.W. BURCHIEL ET AL.: "Tumor Imaging: The Radiochemical Detection of Cancer", 1982, MASSON PUBLISHING INC., article "Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments."
SALCEDA, S. ET AL.: "The Immunomodulatory Protein B7-H4 Is Overexpressed In Breast And Ovarian Cancers And Promotes Epithelial Cell Transformation,", EXP. CELL RES., vol. 306, 2005, pages 128 - 141
SALISCH ET AL.: "Inhibitory TCR Coreceptor PD-1 Is a Sensitive Indicator of Low-Level Replication of SIV and HIV-1,", J. IMMUNOL., vol. 184, no. 1, 2010, pages 476 - 487
SCATENA, R. ET AL.: "Cancer Stem Cells: The Development Of New Cancer Therapeutics,", EXPERT OPIN. BIOL. THER., vol. 11, no. 7, 2011, pages 875 - 892
SCHIETINGER, A. ET AL.: "Rescued Tolerant CD8 T Cells Are Preprogrammed to Reestablish the Tolerant State,", SCIENCE, vol. 335, 2012, pages 723 - 727
SEGER, R. ET AL.: "Human T-Cell Mitogen-Activated Protein Kinase Kinases Are Related To Yeast Signal Transduction Kinases,", J. BIOL. CHEM, vol. 267, 1992, pages 25628 - 25631
SFANOS ET AL.: "Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1 +,", PROSTATE, vol. 69, no. 15, 2009, pages 1694 - 1703
SHARMA, A. ET AL.: "Mutant V599EB-Raf Regulates Growth And Vascular Development Of Malignant Melanoma Tumors,", CANCER RES., vol. 65, 2005, pages 2412 - 2421
SHARMA, A. ET AL.: "Targeting Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase In The Mutant (V600E) B-Raf Signaling Cascade Effectively Inhibits Melanoma Lung Metastases,", CANCER RES., vol. 66, 2006, pages 8200 - 8209
SHARPE, A.H. ET AL.: "The B7-CD28 Superfamily,", NATURE REV. IMMUNOL., vol. 2, 2002, pages 116 - 126
SHI ET AL., PD-1 AND PD-LI UPREGULATION PROMOTES CD8(+) T-CELL APOPTOSIS AND POSTOPERATIVE RECURRENCE IN HEPATOCELLULAR CARCINOMA PATIENTS,, vol. 128, no. 4, 2011, pages 887 - 896
SHI, F. ET AL.: "PD-1 And PD-LI Upregulation Promotes CD8(+) T-Cell Apoptosis And PostOperative Recurrence In Hepatocellular Carcinoma Patients,", INT. J. CANCER, vol. 128, no. 4, 2011, pages 887 - 896
SICA ET AL., IMMUNITY, vol. 18, 2003, pages 849 - 861
SICA, G.L. ET AL.: "B7-H4, A Molecule Of The B7 Family, Negatively Regulates T Cell Immunity,", IMMUNITY, vol. 18, 2003, pages 849 - 861
SIMON, 1. ET AL.: "B7-h4 Is A Novel Membrane-Bound Protein And A Candidate Serum And Tissue Biomarker For Ovarian Cancer,", CANCER RES., vol. 66, 2006, pages 1570 - 1575
SOLINAS, G. ET AL.: "Tumor-Associated Macrophages (TAM) As Major Players Of The Cancer-Related Inflammation,", J. LEUKOC. BIOL., vol. 86, no. 5, 2009, pages 1065 - 1073
SOSA, M.S. ET AL.: "Regulation Of Tumor Cell Dormancy By Tissue Microenvironments And Autophagy,", ADV. EXP. MED. BIOL., vol. 734, 23 October 2012 (2012-10-23), pages 73 - 89
STERLING, J. ET AL.: "Current Trends In High-Throughput Screening,", ASSAY DRUG DEV. TECHNOL., vol. 6, no. 4, 2008, pages 491 - 504
