WO2023203506A1 - Procédé d'évaluation d'une thérapie par lymphocytes t tcr destinés à cibler un antigène ny-eso-1 - Google Patents

Procédé d'évaluation d'une thérapie par lymphocytes t tcr destinés à cibler un antigène ny-eso-1 Download PDF

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WO2023203506A1
WO2023203506A1 PCT/IB2023/054003 IB2023054003W WO2023203506A1 WO 2023203506 A1 WO2023203506 A1 WO 2023203506A1 IB 2023054003 W IB2023054003 W IB 2023054003W WO 2023203506 A1 WO2023203506 A1 WO 2023203506A1
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cancer
eso
antigen
tcr
polypeptide
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PCT/IB2023/054003
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English (en)
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Martijn BRUGMAN
Ya-fang CHANG
Ioanna ELEFTHERIADOU
Alexandra GYURDIEVA
Aisha HASAN
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Glaxosmithkline Intellectual Property Development Limited
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Publication of WO2023203506A1 publication Critical patent/WO2023203506A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4632—T-cell receptors [TCR]; antibody T-cell receptor constructs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464484—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
    • A61K39/464488—NY-ESO
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites

Definitions

  • this document provides methods and materials for determining whether a mammal (e.g., a human) having cancer (e.g., a cancer including one or more solid tumors) is likely to respond to one or more cancer immunotherapies (e.g., a T cell receptor (TCR) T cell therapy) and/or is responding to a particular immunotherapy.
  • cancer immunotherapies e.g., a T cell receptor (TCR) T cell therapy
  • this document provides methods and materials for using one or more cancer immunotherapies (e.g., a TCR T cell therapy) to treat a mammal (e.g., a human) having cancer (e.g., having a cancer including one or more solid tumors) and identified as being likely to respond to one or more cancer immunotherapies.
  • NCT00670748 reactive TCR T cell therapy
  • NCT00670748 a more recent Phase I study (208466; NCT01343043) identified antitumor responses in 50% of patients with advanced SS treated with NY-ESO-1–specific T cells (letetresgene autoleucel (lete-cel); GSK3377794) (D'Angelo et al., Can. Discov., 8:944- 957 (2018)).
  • this document provides methods and materials for identifying a mammal having cancer (e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen) as being likely to respond to one or more cancer immunotherapies (e.g., a TCR T cell therapy designed to target an NY-ESO-1 antigen) and/or is responding to a particular immunotherapy (e.g., a TCR T cell therapy designed to target an NY-ESO- 1 antigen).
  • cancer immunotherapies e.g., a TCR T cell therapy designed to target an NY-ESO-1 antigen
  • a particular immunotherapy e.g., a TCR T cell therapy designed to target an NY-ESO- 1 antigen
  • the presence or absence of one or more biomarkers in a sample obtained from a mammal having a cancer including one or more solid tumors can be used to determine whether the mammal is likely to respond to one or more cancer immunotherapies.
  • the presence or absence of one or more biomarkers in a sample obtained from a mammal having a cancer include one or more solid tumors and having been administered a TCR T cell therapy designed to target an NY-ESO-1 antigen can be used to determine whether the mammal is responding to the TCR T cell therapy.
  • this document provides methods and materials for treating a mammal having cancer (e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen) where the treatment is selected, and optionally adjusted over time, based at least in part, on the presence or absence of one or more biomarkers in a sample obtained from a mammal.
  • cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen
  • TEM cells effector memory T cells
  • IFN interferon
  • an elevated level of one or more inflammatory chemokines and/or a decreased level of macrophages in a sample obtained from a mammal (e.g., a human) having a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen can be used to determine whether or not that cancer will be responsive to a TCR T cell therapy designed to target an NY-ESO-1 antigen.
  • the presence or absence of a decreased level of macrophages and/or an elevated peak cell expansion in a sample obtained from a mammal (e.g., a human) having a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen and having been administered a TCR T cell therapy designed to target an NY-ESO-1 antigen can be used to determine whether or not that mammal is responding to the TCR T cell therapy designed to target an NY-ESO-1 antigen.
  • one aspect of this document features methods for treating a human having a cancer including a solid tumor expressing an NY-ESO-1 antigen, wherein said human has previously been administered a TCR T cell therapy designed to target said NY- ESO-1 antigen.
  • the methods can include, or consist essentially of, (a) identifying a tumor microenvironment (TME) within the human as having a decreased level of macrophages, and (b) administering a cancer treatment to the human.
  • the identifying can include determining that a tumor sample obtained from the TME includes decreased expression of one or more of a CD163 polypeptide, a CD68 polypeptide, and a CD84 polypeptide.
  • the cancer can be a HPV-associated carcinoma, a melanoma, a synovial sarcoma (SS), a myxoid/round cell liposarcoma (MRCLS), an undifferentiated pleomorphic sarcoma, a leiomyosarcoma, a non-small cell lung cancer, a gastric cancer, a gastroesophageal junction cancer, an esophageal cancer, an ovarian cancer, a squamous cell carcinoma of the head and neck, a breast cancer, or a bladder cancer.
  • the cancer can be a SS.
  • the TCR T cell therapy designed to target said NY-ESO-1 antigen can be letetresgene autoleucel.
  • the treatment of the TCR T cell therapy designed to target the NY-ESO-1 antigen can include from about 3.2 million CD8 TEM cells designed to target the NY-ESO-1 antigen per kg body weight of the human (cells/kg) to about 28.4 million CD8 TEM cells/kg.
  • the treatment of the TCR T cell therapy designed to target the NY- ESO-1 antigen can include about 12 million CD8 TEM cells/kg.
  • the cancer treatment can include administering the TCR T cell therapy designed to target the NY-ESO-1 antigen.
  • this document features methods for treating a human having a cancer including a solid tumor expressing an NY-ESO-1 antigen.
  • the methods can include, or consist essentially of, administering a TCR T cell therapy designed to target an NY-ESO-1 antigen to a human having a cancer including a solid tumor expressing an NY- ESO-1 antigen, where the TCR T cell therapy includes from about 3.2 million CD8 T EM cells/kg to about 28.4 million CD8 T EM cells/kg.
  • the treatment of the TCR T cell therapy designed to target the NY-ESO-1 antigen can include about 12 million CD8 TEM cells/kg.
  • the cancer can be a HPV-associated carcinoma, a melanoma, a SS, a MRCLS, an undifferentiated pleomorphic sarcoma, a leiomyosarcoma, a non-small cell lung cancer, a gastric cancer, a gastroesophageal junction cancer, an esophageal cancer, an ovarian cancer, a squamous cell carcinoma of the head and neck, a breast cancer, or a bladder cancer.
  • the cancer can be a SS.
  • the TCR T cell therapy designed to target the NY-ESO- 1 antigen can be letetresgene autoleucel.
  • this document features methods for assessing a human having a cancer including a solid tumor expressing an NY-ESO-1 antigen.
  • the methods can include, or consist essentially of, (a) detecting CD8 T EM cells in a population of CD8 cells in a blood sample from a human having a cancer including a solid tumor expressing an NY-ESO-1 antigen; (b) identifying the human as not being likely to respond to a TCR T cell therapy designed to target the NY-ESO-1 antigen if the CD8 T EM cells comprise less than 30% of the population of the CD8 cells; and (c) identifying the human as being likely to respond to the TCR T cell therapy designed to target the NY-ESO-1 antigen if the CD8 TEM cells comprise 30% or more of the population of the CD8 cells.
  • the blood sample can include apheresis material.
  • the cancer can be a HPV-associated carcinoma, a melanoma, a SS, a MRCLS, an undifferentiated pleomorphic sarcoma, a leiomyosarcoma, a non-small cell lung cancer, a gastric cancer, a gastroesophageal junction cancer, an esophageal cancer, an ovarian cancer, a squamous cell carcinoma of the head and neck, a breast cancer, or a bladder cancer.
  • the cancer can be a SS.
  • the TCR T cell therapy designed to target the NY-ESO-1 antigen can be letetresgene autoleucel.
