Immune-related gene expression signatures and methods relating thereto

Abstract

Among other things, the present disclosure provides methods for determining responsiveness to cancer treatments and methods of treating a subject having cancer comprising administering a cancer treatment, wherein the subject has been determined to be responsive to the cancer treatment. In some embodiments, a subject is determined to be responsive to a cancer treatment when a level of a gene expression signature is elevated. In some embodiments, a cancer treatment comprises a pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor. In some embodiments, a cancer treatment comprises a pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor and one or more pharmaceutical compositions comprising one or more therapeutic agents.

Description

IMMUNE-RELATED GENE EXPRESSION SIGNATURES AND METHODS RELATINGTHERETOBACKGROUND

[0001] A plethora of therapeutics, including antibodies and chemotherapeutic agents, have been developed for the treatment of cancer. However, the great variation in tumor genotypes and phenotypes offers a challenge in determining treatments most likely to result in clinical benefits, including, e.g., increased progression free survival. Accordingly, new approaches to predicting subject responsiveness to cancer treatments are needed. Through the usage of gene expression signatures (GES), which comprise multiple biomarkers, subject responsiveness to cancer treatments can be determined and improved methods of treating cancers may be implemented.SUMMARY

[0002] Some aspects of the present disclosure are based, at least in part, on identified gene expression signatures (GES) that may be used to classify a subject having cancer as responsive to a cancer treatment comprising, e.g., a pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor, or a pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor and one or more pharmaceutical compositions comprising one or more therapeutic agents, if a level of the GES is elevated as compared to a threshold level of the GES. In certain aspects of the disclosure, a GES comprises or is an immune-related GES. In certain aspects of the disclosure, methods are provided utilizing an immune-related GES to classify a subject having cancer as responsive to a cancer treatment if a level of the immune-related GES is elevated as compared to a threshold level of the immune-related GES.

[0003] In certain aspects of the disclosure, methods are provided. In some embodiments, a method comprises steps of (a) providing or obtaining a sample from the subject, (b) testing for or detecting an immune-related GES in the sample, (c) comparing a level of the immune-related GES in the sample to a threshold level of the immune-related GES, and (d) classifying the subject as responsive to the cancer treatment when the sample exhibits an elevated level of the immune-related GES relative to the threshold level of the immune-related GES. In someembodiments, a method comprises steps of (a) providing or obtaining a sample from the subject;(b) testing for or detecting an immune-related GES in the sample, wherein the immune-related GES comprises one or more biomarkers chosen from one, two, three, or more of (i) an anti-viral response biomarker chosen from one or both of IFIT1 and OAS2, (ii) an interferon signaling biomarker chosen from one, two, or more of SP110, JAK2, and STAT1, (iii) a macrophage regulation biomarker chosen from one or both of EPSTI1 and SLAMF8, and (iv) a T cell-related function biomarker chosen from one, two, three, or more of IL7R, CCL4, HLA.A, and SELPLG;(c) comparing a level of the immune-related GES in the sample to a threshold level of the immune-related GES; and (d) classifying the subject as responsive to the cancer treatment when the sample exhibits an elevated level of the immune-related GES relative to the threshold level of the immune-related GES, wherein the cancer treatment comprises a pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor. In some embodiments, a cancer treatment further comprises one or more pharmaceutical compositions comprising one or more therapeutic agents. In some embodiments, a method further comprises administering the cancer treatment to the subject if the subject is classified as responsive to the cancer treatment.

[0004] In certain aspects of the disclosure, methods of determining responsiveness of a subject having cancer to a cancer treatment are provided. In some embodiments, a method of determining responsiveness of a subject having cancer to a cancer treatment comprises (a) providing or obtaining a sample from the subject, (b) testing for or detecting an immune-related GES in the sample, (c) comparing a level of the immune-related GES in the sample to a threshold level of the immune-related GES, and (d) classifying the subject as responsive to the cancer treatment when the sample exhibits an elevated level of the immune-related GES relative to the threshold level of the immune- related GES. In some embodiments, a method of determining responsiveness of a subject having cancer to a cancer treatment comprises (a) providing or obtaining a sample from the subject; (b) testing for or detecting an immune-related GES in the sample, wherein the immune-related GES comprises one or more biomarkers chosen from one, two, three, or more of (i) an anti-viral response biomarker chosen from one or both of IFIT1 and OAS2, (ii) an interferon signaling biomarker chosen from one, two, or more of SP110, JAK2, and STAT1, (iii) a macrophage regulation biomarker chosen from one or both of EPSTI1 and SLAMF8, and (iv) a T cell-related function biomarker chosen from one, two, three, or moreof IL7R, CCL4, HLA.A, and SELPLG; (c) comparing a level of the immune-related GES in the sample to a threshold level of the immune- related GES; and (d) classifying the subject as responsive to the cancer treatment when the sample exhibits an elevated level of the immune- related GES relative to the threshold level of the immune-related GES, wherein the cancer treatment comprises a pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor. In some embodiments, a cancer treatment further comprises one or more pharmaceutical compositions comprising one or more therapeutic agents. In some embodiments, a method of determining responsiveness of a subject having cancer to a cancer treatment further comprises administering the cancer treatment to the subject if the subject is classified as responsive to the cancer treatment.