STRASSER, A. ET AL.: "Deciphering The Rules Of Programmed Cell Death To Improve Therapy Of Cancer And Other Diseases,", EMBO J., vol. 30, no. 18, 2011, pages 3667 - 3683
STRAUSSMAN, R. ET AL.: "Tumour MicroEnvironment Elicits Innate Resistance To RAF Inhibitors Through HGF Secretion,", NATURE, vol. 487, no. 7408, 2012, pages 500 - 504
SUBUDHI, S.K. ET AL.: "The Balance Of Immune Responses: Costimulation Verse Coinhibition,", J. MOLEC. MED., vol. 83, 2005, pages 193 - 202
SUN, Y. ET AL.: "B7-H3 And B7-H4 Expression In Non-Small-Cell Lung Cancer,", LUNG CANCER, vol. 53, 2006, pages 143 - 151
SUZANNE L TOPALIAN ET AL: "Safety, activity, and immune correlates of anti-PD-1 antibody in cancer", THE NEW ENGLAND JOURNAL OF MEDICINE, 28 June 2012 (2012-06-28), United States, pages 2443 - 2454, XP055098235, Retrieved from the Internet <URL:http://search.proquest.com/docview/1022620071> DOI: 10.1056/NEJMoa1200690 *
SWANN ET AL., CUR. OPIN. IMMUN., vol. 20, 2008, pages 493 - 499
THOMPSON ET AL.: "Tumor B7-H1 Is Associated with Poor Prognosis in Renal Cell Carcinoma Patients with Long-term Follow-up,", CANCER RES., vol. 66, no. 7, 2006, pages 3381 - 3385
THOMPSON, R.H. ET AL.: "Implications Of B7-H1 Expression In Clear Cell Carcinoma Of The Kidney For Prognostication And Therapy,", CLIN. CANCER RES., vol. 13, no. 2, 2007, pages 709S - 715S
THOMPSON, R.H. ET AL.: "Significance of B7-H1 overexpression in kidney cancer", CLIN. GENITOURIN. CANCER, vol. 5, no. 3, 2006, pages 206 - 211
THORP, E. ET AL.: "The Role Of Macrophages And Dendritic Cells In The Clearance Of Apoptotic Cells In Advanced Atherosclerosis,", EUR. J. IMMUNOL., vol. 41, no. 9, 2011, pages 2515 - 2518
TRINGLER, B. ET AL.: "B7-H4 Is Highly Expressed In Ductal And Lobular Breast Cancer,", CLIN. CANCER RES., vol. 11, 2005, pages 1842 - 1848
TRINGLER, B. ET AL.: "B7-H4 Overexpression In Ovarian Tumors,", GYNECOL. ONCOL., vol. 100, 2006, pages 44 - 52
TSENG, S.Y. ET AL.: "B7-DC, A New Dendritic Cell Molecule With Potent Costimulatory Properties For T Cells,", J. EXP. MED., vol. 193, no. 7, 2001, pages 839 - 846
TUVESON, D.A. ET AL.: "BRAF As A Potential Therapeutic Target In Melanoma And Other Malignancies,", CANCER CELL, vol. 4, 2003, pages 95 - 98
VAN CUTSEM, E. ET AL.: "Randomized, Placebo-Controlled, Phase III Study Of Oxaliplatin, Fluorouracil, And Leucovorin With Or Without PTK787/ZK 222584 In Patients With Previously Treated Metastatic Colorectal Adenocarcinoma,", J. CLIN. ONCOL., vol. 29, no. 15, 2011, pages 2004 - 2010
VAN DE RIJN, M. ET AL.: "Applications Of Microarrays To Histopathology,", HISTOPATHOLOGY, vol. 44, no. 2, 2004, pages 97 - 108
VAN IMHOFF, G.W. ET AL.: "Impact Of Three Courses Of Intensified CHOP Prior To High-Dose Sequential Therapy Followed By Autologous Stem-Cell Transplantation As First-Line Treatment In Poor-Risk, Aggressive NonHodgkin's Lymphoma: Comparative Analysis Of Dutch-Belgian Hemato-Oncology Cooperative Group Studies 27 And 40,", J. CLIN. ONCOL., vol. 23, no. 16, 2005, pages 3793 - 3801