  • the method can include identifying the human as not being likely to respond to the TCR T cell therapy, and method can include administering a cancer treatment to the human that is not the TCR T cell therapy designed to target the NY-ESO-1 antigen.
  • the method can include identifying the human as being likely to respond to the TCR T cell therapy, and the method can include administering the TCR T cell therapy designed to target the NY-ESO- 1 antigen to the human.
  • this document features methods for identifying a human having a cancer including a solid tumor expressing an NY-ESO-1 antigen as being likely to respond to a TCR T cell therapy designed to target the NY-ESO-1 antigen.
  • the methods can include, or consist essentially of, (a) obtaining a population of CD8 T cells from a blood sample from a human having a cancer including a solid tumor expressing an NY- ESO-1 antigen; and (b) determining that CD8 TEM cells comprise 30% or more of the population of CD8 T cells.
  • the blood sample can include apheresis material.
  • the cancer can be a HPV-associated carcinoma, a melanoma, a SS, a MRCLS, an undifferentiated pleomorphic sarcoma, a leiomyosarcoma, a non-small cell lung cancer, a gastric cancer, a gastroesophageal junction cancer, an esophageal cancer, an ovarian cancer, a squamous cell carcinoma of the head and neck, a breast cancer, or a bladder cancer.
  • the cancer can be a SS.
  • the TCR T cell therapy designed to target the NY-ESO-1 antigen can be letetresgene autoleucel.
  • the method can include administering the TCR T cell therapy designed to target the NY-ESO-1 antigen to the human.
  • this document features methods for assessing a human having a cancer including a solid tumor expressing an NY-ESO-1 antigen.
  • the methods can include, or consist essentially of, (a) detecting the presence or absence of a decreased level of a polypeptide downstream of IFN in a tumor sample from a human having a cancer including a solid tumor expressing an NY-ESO-1 antigen; (b) identifying the human as being likely to respond to a TCR T cell therapy designed to target the NY-ESO- 1 antigen if the presence is detected; and (c) identifying the human as not being likely to respond to the TCR T cell therapy designed to target the NY-ESO-1 antigen if the absence is detected.
  • the polypeptide downstream of IFN can be a IFIT1 polypeptide, a IFIT2 polypeptide, a STAT2 polypeptide, a IFI16 polypeptide, a ISG15 polypeptide, a IFI35 polypeptide, a IFITM2 polypeptide, a IFITM1 polypeptide, a MX1 polypeptide, a IFI27 polypeptide, a IRF1 polypeptide, or a PSMB9 polypeptide.
  • the cancer can be a HPV- associated carcinoma, a melanoma, a SS, a MRCLS, an undifferentiated pleomorphic sarcoma, a leiomyosarcoma, a non-small cell lung cancer, a gastric cancer, a gastroesophageal junction cancer, an esophageal cancer, an ovarian cancer, a squamous cell carcinoma of the head and neck, a breast cancer, or a bladder cancer.
  • the cancer can be a SS.
  • the TCR T cell therapy designed to target the NY-ESO-1 antigen can be letetresgene autoleucel.
  • the method can include identifying the human as not being likely to respond to the TCR T cell therapy, and method can include administering a cancer treatment to the human that is not the TCR T cell therapy designed to target the NY-ESO-1 antigen.
  • the method can include identifying the human as being likely to respond to the TCR T cell therapy, and method can include administering the TCR T cell therapy designed to target the NY-ESO-1 antigen to the human.
  • this document features methods for identifying a human having a cancer including a solid tumor expressing an NY-ESO-1 antigen as being likely to respond to a TCR T cell therapy designed to target said NY-ESO antigen.
  • the methods can include, or consist essentially of, (a) obtaining a tumor sample from a human having a cancer including a solid tumor expressing an NY-ESO-1 antigen; and (b) determining that the tumor sample including a decreased level of a polypeptide downstream of IFN.
  • the polypeptide downstream of IFN can be a IFIT1 polypeptide, a IFIT2 polypeptide, a STAT2 polypeptide, a IFI16 polypeptide, a ISG15 polypeptide, a IFI35 polypeptide, a IFITM2 polypeptide, a IFITM1 polypeptide, a MX1 polypeptide, a IFI27 polypeptide, a IRF1 polypeptide, or a PSMB9 polypeptide.
  • the cancer can be a HPV-associated carcinoma, a melanoma, a SS, a MRCLS, an undifferentiated pleomorphic sarcoma, a leiomyosarcoma, a non-small cell lung cancer, a gastric cancer, a gastroesophageal junction cancer, an esophageal cancer, an ovarian cancer, a squamous cell carcinoma of the head and neck, a breast cancer, or a bladder cancer.
  • the cancer can be a SS.
  • the TCR T cell therapy designed to target the NY-ESO-1 antigen can be letetresgene autoleucel.
  • PFS was defined as the time from T-cell infusion to the earliest documentation of disease progression or death from any cause or surgical resection or start of prohibited medication. Box plots depict median, first, and third quartiles. Two-sided p-values were calculated via Wilcoxon test (a,c,d) or linear (b) regression, and Cox proportional hazards model (e). CR, complete response; LDR, lymphodepleting chemotherapy regimen; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.
  • Figure 3 T-cell product enriched with activated, effector memory CD8 cells is associated with response. a, Number of memory phenotype CD8+Pentamer+ cells/kg infused in non-responders vs responders.
  • d Association of EM phenotype between apheresis and product.
  • e Association of % and number of CD8+Pentamer+EM cells/kg with PFS.
  • PFS was defined as the time from T-cell infusion to the earliest documentation of disease progression or death from any cause or surgical resection or start of prohibited medication.
  • f Levels of CD8+Pentamer+ cells at Week 4.
  • g Levels and composition of memory phenotypes of CD8+Pentamer+ cells post-infusion.
  • Product analyses consist of 36 patients. Apheresis analyses consist of 34 patients. Number of patients for post-infusion analyses are listed on figures. Box plots depict median, first, and third quartiles. Nominal two-sided p-values based on the Wilcoxon rank sum test or log-rank test for PFS are presented and correlations are based on Spearman method. Line of best fit shown in blue for significant associations and grey area represents 95% confidence interval.
  • CM central memory
  • CR complete response
  • EM effector memory
  • CD45RA-CCR7- Na ⁇ ve
  • PFS progression-free survival
  • PD progressive disease
  • PR partial response
  • SD stable disease
  • TEMRA T effector memory RA
  • TSCM T stem cell memory (CD45RA+CCR7+CD45RO-CD95+CD127+).
  • Figure 4 Increase in pro-inflammatory cytokines in responders post lete-cel infusion and correlation to peak cell expansion.
  • a Heatmap of Responder vs Nonresponder ratios in cytokine levels over time obtained from linear mixed effects (LME) model.
  • T-cell infusion occurred on Day 0. Nominal p-values are shown as one dot for 0.01 ⁇ p ⁇ 0.05 and two dots for p ⁇ 0.01.
  • b Time courses of IFN ⁇ , IL-6, IL-17A, and GM-CSF, cytokines differentially upregulated by responders. Geometric means and 95% confidence intervals from LME model (accounting for left-censoring where appropriate) are plotted. Dashed, horizontal lines represented lower limit of quantification.
  • c Time course of soluble IL-2R ⁇ levels showing increase in responders and correlation to peak cell expansion. Sample size varied across timepoints and cytokines, with an overall median of 32 patients (range, 15–38 depending on cytokine/timepoint).
  • c–d Average expression and heatmap of IFN downstream genes pre-infusion.
  • e Association between CD163 (left) and CD68 (right) and IFN downstream genes.
  • Pre- infusion samples from 7 archival screening samples ( ⁇ 1 year pre-infusion) and 3 fresh baseline samples (pre-lymphodepletion). Box plots depict median, first, and third quartiles. Heatmap show z-scores per gene. P-values obtained from linear mixed effects models (a), limma models (c), and standard test for Spearman correlation coefficient (e).
  • IFN interferon
  • IHC immunohistochemistry
  • NR non-responder
  • R responder.