[0005] In certain aspects of the disclosure, methods of treating a subject having cancer comprising administering a cancer treatment are provided. In some embodiments, a method of treating a subject having cancer comprises administering a cancer treatment, wherein the subject has been determined to be responsive to the cancer treatment. In some embodiments, a subject has been determined to be responsive to a cancer treatment by a method comprising (a) providing or obtaining a sample from the subject, (b) testing for or detecting an immune-related GES in the sample, (c) comparing a level of the immune-related GES in the sample to a threshold level of the immune-related GES, and (d) classifying the subject as responsive to the cancer treatment when the sample exhibits an elevated level of the immune-related GES relative to the threshold level of the immune- related GES. In some embodiments, a method of treating a subject having cancer comprises administering a cancer treatment, wherein the subject has been determined to be responsive to the cancer treatment by a method comprising (a) providing or obtaining a sample from the subject; (b) testing for or detecting an immune-related GES in the sample, wherein the immune-related GES comprises one or more biomarkers chosen from one, two, three, or more of (i) an anti-viral response biomarker chosen from one or both of IFIT1 and OAS2, (ii) an interferon signaling biomarker chosen from one, two, or more of SP110, JAK2, and STAT1, (iii) a macrophage regulation biomarker chosen from one or both of EPSTI1 and SLAMF8, and (iv) a T cell-related function biomarker chosen from one, two, three, or more of IL7R, CCL4, HLA.A, and SELPLG; (c) comparing a level of the immune-related GES in the sample to a threshold level of the immune- related GES; and (d) classifying the subject asresponsive to the cancer treatment when the sample exhibits an elevated level of the immune- related GES relative to the threshold level of the immune-related GES, wherein the cancer treatment comprises a pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor. In some embodiments, a cancer treatment further comprises one or more pharmaceutical compositions comprising one or more therapeutic agents.

[0006] In certain aspects of the disclosure, methods of treating a subject having cancer are provided. In some embodiments, a method of treating a subject having cancer comprises (a) providing or obtaining a sample from the subject, (b) testing for or detecting an immune-related GES in the sample, (c) comparing a level of the immune-related GES in the sample to a threshold level of the immune-related GES, (d) classifying the subject as responsive to the cancer treatment when the sample exhibits an elevated level of the immune-related GES relative to the threshold level of the immune-related GES, and (e) administering the cancer treatment to the subject if the subject is classified as responsive to the cancer treatment. In some embodiments, a method of treating a subject having cancer comprises (a) providing or obtaining a sample from the subject; (b) testing for or detecting an immune- related GES in the sample, wherein the immune-related GES comprises one or more biomarkers chosen from one, two, three, or more of (i) an anti-viral response biomarker chosen from one or both of IFIT1 and OAS2, (ii) an interferon signaling biomarker chosen from one, two, or more of SP110, JAK2, and STAT1, (iii) a macrophage regulation biomarker chosen from one or both of EPSTI1 and SLAMF8, and (iv) a T cell-related function biomarker chosen from one, two, three, or more of IL7R, CCL4, HLA.A, and SELPLG; (c) comparing a level of the immune-related GES in the sample to a threshold level of the immune-related GES; (d) classifying the subject as responsive to the cancer treatment when the sample exhibits an elevated level of the immune-related GES relative to the threshold level of the immune-related GES; and (e) administering the cancer treatment to the subject if the subject is classified as responsive to the cancer treatment, wherein the cancer treatment comprises a pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor. In some embodiments, a cancer treatment further comprises one or more pharmaceutical compositions comprising one or more therapeutic agents.