VAN'T VEER, L.J. ET AL.: "N-ras Mutations In Human Cutaneous Melanoma From Sun-Exposed Body Sites,", MOL. CELL. BIOL., vol. 9, 1989, pages 3114 - 3116
VAUGHAN, H.A. ET AL.: "Immunohistochemical And Molecular Analysis Of Human Melanomas For Expression Of The Human Cancer-Testis Antigens NY-ESO-1 And IAGE-I ,", CLIN. CANCER RES., vol. 10, no. 24, 2004, pages 8396 - 8404
VIGLIETTA, V. ET AL.: "Modulating Co-Stimulation,", NEUROTHERAPEUTICS, vol. 4, 2007, pages 666 - 675
VOGELSTEIN, B. ET AL.: "Genetic Alterations During Colorectal-Tumour Development,", N. ENGL. J. MED., vol. 319, 1988, pages 525 - 532
WAN, P.T. ET AL.: "Mechanism Of Activation Of The RAF-ERK Signaling Pathway By Oncogenic Mutations Of B-RAF,", CELL, vol. 116, 2004, pages 855 - 867
WANG, H. ET AL.: "Key Role Of Macrophages In The Pathogenesis Of CD]8 Hypomorphic Murine Model Of Psoriasis,", J. INVEST. DERMATOL., vol. 129, no. 5, 2009, pages 1100 - 1114
WANG, L. ET AL.: "VISTA, A Novel Mouse Ig Superfamily Ligand That Negatively Regulates T Cell Responses,", J. EXP. MED., 7 March 2011 (2011-03-07)
WANG, S. ET AL.: "Co-Signaling Molecules Of The B7-CD28 Family In Positive And Negative Regulation Of T Lymphocyte Responses,", MICROBES INFECT., vol. 6, 2004, pages 759 - 766
WANG, W. ET AL.: "PD-1 Blockade Reverses The Suppression Of Melanoma Antigen-Specific CTL By CD4+ CD25(Hi) Regulatory T Cells,", INT. IMMUNOL., vol. 21, no. 9, 2009, pages 1065 - 1077
WILLIER, S. ET AL.: "Defining The Role Of TRIP6 In Cell Physiology And Cancer,", BIOL CELL, vol. 103, no. 12, 2011, pages 573 - 591
WILSON ET AL., CELL, vol. 37, 1984, pages 767
XIA ET AL.: "RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance", J. EXPERIMENTAL MED., vol. 211, no. 5, 2014, pages 943 - 959
YAMAMOTO, R. ET AL.: "B7-H] Expression Is Regulated By MEK/ERK Signaling Pathway In Anaplastic Large Cell Lymphoma And Hodgkin Lymphoma,", CANCER SCI., vol. 100, no. 11, 1 August 2009 (2009-08-01), pages 2093 - 2100
YAMANAKA, T. ET AL.: "The Baseline Ratio Of Neutrophils To Lymphocytes Is Associated With Patient Prognosis In Advanced Gastric Cancer,", ONCOLOGY, vol. 73, no. 3-4, 2007, pages 215 - 220
YAMAZAKI, T. ET AL.: "Expression Of Programmed Death 1 Ligands By Murine T Cells And APC,", J. IMMUNOL., vol. 169, 2002, pages 5538 - 5545
YIM, K.L. ET AL.: "Targeted Drug Therapies And Cancer,", RECENT RESULTS CANCER RES., vol. 185, 2011, pages 159 - 171
YOKOSUKA, T. ET AL.: "Programmed Cell Death 1 Forms Negative Costimulatory Microclusters That Directly Inhibit T Cell Receptor Signaling By Recruiting Phosphatase SHP2,", J. EXP. MED., vol. 209, no. 6, 28 May 2012 (2012-05-28), pages 1201 - 1217
YONEDA, A. ET AL.: "Breast And Ovarian Cancers: A Survey And Possible Roles For The Cell Surface Heparan Sulfate Proteoglycans,", J. HISTOCHEM. CYTOCHEM., vol. 60, no. 1, 2012, pages 9 - 21