  • Figure 6 Decreased expression of HLA-A and antigen presenting genes at progression.
  • a Change in gene expression of CTAG1 (NY-ESO-1) and HLA-A between pre-infusion and at progression.
  • b Average expression and heatmap of antigen presentation genes at pre-infusion and progression. The following genes had background expression across all samples: KLRC2, KIR3DL2, KIR3DL1, KIR2DS1, and KR2DL1.
  • c Characterization of patient 32 biopsy taken 919 days post-infusion. RNAScope results show CD3 cells in blue and lete-cel in red (left). PDL1 and LAG3 staining in brown by IHC (middle and right images).
  • d Persistence of lete-cel in blood of patient 32. Tumor samples were primarily from lung metastases.
  • FIG. 8 Expression of NY-ESO-1 and cytokines prior to infusion and T-cell dose.
  • b IL-15 levels prior to 1 st and 2 nd infusion in 2 patients from Cohort 3 which received 2 different LDR prior to each infusion.
  • Figure 9 Further characterization of impact of peak cell expansion on response, PFS, and factors that impact expansion.
  • a Association of cell dose with peak cell expansion.
  • b Association of AUC0_28 with peak cell expansion.
  • c Association of AUC0_28 with response.
  • a-e show data from 43 patients.
  • AUC0_28 Area under the cell expansion curve from day 0 to day 28; CR, complete response; LDR, lymphodepleting chemotherapy regimen; NY-ESO-1, New York esophageal squamous cell carcinoma 1; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.
  • Figure 10 Further characterization of product attributes and associations with response.
  • a Memory phenotype distribution (a) of CD8+Pentamer+ cells in product of non-responders vs responders.
  • b Frequency of memory phenotypes in CD8+Pentamer+ cells and association with response.
  • c Logistic regression showing probability of response with number of infused CD8+ Pentamer+ EM cells/kg.
  • d Relationship of percent memory phenotypes in apheresis with response.
  • e Association of CD8+Pentamer+ cells and persistence at Week 4.
  • f Expression of CD40L and ICOS in product.
  • g Association of CD40L with EM phenotype in CD8+Pentamer+ cells (left) and CD4+Pentamer+ cells (right) in product.
  • h Expression of PD-1, LAG3, CTLA4, and TIM3 in CD8+Pentamer+ cells in product.
  • Ratio of total CD8 to CD4 cells in product i, Ratio of total CD8 to CD4 cells in product.
  • Product analyses consist of 36 patients. Number of patients for Week 4 analyses are 18. Lines of best fit are shown in black or blue with grey areas showing 95% confidence intervals. Nominal two-sided P-values based on the Wilcoxon rank sum test and correlations are based on Spearman method.
  • CM central memory
  • CR complete response
  • EM effector memory
  • PD progressive disease
  • PR partial response
  • SD stable disease
  • TEMRA T effector memory RA
  • TSCM T stem cell memory
  • FIG. 12 Immune landscape of SS tumors.
  • a Immune cell composition prior to infusion by gene expression analysis.
  • b Immune cell composition prior to infusion by IHC.
  • c Changes in immune cell composition pre T-cell infusion and at-progression by IHC.
  • T stem cell memory (Tscm) gating was performed via Boolean gating (CD45RA+CCR7+CD45RO-CD95+CD127+) so is not shown here.
  • this document provides methods and materials for identifying a mammal having cancer (e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen) as being responsive one or more cancer immunotherapies (e.g., a TCR T cell therapy designed to target an NY-ESO-1 antigen) and/or as responding to a particular immunotherapy (e.g., TCR T cell therapy designed to target an NY-ESO-1 antigen).
  • cancer immunotherapies e.g., a TCR T cell therapy designed to target an NY-ESO-1 antigen
  • a particular immunotherapy e.g., TCR T cell therapy designed to target an NY-ESO-1 antigen
  • a sample obtained from a mammal having cancer can be assessed to determine if the mammal is likely to be responsive to one or more cancer immunotherapies based, at least in part, on the presence or absence of one or more biomarkers in the sample.
  • a sample obtained from a mammal having cancer and having been administered a TCR T cell therapy designed to target an NY-ESO-1 antigen can be assessed to determine whether the mammal is responding to the TCR T cell therapy based, at least in part, the presence or absence of one or more biomarkers in the sample.
  • the presence or absence of one or more markers described herein e.g., an elevated level of T EM cells such as CD8 T EM cells, an elevated level of one or more polypeptides involved in T cell activation, a decreased level of one or more polypeptides downstream of IFN, an elevated level of one or more inflammatory chemokines and/or a decreased level of macrophages
  • a sample obtained from a mammal e.g., a human
  • a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen can be used to determine whether or not that cancer will be responsive to a TCR T cell therapy designed to target an NY-ESO-1 antigen.
  • the presence or absence of one or more markers described herein e.g., an elevated level of one or more proinflammatory cytokines and/or an elevated peak cell expansion
  • a sample obtained from a mammal e.g., a human
  • a mammal e.g., a human
  • a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen and having been administered a TCR T cell therapy designed to target an NY-ESO-1 antigen
  • TCR T cell therapy designed to target an NY-ESO-1 antigen can be used to determine whether or not that mammal is responding to the TCR T cell therapy designed to target an NY-ESO-1 antigen.
  • this document also provides methods and materials for treating a mammal having cancer where the treatment is selected, and optionally adjusted over time, based at least in part, on the presence or absence of one or more biomarkers described herein in a sample obtained from a mammal.
  • Any appropriate mammal having cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen
  • mammals that can have cancer and can be assessed as described herein (e.g., for the presence or absence of one or more biomarkers described herein) and/or treated as described herein (e.g., by administering one or more cancer immunotherapies such as one or more TCR T cell therapies to the mammal) include, without limitation, humans, non- human primates (e.g., monkeys), dogs, cats, horses, cows, pigs, sheep, mice, and rats.
  • a human having cancer can be assessed and/or treated as described herein.
  • a mammal e.g., a human having cancer (e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen) that can be assessed as described herein (e.g., for the presence or absence of one or more biomarkers described herein) and/or treated as described herein (e.g., by administering one or more cancer immunotherapies such as one or more TCR T cell therapies to the mammal) can have any type of cancer.
  • a cancer can be a blood cancer.
  • a cancer can include one or more solid tumors.
  • a cancer can be a recurrent cancer.
  • a cancer can be a primary cancer.
  • a cancer can be a metastatic cancer.
  • a cancer can be a chemo-resistant cancer.
  • Examples of cancers that a mammal can have such that the mammal can be assessed as described herein and/or treated as described herein include, without limitation, soft tissue sarcomas (STSs), HPV-associated carcinomas (e.g., metastatic HPV-associated carcinomas), melanomas, synovial sarcomas (SSs), myxoid/round cell liposarcomas (MRCLSs), undifferentiated pleomorphic sarcomas, leiomyosarcomas, lung cancers (e.g., non-small cell lung cancers), gastric cancers, gastroesophageal junction cancers, esophageal cancers, ovarian cancers, squamous cell carcinomas of the head and neck, breast cancers (e.g., triple negative
  • a cancer can be a STS.
  • a STS can be a SS or a MRCLS.
  • a mammal having cancer that can assessed as described herein (e.g., for the presence or absence of one or more biomarkers described herein) and/or treated as described herein (e.g., by administering one or more cancer immunotherapies such as one or more TCR T cell therapies to the mammal) can have a cancer where one or more cancer cells of the cancer express an NY-ESO-1 antigen.
  • an NY-ESO- 1 antigen can be an intracellular antigen can be expressed by a cancer cell and then presented on the cell surface by a human leukocyte antigen (HLA) molecule or a major histocompatibility (MHC) molecule.
  • HLA human leukocyte antigen
  • MHC major histocompatibility
  • the methods described herein can include identifying a mammal (e.g., a human) as having cancer. Any appropriate method can be used to identify a mammal as having a cancer. For example, imaging techniques and/or biopsy techniques can be used to identify mammals (e.g., humans) having cancer.