[0007] In certain aspects of the disclosure, methods comprising steps of selecting a subject for treatment with tislelizumab based on the presence of an immune-related GES in a tumorspecimen and administering a therapeutically effective amount of tislelizumab to the subject are provided. In some embodiments, a method comprises steps of selecting a subject for treatment with tislelizumab based on the presence of an immune-related GES in a tumor specimen, wherein the immune-related GES comprises one or more biomarkers chosen from one, two, three, or more of (i) an anti-viral response biomarker chosen from one or both of IFIT1 and OAS2, (ii) an interferon signaling biomarker chosen from one, two, or more of SP110, JAK2, and STAT1, (iii) a macrophage regulation biomarker chosen from one or both of EPSTI1 and SLAMF8, and (iv) a T cell-related function biomarker chosen from one, two, three, or more of IL7R, CCL4, HLA.A, and SELPLG, and administering a therapeutically effective amount of tislelizumab to the subject are provided. In some embodiments, a method further comprises administering one or more chemotherapeutic agents to a subject. In some embodiments, a subject exhibits prolonged progression free survival (PFS) as compared to a reference subject or an increased likelihood of prolonged PFS as compared to a reference subject. In some embodiments, a method increases one or both of overall survival (OS) or PFS of a subject. In some embodiments, a subject is refractory to chemotherapy.

[0008] In some embodiments, an immune-related GES comprises one or more biomarkers chosen from one, two, three, or more of (i) an anti-viral response biomarker, (ii) an interferon signaling biomarker, (iii) a macrophage regulation biomarker, and (iv) a T cell-related function biomarker. In some embodiments, an anti-viral response biomarker is chosen from one or both of IFIT1 and OAS2. In some embodiments, an interferon signaling biomarker is chosen from one, two, or more of SP110, JAK2, and STATE In some embodiments, a macrophage regulation biomarker is chosen from one or both of EPSTIl and SLAMF8. In some embodiments, a T cell-related function biomarker is chosen from one, two, three, or more of IL7R, CCL4, HLA.A., and SELPLG. In some embodiments, an immune-related GES comprises one or more biomarkers chosen from one, two, three, or more of (i) an anti-viral response biomarker chosen from one or both of IFIT1 and OAS2, (ii) an interferon signaling biomarker chosen from one, two, or more of SP110, JAK2, and STAT1, (iii) a macrophage regulation biomarker chosen from one or both of EPSTIl and SLAMF8, and (iv) a T cell-related function biomarker chosen from one, two, three, or more of IL7R, CCL4, HLA.A, and SELPLG. In some embodiments, an immune-related GES comprises IFIT1, OAS2, SP110, JAK2, STAT1, EPSTIl,SLAMF8, IL7R, CCL4, HLA.A, and SELPLG biomarkers. In some embodiments, an immune- related GES comprises or is an immune-related GES as described herein.

[0009] In some embodiments, a method comprises testing for or detecting a NRF2 pathway signature in a sample provided or obtained from a subject. In some embodiments, a method comprises testing for or detecting a NRF2 pathway signature in a sample provided or obtained from a subject and comparing a level of the NRF2 pathway signature in the sample to a threshold level of the NRF2 pathway signature. In some embodiments, a NRF2 pathway signature comprises one or more NRF2 pathway signature biomarkers as described herein. In some embodiments, a NRF2 pathway signature comprises one or more biomarkers chosen from one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more of G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1 A, ABCG2, and ABCC2. In some embodiments, a NRF2 pathway signature comprises G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1A, ABCG2, and ABCC2 biomarkers. In some embodiments, a NRF2 pathway signature comprises or is a NRF2 pathway signature as described herein.

[0010] In some embodiments, a method comprises testing for or detecting one or more activating NRF2 pathway mutations in a sample provided or obtained from a subject. In some embodiments, one or more activating NRF2 pathway mutations comprise or are one, two, or more of (i) one or more gain of function mutations in NFE2L2, (ii) one or more loss of function mutations in KEAP1, or (iii) one or more loss of function mutations in CUL3.

[0011] In some embodiments, a threshold level is a threshold level of an immune-related GES. In some embodiments, a threshold level of an immune-related GES is a predetermined mean or median level of an immune-related GES of a population of samples provided or obtained from a population of subjects. In some embodiments, a threshold level of an immune- related GES is a level of an immune-related GES in a second sample. In some embodiments, a threshold level is a threshold level of a NRF2 pathway signature. In some embodiments, a threshold level of a NRF2 pathway signature is a predetermined mean or median level of a NRF2 pathway signature of a population of samples provided or obtained from a population of subjects.In some embodiments, a threshold level of a NRF2 pathway signature is a level of a NRF2 pathway signature in a second sample.