YOONG, J. ET AL.: "Targeted Therapies For Gastric Cancer: Current Status,", DRUGS, vol. 71, no. 11, 2011, pages 1367 - 1384
YOUNG, H.A.: "Cytokine Multiplex Analysis (Chapter 4). Inflammation and Cancer", METHODS IN MOLECULAR BIOLOGY, vol. 511, 2009, pages 85 - 105
YUAN, J. ET AL.: "CTLA-4 Blockade Enhances Polyfunctional NY-ESO-1 Specific T Cell Responses In Metastatic Melanoma Patients With Clinical Benefit,", PROC. NATL. ACAD. SCI. (U.S.A., vol. 105, no. 51, 2008, pages 20410 - 20415
ZANG, X ET AL.: "B7x: A Widely Expressed B7 Family Member That Inhibits T Cell Activation,", PROC. NATL. ACAD. SCI. (USA, vol. 100, 2003, pages 10388 - 10392
ZANG, X. ET AL.: "B7x: A Widely Expressed B7 Family Member That Inhibits T Cell Activation,", PROC. NATL. ACAD. SCI. (USA, vol. 100, 2003, pages 10388 - 10392
ZELINSKYY, G. ET AL.: "Virus-Specific CD8+ T Cells Upregulate Programmed Death-1 Expression During Acute Friend Retrovirus Infection But Are Highly Cytotoxic And Control Virus Replication,", J. IMMUNOL., vol. 187, no. 7, 2011, pages 3730 - 3737
ZHANG, A. ET AL.: "Small Interfering RNA And Gene Expression Analysis Using A Multiplex Branched DNA Assay Without RNA Purification,", J. BIOMOL. SCREEN., vol. 10, no. 6, 2005, pages 549 - 556
ZHENG, Z. ET AL.: "Sensitive And Quantitative Measurement Of Gene Expression Directly From A Small Amount Of Whole Blood,", CLIN. CHEM., vol. 52, no. 7, 2006, pages 1294 - 1302
ZHU, Z. ET AL.: "High-Avidity T Cells Are Preferentially Tolerized In The Tumor Microenvironment,", CANCER RES., vol. 73, no. 2, 30 November 2012 (2012-11-30), pages 595 - 604
ZOU, W ET AL.: "Inhibitory B7-Family Molecules In The Tumour Microenvironment,", NAT. REV. IMMUNOL., vol. 8, no. 6, 2008, pages 467 - 771
ZOU; CHEN: "Inhibitory B7-Family Molecules In The Tumour Microenvironment,", NATURE REVIEWS, IMMUNOLOGY, vol. 8, 2008, pages 467 - 477

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9920123B2 (en) 2008-12-09 2018-03-20 Genentech, Inc. Anti-PD-L1 antibodies, compositions and articles of manufacture
US11299544B2 (en) 2013-03-15 2022-04-12 Genentech, Inc. Biomarkers and methods of treating PD-1 and PD-L1 related conditions
US10736940B2 (en) 2013-12-19 2020-08-11 Immutep S.A.S. Combined preparations for the treatment of cancer
US9938345B2 (en) 2014-01-23 2018-04-10 Regeneron Pharmaceuticals, Inc. Human antibodies to PD-L1
US11117970B2 (en) 2014-01-23 2021-09-14 Regeneron Pharmaceuticals, Inc. Human antibodies to PD-L1
US10737113B2 (en) 2014-01-23 2020-08-11 Regeneron Pharmaceuticals, Inc. Human antibodies to PD-1
US9987500B2 (en) 2014-01-23 2018-06-05 Regeneron Pharmaceuticals, Inc. Human antibodies to PD-1
US10775383B2 (en) 2014-05-29 2020-09-15 Ventana Medical Systems, Inc. PD-L1 antibodies and uses thereof
US9885721B2 (en) 2014-05-29 2018-02-06 Spring Bioscience Corporation PD-L1 antibodies and uses thereof
US11530269B2 (en) 2014-07-11 2022-12-20 Ventana Medical Systems, Inc. Anti-PD-L1 antibodies and diagnostic uses thereof