  • methods described herein can include assessing a sample obtained from a mammal (e.g., human) having cancer for the presence or absence of one or more biomarkers described herein.
  • a biomarker can be any type of biological molecule.
  • biological molecules that can be used as a biomarker as described herein can include, without limitation, particular cell types (e.g., immune cells such as T cells), polypeptides (e.g., cytokines), and nucleic acid sequences.
  • a biomarker is a particular cell type (e.g., an immune cell such as a T cell)
  • the cell can be any type of cell.
  • a cell type that can be used as a biomarker as described herein can be a particular type of T cell.
  • a T EM cell e.g., a CD8 T EM cell
  • a biomarker as described herein can be used as a biomarker as described herein.
  • a CD4 to CD8 cell ratio can be used as a biomarker as described herein.
  • the polypeptide can be any appropriate polypeptide.
  • a polypeptide that can be used as a biomarker as described herein can be a polypeptide that is involved in T cell activation.
  • a polypeptide that can be used as a biomarker as described herein can be a polypeptide that is involved in IFN signaling.
  • a polypeptide that can be used as a biomarker as described herein can be an inflammatory chemokine.
  • a polypeptide that can be used as a biomarker as described herein can be a proinflammatory cytokine.
  • polypeptides that can be used as biomarkers as described herein include, without limitation, IFN polypeptides, IL-6 polypeptides, IL-2 receptor alpha (IL- 2RA) polypeptides (e.g., soluble IL-2RA polypeptides), GMCSF polypeptides, IL-17a polypeptides, CD40 ligand (CD40L) polypeptides, inducible T cell co-stimulator (ICOS) polypeptides, IFN ⁇ polypeptides, IFN ⁇ polypeptides, and polypeptides downstream of IFN (e.g., IFIT1 polypeptides, IFIT2 polypeptides, STAT2 polypeptides, IFI16 polypeptides, ISG15 polypeptides, IFI35 polypeptides, IFITM2 polypeptides, IFITM1 polypeptides, MX
  • a biomarker described herein can be as described in Example 1.
  • one or more biomarkers described herein that can be used to determine whether a mammal having cancer is likely to be responsive to one or more cancer immunotherapies e.g., a TCR T cell therapy designed to target an NY-ESO-1 antigen
  • a particular immunotherapy e.g., a TCR T cell therapy designed to target an NY-ESO-1 antigen
  • a particular cell type e.g., an immune cell such as a T cell.
  • the presence or absence of an elevated level of one or more biomarkers described herein can be used to determine whether a mammal having cancer is likely to be responsive to one or more cancer immunotherapies and/or is responding to a particular immunotherapy.
  • elevated level as used herein with respect to a level of a particular cell type (e.g., an immune cell such as a T cell) refers to any level that is greater than a reference level of that particular cell type.
  • decreased level as used herein with respect to a level of a particular cell type (e.g., a macrophage) refers to any level that is lower than a reference level of that particular cell type.
  • an elevated level of TEM cells can be a level that is at least 2 (e.g., at least 5, at least 10, at least 15, at least 20, at least 25, at least 35, or at least 50) fold greater relative to a reference level of TEM cells (e.g., CD8 TEM cells).
  • an elevated level of TEM cells can be a level that is at least 30% (e.g., about 30%, about 35%, about 40% about 45%, about 50%, or more) of a population of T cells (e.g., CD8 T cells) present in a blood sample obtained from a mammal. It will be appreciated that levels from comparable samples are used when determining whether or not a particular level is an elevated level.
  • a level of a particular cell type e.g., a macrophage
  • a decreased level of one or more macrophage cell surface markers can be indicative of a decreased level of macrophages.
  • macrophage cell surface markers include, without limitation, CD163 polypeptides, CD68 polypeptides, and CD84 polypeptides.
  • Elevated level refers to any peak cell expansion that is greater than a reference level of peak cell expansion.
  • reference level refers to the peak cell expansion typically observed in a sample (e.g., a control sample) from one or more mammals (e.g., humans) that are not responsive to one or more cancer immunotherapies (e.g., healthy mammals).
  • an elevated level of peak cell expansion can be a peak cell expansion having a Cmax that is at least 2 (e.g., at least 5, at least 10, at least 15, at least 20, at least 25, at least 35, or at least 50) fold greater than a reference Cmax of peak cell expansion.
  • an elevated level of peak cell expansion can be a peak cell expansion having a Cmax that is at least 30% (e.g., about 30%, about 35%, about 40% about 45%, about 50%, or more) greater than a reference Cmax of a peak cell expansion. It will be appreciated that levels from comparable samples are used when determining whether or not a particular level is an elevated level.
  • the term “elevated level” as used herein with respect to a level of a polypeptide refers to any level that is greater than a reference level of the polypeptide.
  • the term “decreased level” as used herein with respect to a level of a polypeptide refers to any level that is lower than a reference level of the polypeptide.
  • the term “reference level” as used herein with respect to a polypeptide refers to the level of the polypeptide typically observed in a sample (e.g., a control sample) from one or more mammals (e.g., humans) that are not responsive to one or more cancer immunotherapies (e.g., healthy mammals).
  • an elevated level of a polypeptide can be a level that is at least 2 (e.g., at least 5, at least 10, at least 15, at least 20, at least 25, at least 35, or at least 50) fold greater relative to a reference level of the polypeptide.
  • an elevated level of a IL-15 polypeptide can be a level that is at least 30 picograms of the IL-15 polypeptide per milliliter (pg/mL) of sample (e.g., serum).
  • sample e.g., serum
  • an elevated level of a IL-15 polypeptide can be a level that is from about 30 pg/mL to about 50 pg/mL of the IL-15 polypeptide.
  • an elevated level of an IL-17 polypeptide can be a level that is at least 2 picograms of the IL-17 polypeptide per milliliter (pg/mL) of sample (e.g., serum).
  • an elevated level of a IL-17 polypeptide can be a level that is from about 2 pg/mL to about 10 pg/mL of the IL-17 polypeptide.
  • an elevated level of an IFN ⁇ polypeptide can be a level that is at least 10 picograms of the IFN ⁇ polypeptide per milliliter (pg/mL) of sample (e.g., serum).
  • an elevated level of an IFN ⁇ polypeptide can be a level that is from about 10 pg/mL to about 1000 pg/mL of the IFN ⁇ polypeptide.
  • an elevated level of a GMCSF polypeptide can be a level that is at least 1 picograms of the GMCSF polypeptide per milliliter (pg/mL) of sample (e.g., serum).
  • sample e.g., serum
  • an elevated level of a GMCSF polypeptide can be a level that is from about 1 pg/mL to about 10 pg/mL of the GMCSF polypeptide.
  • an elevated level of an IL-6 polypeptide can be a level that is at least 5 picograms of the IL-6 polypeptide per milliliter (pg/mL) of sample (e.g., serum).
  • an elevated level of an IL-6 polypeptide can be a level that is from about 35 pg/mL to about 5 pg/mL of the IL-6 polypeptide.
  • an elevated level of an IL-2RA polypeptide can be a level that is at least 3000 picograms of the IL-2RA polypeptide per milliliter (pg/mL) of sample (e.g., serum).
  • an elevated level of an IL-2RA polypeptide can be a level that is from about 3000 pg/mL to about 5500 pg/mL of the IL- 2RA polypeptide.
  • an elevated level when control samples have undetectable levels of a polypeptide, an elevated level can be a detectable level of the polypeptide.
  • a decreased level of a polypeptide downstream of IFN can be a level that is at least 2 (e.g., at least 5, at least 10, at least 15, at least 20, at least 25, at least 35, or at least 50) fold less relative to a reference level of that polypeptide.
  • a decreased level of a polypeptide downstream of IFN can be a level that is at least 30% (e.g., about 30%, about 35%, about 40% about 45%, about 50%, or more) less than a reference level of that polypeptide. It will be appreciated that levels from comparable samples are used when determining whether or not a particular level is an elevated level.