[0012] In some embodiments, a population of subjects is a population of healthy subjects. In some embodiments, a population of subjects is a population of subjects diagnosed with a benign tumor. In some embodiments, a population of subjects is a population of subjects diagnosed with a cancer.

[0013] In some embodiments, a second sample is from a subject prior to administration of a cancer treatment. In some embodiments, a second sample is from a subject after administration of at least one cancer treatment. In some embodiments, a second sample is from a subject after administration of at least 1, 2, 3, 4, 5, or more cancer treatments. In some embodiments, a second sample is from a second subject. In some embodiments, a second subject is a healthy subject or a subject diagnosed with a benign tumor. In some embodiments, a second subject is a healthy subject. In some embodiments, a second subject is a subject diagnosed with a benign tumor.

[0014] In some embodiments, a cancer comprises or is a lung cancer. In some embodiments, a lung cancer comprises or is non-small cell lung cancer (NSCLC). In some embodiments, NSCLC comprises or is lung squamous cell carcinoma (LUSC) or lung adenocarcinoma (LU AD). In some embodiments, NSCLC comprises or is LUSC. In some embodiments, NSCLC comprises or is LU AD. In some embodiments, a cancer comprises or is a liver cancer. In some embodiments, a liver cancer comprises or is hepatocellular carcinoma. In some embodiments, a cancer comprises or is a nasopharynx cancer. In some embodiments, a nasopharynx cancer comprises or is nasopharyngeal carcinoma (NPC). In some embodiments, a cancer comprises or is a gastric cancer. In some embodiments, a cancer comprises or is a kidney cancer. In some embodiments, a kidney cancer comprises or is renal cell carcinoma (RCC). In some embodiments, a cancer is an advanced stage cancer. In some embodiments, a cancer is a cancer described herein.

[0015] In some embodiments, responsive to a cancer treatment comprises prolonged progression free survival (PFS) as compared to a reference subject or an increased likelihood of prolonged PFS as compared to a reference subject. In some embodiments, responsive to a cancertreatment comprises prolonged PFS as compared to a reference subject. In some embodiments, responsive to a cancer treatment comprises an increased likelihood of prolonged PFS as compared to a reference subject. In some embodiments, responsive to a cancer treatment comprises increased objective response rate (ORR) as compared to a reference subject or an increased likelihood of increased ORR as compared to a reference subject. In some embodiments, responsive to a cancer treatment comprises increased ORR as compared to a reference subject. In some embodiments, responsive to a cancer treatment comprises an increased likelihood of increased ORR as compared to a reference subject. In some embodiments, responsive to a cancer treatment comprises increased duration of response (DOR) as compared to a reference subject or an increased likelihood of increased DOR as compared to a reference subject. In some embodiments, responsive to a cancer treatment comprises increased DOR as compared to a reference subject. In some embodiments, responsive to a cancer treatment comprises increased likelihood of increased DOR as compared to a reference subject. In some embodiments, one, two, or more of PFS, ORR, or DOR is measured according to Responsive Evaluation Criteria in Solid Tumors (RECIST). In some embodiments, responsive to cancer treatment comprises prolonged overall survival (OS) as compared to a reference subject or an increased likelihood of prolonged OS as compared to a reference subject. In some embodiments, responsive to a cancer treatment comprises prolonged OS as compared to a reference subject. In some embodiments, responsive to a cancer treatment comprises an increased likelihood of prolonged OS as compared to a reference subject. In some embodiments, responsive to a cancer treatment comprises increased health-related quality of life (HRQoL) as compared to a reference subject or an increased likelihood of increased HRQoL as compared to a reference subject. In some embodiments, responsive to a cancer treatment comprises increased HRQoL as compared to a reference subject. In some embodiments, an increased likelihood of increased HRQoL as compared to a reference subject. In some embodiments, HRQoL is measured using one or both of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13) or European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ- C30). In some embodiments, HRQoL is measured using EORTC QLQ-LC13. In some embodiments, HRQoL is measured using EORTC QLQ-C30.