WO2016071890A1 (fr) * 2014-11-07 2016-05-12 Immunid Méthode théranostique pour optimiser le choix du bloqueur de point de contrôle immunitaire à administrer à un patient atteint de cancer
EP3230498A4 (fr) * 2014-12-09 2018-08-01 Merck Sharp & Dohme Corp. Système et procédés pour dériver des marqueurs biologiques de signature génique de réponse à des antagonistes de pd-1
WO2016094377A1 (fr) 2014-12-09 2016-06-16 Merck Sharp & Dohme Corp. Système et procédés pour dériver des marqueurs biologiques de signature génique de réponse à des antagonistes de pd-1
US11377693B2 (en) 2014-12-09 2022-07-05 Merck Sharp & Dohme Llc System and methods for deriving gene signature biomarkers of response to PD-1 antagonists
JP2018505658A (ja) * 2014-12-09 2018-03-01 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． Ｐｄ−１アンタゴニストに対する応答の遺伝子シグネチャーバイオマーカーを得るための系および方法
US11684654B2 (en) 2015-01-09 2023-06-27 Immutep S.A.S. Combined preparations for the treatment of cancer or infection
RU2777945C2 (ru) * 2015-01-09 2022-08-12 Иммутеп С.А.С. Комбинированные препараты для лечения рака или инфекции
US10940181B2 (en) 2015-01-09 2021-03-09 Immutep S.A.S. Combined preparations for the treatment of cancer or infection
US10874713B2 (en) 2015-01-09 2020-12-29 Immutep S.A.S. Combined preparations for the treatment of cancer or infection
US10620211B2 (en) 2015-02-03 2020-04-14 Ventana Medical Systems, Inc. Histochemical assay for evaluating expression of programmed death ligand 1 (PD-L1)
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US10948492B2 (en) 2015-03-06 2021-03-16 Dana-Farber Cancer Institute, Inc. PD-L2 biomarkers predictive of PD-1 pathway inhibitor responses in esophagogastric cancers
EP3283882B1 (fr) 2015-04-17 2020-12-16 Merck Sharp & Dohme Corp. Biomarqueurs sanguins de la sensibilité d'une tumeur à des antagonistes de pd-1
US11326211B2 (en) 2015-04-17 2022-05-10 Merck Sharp & Dohme Corp. Blood-based biomarkers of tumor sensitivity to PD-1 antagonists
IL255372B (en) * 2015-05-29 2022-07-01 Genentech Inc Therapeutic and diagnostic methods for cancer
AU2016270625B2 (en) * 2015-05-29 2022-10-06 Genentech, Inc. Therapeutic and diagnostic methods for cancer
CN107532217A (zh) * 2015-05-29 2018-01-02 豪夫迈·罗氏有限公司 用于癌症的治疗和诊断方法
EP3708681A1 (fr) * 2015-05-29 2020-09-16 F. Hoffmann-La Roche AG Méthodes diagnostiques et thérapeutiques pour le cancer
US11535671B2 (en) 2015-05-29 2022-12-27 Genentech, Inc. Therapeutic and diagnostic methods for cancer
EP4335931A3 (fr) * 2015-05-29 2024-06-19 F. Hoffmann-La Roche AG Méthodes thérapeutiques et diagnostiques du cancer
WO2016196298A1 (fr) * 2015-05-29 2016-12-08 Genentech, Inc. Méthodes diagnostiques et thérapeutiques pour le cancer
US10513558B2 (en) 2015-07-13 2019-12-24 Cytomx Therapeutics, Inc. Anti-PD1 antibodies, activatable anti-PD1 antibodies, and methods of use thereof