  • a sample from a mammal e.g., a human having cancer (e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen) can be assessed as described herein (e.g., for the presence or absence of one or more biomarkers described herein within a sample obtained from a mammal such as a human).
  • a sample can be a biological sample.
  • a sample can contain one or more biological molecules (e.g., nucleic acids such as DNA and RNA, polypeptides, carbohydrates, lipids, hormones, and/or metabolites).
  • samples that can be assessed as described herein include, without limitation, fluid samples (e.g., whole blood, serum, plasma, and PBMCs) and tissue samples (e.g., tumor tissue samples).
  • a blood sample can include apheresis material.
  • a sample can be a fresh sample or a fixed sample (e.g., EDTA plasma, citrate plasma, and heparinized plasma).
  • a sample can be a processed sample (e.g., an embedded sample such as a paraffin or OCT embedded sample, or processed to isolate or extract one or more biological molecules).
  • a blood (e.g., plasma) sample can be obtained from a mammal and can be assessed for the presence or absence of one or more biomarkers described herein.
  • Any appropriate method can be used to detect the presence or absence of an elevated level of a particular cell type (e.g., an immune cell such as a T cell) within a sample obtained from a mammal (e.g., a human).
  • flow cytometry can be used to determine the presence, absence, or level of a particular cell type in a sample.
  • the presence or absence of an elevated level of a particular cell type within a sample from a mammal having cancer can be determined as described in Example 1.
  • a level of polypeptide expression within a sample can be determined by detecting the presence, absence, or level of the polypeptide in the sample.
  • immunoassays e.g., immunohistochemistry (IHC) techniques and western blotting techniques
  • mass spectrometry techniques e.g., proteomics-based mass spectrometry assays or targeted quantification-based mass spectrometry assays
  • enzyme-linked immunosorbent assays ELISAs
  • radio-immunoassays e.g., radio-immunoassays, and flow cytometry
  • PCR polymerase chain reaction
  • gene expression panel e.g., next generation sequencing (NGS) such as RNA- seq
  • in situ hybridization can be used to determine the presence, absence, or level of mRNA encoding the polypeptide in the sample.
  • NGS next generation sequencing
  • the presence or absence of an elevated level of a polypeptide within a sample from a mammal having cancer can be determined as described in Example 1.
  • the presence or absence of one or more biomarkers described herein within a sample obtained from a mammal (e.g., a human) having cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen
  • cancer immunotherapies e.g., a TCR T cell therapy designed to target an NY-ESO-1 antigen
  • TEM cells e.g., CD8 TEM cells
  • a sample e.g., a sample obtained from a mammal such as a human
  • TEM cells e.g., CD8 TEM cells
  • the presence of a decreased level of one or more polypeptides downstream of IFN e.g., IFIT1 polypeptides, IFIT2 polypeptides, STAT2 polypeptides, IFI16 polypeptides, ISG15 polypeptides, IFI35 polypeptides, IFITM2 polypeptides, IFITM1 polypeptides, MX1 polypeptides, IFI27 polypeptides, IRF1 polypeptides, and PSMB9 polypeptides
  • a sample e.g., a sample obtained from a mammal such as a human
  • a sample obtained from a mammal such as a human
  • a treatment option can be selected for a mammal (e.g., a human) having cancer (e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen) based, at least in part, on whether that mammal is identified as being likely to be responsive to one or more cancer immunotherapies (e.g., a TCR T cell therapy designed to target an NY-ESO-1 antigen) as described herein (e.g., based, at least in part, on the presence or absence of one or more biomarkers described herein in a sample obtained from the mammal).
  • cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen
  • cancer immunotherapies e.g., a TCR T cell therapy designed to target an NY-ESO-1 antigen
  • this document also provides methods and materials for treating mammals (e.g., humans) having cancer (e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen) where the treatment is selected based, at least in part, on whether or not the mammal is identified as being likely to be responsive to one or more cancer immunotherapies (e.g., a TCR T cell therapy designed to target an NY-ESO-1 antigen) as described herein (e.g., based, at least in part, on the presence or absence of one or more biomarkers described herein within a sample obtained from the mammal).
  • cancer immunotherapies e.g., a TCR T cell therapy designed to target an NY-ESO-1 antigen
  • a mammal having cancer and assessed as described herein can be administered or instructed to self-administer one or more (e.g., one, two, three, four, five, or more) cancer treatments, where the one or more cancer treatments are selected based, at least in part, on whether or not the mammal is identified as being likely to respond to one or more cancer immunotherapies.
  • a mammal having cancer can be administered or instructed to self-administer one or more cancer treatments that are selected based, at least in part, on the presence or absence of one or more biomarkers described herein within a sample obtained from the mammal.
  • a mammal e.g., a human
  • cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen
  • cancer immunotherapies e.g., a TCR T cell therapy designed to target an NY-ESO-1 antigen
  • the mammal can be administered or instructed to self-administer one or more (e.g., one, two, three, four, five, or more) cancer immunotherapies.
  • a cancer immunotherapy can be an autologous T cell therapy.
  • a cancer immunotherapy can target an NY-ESO-1 antigen.
  • a cancer immunotherapy can be an autologous T cell therapy that targets an NY-ESO-1 antigen.
  • a cancer immunotherapy can include TEM cells (e.g., CD8 TEM cells) that contain a nucleic acid that can encode (e.g., are transduced with a viral vector including a nucleic acid that can encode) a polypeptide (e.g., a TCR) designed to target an NY-ESO-1 antigen.
  • TEM cells e.g., CD8 TEM cells
  • a nucleic acid that can encode e.g., are transduced with a viral vector including a nucleic acid that can encode
  • a polypeptide e.g., a TCR
  • a cancer immunotherapy can include CD8 TEM cells that are transduced with a nucleic acid that can encode a TCR designed to target an NY-ESO-1 antigen such that the transduced CD8 TEM cells can target cancer cells expressing an NY- ESO-1 antigen.
  • An exemplary cancer immunotherapy can be, without limitation, letetresgene autoleucel (lete-cel; GSK3377794).
  • a cancer immunotherapy can be as described elsewhere (see., e.g., Milone et al., Mol. Ther. Meth. Clin. Dev., 8:210-221 (2016).
  • any appropriate dose of the cancer immunotherapy that can target an NY-ESO-1 antigen can be administered.
  • a mammal e.g., a human
  • a cancer immunotherapy that can target an NY-ESO-1 antigen e.g., letetresgene autoleucel
  • any appropriate dose of the cancer immunotherapy that can target an NY-ESO-1 antigen can be administered.
  • an effective dose of a cancer immunotherapy that can target an NY-ESO-1 antigen can include from about 3.2 million TEM cells (e.g., CD8 TEM cells) per kg body weight of the human (cells/kg) to about 28.4 million TEM cells (e.g., CD8 TEM cells)/kg (e.g., from about 3.2 million to about 25 million, from about 3.2 million to about 22 million, from about 3.2 million to about 20 million, from about 3.2 million to about 17 million, from about 3.2 million to about 15 million, from about 3.2 million to about 12 million, from about 3.2 million to about 10 million, from about 3.2 million to about 8 million, from about 3.2 million to about 5 million, from about 5 million to about 28.4 million, from about 8 million to about 28.4 million, from about 10 million to about 28.4 million, from about 13 million to about 28.4 million, from about 15 million to about 28.4 million, from about 17 million to about 28.4 million, from about 20 million to about 28.4 million,
  • a mammal having cancer can be administered a cancer immunotherapy that can target an NY-ESO-1 antigen including about 12 million TEM cells (e.g., CD8 TEM cells)/kg.
  • a mammal e.g., a human
  • cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen
  • cancer immunotherapies e.g., a TCR T cell therapy designed to target an NY-ESO-1 antigen
  • one or more cancer immunotherapies can be the only cancer treatment administered to the mammal.
  • a mammal e.g., a human
  • cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen
  • cancer immunotherapies e.g., a TCR T cell therapy designed to target an NY-ESO-1 antigen
  • the mammal also can be treated with one or more additional agents/therapies used to treat cancer.