WO2017065000A1 (fr) * 2015-10-15 2017-04-20 国立大学法人京都大学 Biomarqueur destiné à prévoir un exemple aux effets remarquables d'inhibiteur de voie d'apoptose – 1 (pd-1)
JPWO2017065000A1 (ja) * 2015-10-15 2018-08-02 国立大学法人京都大学 Ｐｄ−１経路阻害薬の著効例を予測するためのバイオマーカー
WO2017085307A1 (fr) * 2015-11-22 2017-05-26 Ventana Medical Systems, Inc. Méthodes d'identification de cellules immunitaires dans un tissu tumoral positif pd-l1
US11899016B2 (en) 2015-11-22 2024-02-13 Ventana Medical Systems, Inc. Methods of identifying immune cells in PD-L1 positive tumor tissue
JP2018536163A (ja) * 2015-11-22 2018-12-06 ヴェンタナ メディカル システムズ， インク． Ｐｄ−ｌ１陽性腫瘍組織における免疫細胞を同定する方法
US12054557B2 (en) 2015-12-22 2024-08-06 Regeneron Pharmaceuticals, Inc. Combination of anti-PD-1 antibodies and bispecific anti-CD20/anti-CD3 antibodies to treat cancer
EP3452936A4 (fr) * 2016-05-05 2020-01-15 Nantomics, LLC Défaillance de point de contrôle et procédés associés
CN109416925A (zh) * 2016-05-05 2019-03-01 南托米克斯有限责任公司 检查点失效和使检查点失效的方法
US10457725B2 (en) 2016-05-13 2019-10-29 Regeneron Pharmaceuticals, Inc. Methods of treating skin cancer by administering a PD-1 inhibitor
US11505600B2 (en) 2016-05-13 2022-11-22 Regeneron Pharmaceuticals, Inc. Methods of treating skin cancer by administering a PD-1 inhibitor
WO2017201036A1 (fr) * 2016-05-17 2017-11-23 Genentech, Inc. Signatures génétiques stromales destinées au diagnostic et à l'utilisation en immunothérapie
US11603407B2 (en) 2017-04-06 2023-03-14 Regeneron Pharmaceuticals, Inc. Stable antibody formulation
CN111094977A (zh) * 2017-07-13 2020-05-01 古斯塔夫·鲁西研究所 监测抗pd-1/pd-l1治疗的肿瘤患者中肿瘤淋巴细胞浸润和预后的基于影像组学的成像工具
CN111094977B (zh) * 2017-07-13 2024-02-13 古斯塔夫·鲁西研究所 监测抗pd-1/pd-l1治疗的肿瘤患者中肿瘤淋巴细胞浸润和预后的基于影像组学的成像工具
CN107502589A (zh) * 2017-08-04 2017-12-22 北京世纪劲得生物技术有限公司 一种肿瘤浸润淋巴细胞与单个核细胞共培养方法
EP3707164A4 (fr) * 2017-11-07 2021-11-24 Memorial Sloan-Kettering Cancer Center Inhibition de ctla-4 et/ou pd-1 pour la régulation de lymphocytes t
WO2019164870A1 (fr) * 2018-02-20 2019-08-29 Medimmune, Llc Expression d'arnm de signature pour l'identification de patients sensibles au traitement par anticorps anti-pd-l1
EP3804758A4 (fr) * 2018-05-31 2022-03-02 ONO Pharmaceutical Co., Ltd. Biomarqueur pour évaluer l'efficacité d'un inhibiteur de point de contrôle immunitaire
WO2021092171A1 (fr) * 2019-11-06 2021-05-14 Genentech, Inc. Méthodes diagnostiques et thérapeutiques pour le traitement de cancers hématologiques
CN114902048A (zh) * 2020-02-18 2022-08-12 创新生物有限公司 伴随诊断用生物标志物组合物及包含其的伴随诊断用试剂盒
WO2022003554A1 (fr) * 2020-07-01 2022-01-06 Pfizer Inc. Biomarqueurs destinés à une thérapie par antagoniste de liaison à l'axe pd-1
WO2022235482A1 (fr) * 2021-05-03 2022-11-10 Rutgers, The State University Of New Jersey Immunothérapie pour une maladie intestinale inflammatoire et/ou un cancer
WO2024102620A3 (fr) * 2022-11-09 2024-06-13 Tempest Therapeutics, Inc. Composés de triazolone et leurs utilisations

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