  • additional agents/therapies used to treat cancer include, without limitation, surgery, radiation therapies, chemotherapies, targeted therapies (e.g., monoclonal antibody therapies), hormonal therapies, angiogenesis inhibitors, immunosuppressants, checkpoint blockade therapies, and/or bone marrow transplants.
  • targeted therapies e.g., monoclonal antibody therapies
  • hormonal therapies e.g., angiogenesis inhibitors
  • immunosuppressants e.g., checkpoint blockade therapies
  • checkpoint blockade therapies e.g., adothelial fibroblasts
  • bone marrow transplants e.g., bone marrow transplants.
  • the one or more additional agents/therapies can be administered at the same time or independently.
  • one or more cancer immunotherapies can be administered first, and the one or more additional agents/therapies can be administered second, or vice versa.
  • a mammal e.g., a human having cancer (e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen) and identified as not being likely to be responsive to one or more cancer immunotherapies (e.g., a TCR T cell therapy designed to target an NY-ESO- 1 antigen) as described herein (e.g., based, at least in part, on the absence of one or more biomarkers within a sample obtained from the mammal), the mammal can be administered or instructed to self-administer one or more (e.g., one, two, three, four, five, or more) alternative cancer treatments (e.g., one or more cancer treatments that do not involve administering T cells designed to target an NY-ESO-1 antigen).
  • cancer immunotherapies e.g., a TCR T cell therapy designed to target an NY-ESO- 1 antigen
  • the mammal can be administered
  • Examples of alternative cancer treatments that do not involve administering T cells designed to target an NY-ESO-1 antigen and that can be used as described herein include, without limitation, administering one or more cancer drugs (e.g., chemotherapeutic agents, targeted cancer drugs, immunotherapy drugs, and hormones) to a mammal in need thereof.
  • an alternative cancer treatment can include radiation therapies.
  • the presence or absence of one or more biomarkers described herein within a sample obtained from a mammal (e.g., a human) having cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen
  • cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen
  • TCR T cell therapy designed to target an NY-ESO-1 antigen can be used to determine whether that mammal is responding to the TCR T cell therapy designed to target an NY-ESO-1 antigen.
  • the presence of an elevated level of one or more proinflammatory cytokines e.g., an IFN ⁇ polypeptide, an IL-6 polypeptide, a soluble IL-2RA polypeptide, a GMCSF polypeptide, and/or an IL-17a polypeptide
  • an elevated peak cell expansion within a sample e.g., a sample obtained from a mammal such as a human
  • a sample obtained from a mammal such as a human can indicate that a mammal is responding to the TCR T cell therapy designed to target an NY- ESO-1 antigen.
  • a treatment option can be selected for a mammal (e.g., a human) having cancer (e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen) and having been administered a TCR T cell therapy designed to target an NY-ESO-1 antigen based, at least in part, on whether that mammal is identified as responding to the TCR T cell therapy designed to target an NY-ESO-1 antigen as described herein (e.g., based, at least in part, on the presence or absence of one or more biomarkers described herein in a sample obtained from the mammal).
  • cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen
  • TCR T cell therapy designed to target an NY-ESO-1 antigen based, at least in part, on whether that mammal is identified as
  • this document also provides methods and materials for treating mammals (e.g., humans) having cancer (e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen) and having been administered a TCR T cell therapy designed to target an NY- ESO-1 antigen where the treatment is adjusted over time based, at least in part, on whether or not the mammal is identified as responding to the TCR T cell therapy designed to target an NY-ESO-1 antigen as described herein (e.g., based, at least in part, on the presence or absence of one or more biomarkers described herein within a sample obtained from the mammal).
  • cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen
  • TCR T cell therapy designed to target an NY- ESO-1 antigen
  • a mammal having cancer having been administered a TCR T cell therapy designed to target an NY-ESO-1 antigen, and assessed as described herein can be administered or instructed to self-administer one or more (e.g., one, two, three, four, five, or more) cancer treatments, where the one or more cancer treatments are selected based, at least in part, on whether or not the mammal is identified as responding to the TCR T cell therapy designed to target an NY-ESO-1 antigen.
  • one or more e.g., one, two, three, four, five, or more
  • a mammal having cancer and having been administered a TCR T cell therapy designed to target an NY-ESO-1 antigen can be administered or instructed to self-administer one or more cancer treatments that are selected based, at least in part, on the presence or absence of one or more biomarkers described herein within a sample obtained from the mammal.
  • a mammal e.g., a human
  • cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen
  • the mammal can be administered or instructed to self-administer one or more (e.g., one, two, three, four, five, or more) additional rounds of the TCR T cell therapy designed to target an NY-ESO-1 antigen.
  • a mammal e.g., a human
  • cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen
  • a TCR T cell therapy designed to target an NY-ESO-1 antigen having been administered a TCR T cell therapy designed to target an NY-ESO-1 antigen, and identified as responding to the TCR T cell therapy designed to target an NY-ESO-1 antigen as described herein (e.g., based, at least in part, on the presence of an elevated level of one or more biomarkers within a sample obtained from the mammal), by administering one or more (e.g., one, two, three, four, five, or more) additional rounds of the TCR T cell therapy designed to target an NY- ESO-1 antigen, the TCR T cell therapy designed to target an NY-ESO-1 antigen can be the only cancer treatment administered to the mammal.
  • a mammal e.
  • a mammal e.g., a human
  • cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen
  • a mammal having cancer
  • a TCR T cell therapy designed to target an NY-ESO-1 antigen
  • identified as responding to the TCR T cell therapy designed to target an NY-ESO-1 antigen as described herein e.g., based, at least in part, on the presence of an elevated level of one or more biomarkers within a sample obtained from the mammal
  • the mammal also can be treated with one or more additional agents/therapies used to treat cancer.
  • additional agents/therapies used to treat cancer include, without limitation, surgery, radiation therapies, chemotherapies, targeted therapies (e.g., monoclonal antibody therapies), hormonal therapies, angiogenesis inhibitors, immunosuppressants, checkpoint blockade therapies, and/or bone marrow transplants.
  • targeted therapies e.g., monoclonal antibody therapies
  • hormonal therapies e.g., angiogenesis inhibitors
  • immunosuppressants e.g., checkpoint blockade therapies
  • checkpoint blockade therapies e.g., adotherapies used to treat cancer
  • bone marrow transplants e.g., bone marrow transplants.
  • the one or more additional agents/therapies can be administered at the same time or independently.
  • one or more rounds of a TCR T cell therapy designed to target an NY-ESO-1 antigen can be administered first, and the one or more additional agents/therapies can be administered second, or vice versa.
  • a mammal e.g., a human having cancer (e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen), having been administered a TCR T cell therapy designed to target an NY-ESO-1 antigen, and identified as not responding to the TCR T cell therapy designed to target an NY-ESO-1 antigen as described herein (e.g., based, at least in part, on the absence of one or more biomarkers within a sample obtained from the mammal), the mammal can be administered or instructed to self-administer one or more (e.g., one, two, three, four, five, or more) alternative cancer treatments (e.g., one or more cancer treatments that do not involve administering T cells designed to target an NY-ESO-1 antigen).
  • cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/
  • Examples of alternative cancer treatments that do not involve administering T cells designed to target an NY-ESO-1 antigen and that can be used as described herein include, without limitation, administering one or more cancer drugs (e.g., chemotherapeutic agents, targeted cancer drugs, immunotherapy drugs, and hormones) to a mammal in need thereof.
  • cancer drugs e.g., chemotherapeutic agents, targeted cancer drugs, immunotherapy drugs, and hormones
  • an alternative cancer treatment can include surgery.
  • an alternative cancer treatment can include radiation therapies.
  • the treatment can be effective to reduce or eliminate the number of cancer cells present within the mammal.
  • a mammal having cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen
  • the treatment can be effective to reduce or eliminate the number of cancer cells present within the mammal.
  • the materials and methods described herein can be used to reduce the number of cancer cells present within a mammal having cancer by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.
  • the materials and methods described herein can be used to reduce the size (e.g., volume) of one or more tumors present within a mammal having cancer by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.
  • the number of cancer cells present within a mammal being treated can be monitored. Any appropriate method can be used to determine whether or not the number of cancer cells present within a mammal is reduced. For example, imaging techniques can be used to assess the number of cancer cells present within a mammal.
  • the treatment can be effective to improve survival of the mammal.
  • a mammal having cancer e.g., a cancer including one or more solid tumors where at least one solid tumor expresses an NY-ESO-1 antigen and/or a LAGE-1a antigen
  • the materials and methods described herein can be used to improve the survival of a mammal having cancer by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.
  • the materials and methods described herein can be used to improve the survival of a mammal having cancer by, for example, at least 6 months (e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 4 years, about 5 years, or more).
  • at least 6 months e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 4 years, about 5 years, or more.
  • the treatment can be effective to increase immune cell (e.g., T cells included in a TCR T cell therapy designed to target an NY- ESO-1 antigen) infiltration into a tumor microenvironment within the mammal.
  • immune cell e.g., T cells included in a TCR T cell therapy designed to target an NY- ESO-1 antigen
  • the materials and methods described herein can be used to increase immune cell infiltration into a tumor microenvironment within a mammal having cancer by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.
  • the treatment can reduce or eliminate administering a cancer treatment to the mammal that will be ineffective.
  • a mammal having cancer is identified as not being likely to respond to one or more immunotherapies (e.g., based, at least in part, on the presence of an elevated level of one or more biomarkers described herein in a sample obtained from the mammal), the mammal is not administered one or more immunotherapies that are likely to be rendered exhausted.
  • a mammal having cancer and having been administered a TCR T cell therapy designed to target an NY-ESO-1 antigen is identified as not responding to the TCR T cell therapy designed to target an NY-ESO-1 antigen (e.g., based, at least in part, on the presence of an elevated level of one or more biomarkers described herein in a sample obtained from the mammal), the mammal is not administered one or more immunotherapies that are likely to be rendered exhausted.
  • the invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.
  • Example 1 Correlations of Response with Biomarkers and Product Attributes for Ny- Eso-1 TCR T cells (Lete-Cel) in Patients with Metastatic Synovial Sarcoma
  • This Example identifies predictive and pharmacodynamic markers of response with TCR T cell therapy in SS. These markers can be used to determine treatment options to enhance patient responses.
  • Methods Study design This was a multicenter, open-label, pilot study to determine the efficacy and safety of lete-cel in patients with unresectable, metastatic, or recurrent SS. Study stages included screening, leukapheresis/manufacture, lymphodepletion, and treatment phases, followed by long-term follow-up performed under a separate protocol ( Figure 7).
  • Patient were screened for HLA and NY-ESO-1 and considered enrolled at the time of leukapheresis.
  • the total population enrolled (underwent apheresis) and thus considered for the intent to treatment analysis (ITT) was 50 patients (cohort 1: 15, cohort 2: 14, cohort 3: 5, cohort 4:16).
  • a total of five patients dropped out between leukapheresis and T cell infusion.
  • Three patients dropped out due to death one each from cohort 1, 2, 4), one patient withdrew consent (cohort 1), and one patient withdrew due to disease progression prior to treatment (cohort 1).
  • the modified ITT (mITT) population was 45 patients (cohort 1: 12, cohort 2: 13, cohort 3: 5, cohort 4 :15).
  • Additional eligibility requirements were: measurable, pathologically, or cytologically-diagnosed unresectable or metastatic or progressive/persistent or recurrent SS previously treated with and intolerant/non-responsive to a standard chemotherapy regimen containing ifosfamide and/or doxorubicin; NY-ESO-1 positivity, with criteria as detailed for individual cohorts in Table 1; and HLA-A*02:01-, HLA-A*02:05-, and/or HLA-A*02:06-positivity by high resolution testing.
  • Exclusion criteria Patients were excluded if they had alanine aminotransferase levels >2.5 times the upper limit of the normal range (ULN) without documented liver metastases/tumor infiltration; total bilirubin >1.5 times ULN (isolated bilirubin >1.5 time ULN was acceptable if bilirubin was fractionated and direct bilirubin was ⁇ 35%); current active liver or biliary disease; clinically significant systemic illness; untreated CNS metastasis; previous treatment with genetically engineered NY-ESO-1–specific T cells; or a history of active, chronic, or recurrent severe autoimmune or immune-mediated disease requiring steroids or other immunosuppressive treatments.
  • Prior to lete-cel infusion patients underwent lymphodepletion dosing as described in Table 1.
  • patients received thawed lete-cel by intravenous infusion patients received thawed lete-cel by intravenous infusion.
  • Patients could receive a maximum of 2 infusions with lete-cel provided eligibility criteria were met. Patients in any cohort who had a confirmed response or had stable disease for >3 months but then progressed were eligible for a second infusion using the same lymphodepleting regimen as for the first infusion. Patients in Cohorts 3 and 4 who had progressive disease or stable disease as best response for ⁇ 3 months could receive a second infusion using the high dose of fludarabine and cyclophosphamide lymphodepletion regimen. The second infusion could be given no sooner than 60 days from the first infusion and no later than 2 years after the first infusion.
  • Biomarkers Exploratory biomarker endpoints included correlation of expansion, phenotype, and functionality of lete-cel in the blood and or tumor with response to treatment as well as correlation of biomarkers in tumor tissue and blood with response following infusion of lete-cel.
  • T cell expansion and phenotypic analyses T cell expansion analysis Peripheral blood mononuclear cells (PBMCs) samples were collected and monitored for expansion of gene-modified cells in patients at baseline (7 days prior to chemotherapy); days 4 and 7; weeks 2, 4 and 8; and months 3, 6, and 12 post-infusion. Thereafter, samples were collected every 3 months until 2 years; every 6 months until 5 years; and then every year until 15 years post-infusion.
  • PBMCs Peripheral blood mononuclear cells
  • T cell kinetics or expansion were measured by quantitative polymerase chain reaction (qPCR) of transgene vector copies in DNA extracted from PMBCs. Samples were tested to detect the presence of the WPRE or Psi gene, which are both included in the lentiviral vector used to transduce the T cells. T cell phenotypic analysis PBMC samples were collected at baseline, 1 week; 1, 2, 6, and 12 months; then every 3 months until 2 years post-infusion; and then every 6 months until 5 years post- infusion. Immunophenotyping was performed on cryopreserved PMBC samples using flow cytometry (Caprion). Detection reagents used for T cell phenotyping in each of 2 individual assays (termed Pheno1 and Pheno2) are described in Table 8.
  • qPCR quantitative polymerase chain reaction
  • PBMCs were thawed (1x10 6 cells/panel) and incubated with Fc blocker (for Pheno2 only) for 10 minutes at room temperature, prior to being washed and subjected to pentamer staining (10 minutes at room temperature). PBMCs were then washed and stained with surface stainer (30 minutes at 4°C), then washed again and fixed in 0.5% paraformaldehyde (30 minutes at 4°C). Cells were then washed again before acquisition. Gating strategy is shown in Figure 14. Hierarchical gating was used for all markers except stem-cell memory cells, which used Boolean gating (CD45RA + CCR7 + CD45RO-CD95 + CD127 + ).
  • Detection reagents used for T-cell phenotyping (A) Panel 1 composition (Pheno1) and (B) Panel 2 composition (Pheno2). Serum cytokine analysis Concentration of serum cytokines was measured at baseline; day 0 pre-infusion; 1, 4 and 7 days post-infusion; and 2, 3, 4, 6, and 8 weeks post-infusion by the Meso Scale Discovery (MSD) immunoassay at Cambridge Biomedical (BioAgilytix).
  • MSD Meso Scale Discovery
  • V-PLEX Proinflammatory Panel 1 V-PLEX Cytokine Panel 1 and U-PLEX Biomarker Group 1 were used to collectively analyze the cytokine profiles of GM-CSF, IFN- ⁇ , IL1 ⁇ , IL1 ⁇ , IL-1RA, IL-2, IL-2R ⁇ , IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, TNF- ⁇ , TNF- ⁇ and VEGF-A.
  • RNA extract was quantified (including assessment of RNA purity) using the Quant-iT RiboGreen RNA Reagent and Kit, and RNA quality was assessed using Agilent RNA Pico chip analysis.
  • RNA was analyzed using the NanoString nCounter® system, with 2 sets of NanoString assays (nCounter® PanCancer Immune Profiling Panel and nCounter® PanCancer Pathway Panel) run on the same extract.
  • RNA in situ hybridization on biopsied tissues was performed using the RNAscope ® 2.5 HD Duplex Reagent Kit (Advanced Cell Diagnostics) comprising TCR- Adapt and CD3 mRNA detection assays. 5- ⁇ m formalin-fixed, paraffin-embedded (FFPE) tissue sections were pretreated with heat and protease prior to hybridization with the target oligo probes. Preamplifier, amplifier, and horseradish peroxidase/alkaline phosphatase-labeled oligos were then hybridized sequentially, followed by chromogenic precipitate development.
  • FFPE paraffin-embedded
  • RNAscope ® CD3 probe comprised a pool of three human CD3 antigens (CD3d, CD3e, and CD3g) mRNA, whereas the TCR probe was custom-made. Specific RNA staining signal was identified as green or red punctate dots. Samples were counterstained with hematoxylin. Protein expression by immunohistochemistry NY-ESO-1 staining was performed using the E978 clone (Sigma).
  • CD4 clone SP35
  • CD8 clone C8/144B
  • CD20 clone L26
  • CD45 clone 2B11 + PD7/26; staining on autostainer
  • CD163 clone MRQ- 26
  • LAG-3 clone 17B4
  • Pan Keratin clone AE1/AE3/PCK16
  • PD-1/CD279 clone SP269
  • PD-L1 clone SP142
  • TIM-3 clone C8/144B
  • the intent-to-treat (ITT) population included all enrolled patients, whereas the modified ITT (mITT) population, used for safety and efficacy assessments, included patients who received lete-cel infusion.
  • the population for biomarker analyses included patients who received lete-cel infusion with available biomarker data; sample size for each population is specified in figure legends.
  • Endpoint Analyses The primary endpoint for the study was pre-defined as objective response (ORR) using RECIST v1.1 based on Investigator assessment. A sensitivity analyses by Independent Review was also assessed. The ORR for each cohort of the mITT population was evaluated using 95% Clopper-Pearson confidence intervals.
  • OS was defined as the time from t-cell infusion to death due to any cause. Subjects known to be alive at this time were censored for the OS analysis. Exploratory biomarker endpoints were evaluated as specified below. P-values are presented for descriptive purposes and are nominal (unadjusted) unless noted otherwise. Evaluation of expansion correlates Post-hoc relationships between cell expansion, biomarker expression, and efficacy were evaluated in a hypothesis-driven manner using Wilcoxon, logistic, linear, and median regression (R version 3.5.1), after log-transforming data when appropriate.
  • %CD4+Pentamer+ (number of CD3/CD4+Pentamer+)/(number of CD3/CD4+Pentamer+ + number of CD3/CD8+Pentamer+). Accordingly, the percentage of CD8+ cells among Pentamer+ cells (%CD8+Pentamer+) was inferred as 1 – %CD4+Pentamer+.
  • the number of transduced cells of memory phenotype X for each sample was inferred as %CD4+Pentamer+ number of transduced cells in sample frequency of CD4+Pentamer+/X.
  • the number of transduced cells of CD8+Pentamer+ memory phenotype X was done similarly.
  • P-values in downstream statistical analyses were based on the Wilcoxon rank sum test, whereas correlations were based on Spearman correlation coefficients. Cytokine analysis Cytokine analysis was based on a linear mixed effects model, log-transformed cytokine level modeled with treatment x time interactions and a random subject intercept (with otherwise independent errors).
  • RNA analysis was conducted in R version 4.0.2.
  • RNA analysis For RNA analysis, both gene-level and gene-set analyses were conducted for Nanostring data, with each of the two panels fit separately.
  • ORR comparisons were based on limma models and implemented via the limma R/Bioconductor package (version 3.44.3), with log2-expression as response and ORR as a single covariate. P-values were adjusted for multiple comparisons using the q-value methodology implemented via the q- value R/Bioconductor package.
  • Pre-treatment versus At-Progression comparisons were conducted using linear mixed effects models (lme4, version 1.1-23) to address repeated measures.
  • PFS comparisons were based on Cox proportional hazards models with PFS as response and log2- expression as a single covariate.
  • PFS was defined as the time from T- cell infusion to the earliest documentation of disease progression or death from any cause or surgical resection or start of prohibited medication.
  • global significance statistics were based on t-statistics from each gene within a set of interest .
  • Corresponding p-values were obtained by permutation test (5000 permutations).
  • “Competitive Fisher" test odds ratios were based on cross-tabulation of gene set membership with nominal significance (p ⁇ 0.05); p-values were obtained by permutation test using Fisher Exact test p-value as objective function.
  • IL-15 and IL-7 are cytokines which support T-cell proliferation and survival and studies have shown that these cytokines are increased post LDR, especially by fludarabine.
  • LDRs containing fludarabine had higher IL-15 levels prior to T-cell infusion.
  • the impact of fludarabine was further supported by data from 2 patients who received cyclophosphamide-only LDR for the first infusion and standard LDR for the second infusion. These patientes had 2- and 7-fold increase in IL- 15 respectively (Figure 8b).
  • responding patients had higher levels of IL-15 prior to T-cell infusion ( Figure 1d).
  • There was no association of IL-7 pre-infusion with response (Figure 8c).
  • able 2 Patient characteristics (mITT population). able 3. Incidence of adverse events with toxicity grade ⁇ 3 occurring in ⁇ 10% of subjects.
  • esponders received lete-cel product enriched with activated, effector memory CD8 cells and ntaining comparable total CD8 to CD4 cell ratio
  • Lete-cel contains a mixture of transduced and non-transduced T cells. In this study,e median transduction efficiency was 35% (range 14–65%).
  • MHC major histocompatibility complex
  • This pentamer is primarily used to stain CD8 cells due to co-receptor stabilization,erefore our analysis focused on CD8+Pentamer+ cells.
  • This gene set is primarily induced by type I terferons, such as IFN ⁇ and IFN ⁇ , with limited involvement of IFN ⁇ .
  • Type I interferonse known to play an important role in antiviral response as well as myeloid differentiation.hey can have both pro- and antitumor effects depending on the TME, cell types, and tokines. It is unclear what triggered the induction of these genes in this analysis as IFN ⁇ d IFN ⁇ RNA was undetectable in tumor cells.
  • Figure 5e shows that the gene set pression was associated with CD163 and CD68 macrophage expression.

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Abstract

La présente invention porte sur les procédés et le matériel nécessaires à l'évaluation et/ou au traitement des mammifères présentant un cancer. Par exemple, des procédés et du matériel pour déterminer si un mammifère (par exemple, un humain) présentant un cancer (par exemple, un cancer comprenant une ou plusieurs tumeurs solides) est susceptible de répondre à une ou plusieurs immunothérapies anticancéreuses (par exemple, une thérapie anticancéreuse à base de récepteurs de lymphocytes T (TCR)) et/ou répond à une immunothérapie plus particulièrement sont proposés. Par exemple, des procédés et du matériel pour l'utilisation d'une ou plusieurs immunothérapies anticancéreuses (par exemple, une thérapie de lymphocytes T TCR) pour traiter un mammifère (par exemple, un humain) présentant un cancer (par exemple, présentant un cancer comprenant une ou plusieurs tumeurs solides) et identifié comme étant susceptible de répondre à une ou plusieurs immunothérapies anticancéreuses sont fournis.
PCT/IB2023/054003 2022-04-22 2023-04-19 Procédé d'évaluation d'une thérapie par lymphocytes t tcr destinés à cibler un antigène ny-eso-1 WO2023203506A1 (fr)

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Non-Patent Citations (21)

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