[0016] In some embodiments a reference subject was administered one or more pharmaceutical compositions comprising one or more therapeutic agents. In some embodiments, a reference subject was administered a PD-1 or PD-L1 inhibitor. In some embodiments, a reference subject was not administered a PD-1 or PD-L1 inhibitor. In some embodiments, a reference subjects exhibits one, two, or more of (i) a lower level of an immune-related GES as compared to a threshold level of an immune-related GES detected in a reference sample provided or obtained from the reference subject, (ii) an elevated level of a NRF2 pathway signature as compared to a threshold level of a NRF2 pathway signature detected in a reference sample provided or obtained from the reference subject, or (iii) one or more activating NRF2 pathway mutations detected in a reference sample provided or obtained from the reference subject. In some embodiments, a reference subjects exhibits a lower level of an immune-related GES as compared to a threshold level of an immune-related GES detected in a reference sample provided or obtained from the reference subject. In some embodiments, a reference subjects exhibits an elevated level of a NRF2 pathway signature as compared to a threshold level of a NRF2 pathway signature detected in a reference sample provided or obtained from the reference subject. In some embodiments, a reference subjects exhibits one or more activating NRF2 pathway mutations detected in a reference sample provided or obtained from the reference subject.

[0017] In some embodiments, a sample comprises or is a biological sample. In some embodiments, a sample comprises or is a tumor specimen. In some embodiments, a sample comprises polynucleotides. In some embodiments, polynucleotides comprise one or both of DNA or RNA. In some embodiments, polynucleotides are detected by performing one, two, three, four, five, or more of quantitative PCR, reverse-transcription-PCR, in situ hybridization, in vitro hybridization, microarray, or nucleic acid sequencing. In some embodiments, nucleic acid sequencing comprises one or both of next-generation sequencing or whole-genome sequencing. In some embodiments, a sample comprises polypeptides. In some embodiments, polypeptides are detected by performing one or both of an immunoassay (e.g., ELISA) and mass spectrometry.

[0018] In some embodiments, a cancer treatment comprises a pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor. In some embodiments, a cancer treatment comprises a pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor and one or more pharmaceutical compositions comprising one or more therapeutic agents.

[0019] In some embodiments, a PD-1 or PD-L1 inhibitor comprises or is a PD-1 inhibitor. In some embodiments, a PD-1 inhibitor comprises or is an anti -PD-1 antibody or antigen-binding fragment thereof. In some embodiments, an anti-PD-1 antibody or antigen-binding fragment thereof comprises or is tislelizumab. In some embodiments, a PD-1 or PD-L1 inhibitor comprises or is a PD-L1 inhibitor. In some embodiments, a PD-L1 inhibitor comprises or is an anti-PD-Ll antibody or antigen-binding fragment thereof.

[0020] In some embodiments, one or more therapeutic agents comprise or are one or both of (i) one or more chemotherapeutic agents or (ii) one or more antibodies or antigen-binding fragments thereof. In some embodiments, one or more chemotherapeutic agents comprise or are one or both of paclitaxel or carboplatin. In some embodiments, paclitaxel is in one or more forms. In some embodiments, paclitaxel comprises or is solvent-based paclitaxel. In some embodiments, paclitaxel comprises or is nanoparticle albumin-bound (nab) paclitaxel. In some embodiments, one or more chemotherapeutic agents comprise or are an anti-vascular endothelial growth factor receptor (VEGFR) therapeutic.

[0021] In some embodiments, a method provides an improvement of a subject in one or more clinical assessments. In some embodiments, a method increases OS of a subject. In some embodiments, a method increases PFS of a subject. In some embodiments, a method increases HRQoL of a subject. In some embodiments, a method increases one or both of OS or PFS of a subject. In some embodiments, a method increases one, two, or more of OS, PFS, or HRQoL. In some embodiments, HRQoL is measured using one or both of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13) or European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). In some embodiments, HRQoL is measured using EORTC QLQ-LC13. In some embodiments, HRQoL is measured using EORTC QLQ-C30.

[0022] In certain aspects of the disclosure, methods are provided. In some embodiments, a method comprises steps of: (a) selecting a subject for treatment with tislelizumab based on the presence of a gene expression signature (GES) in a tumor specimen from the subject, wherein the GES comprises one or more biomarkers chosen from one or more of: (i) a Microsatellite Instability-High (MSI-H) biomarker; and (ii) a Deficient Mismatch Repair (dMMR) biomarker;and (b) administering a therapeutically effective amount of tislelizumab to the subject. In some embodiments, treating is clinically effective or the subject is a responder to treatment by at least one measure of response as compared to a reference subject. In some embodiments, a reference subject does not have an MSI-H biomarker or a dMMR biomarker in a tumor specimen.

[0023] In certain aspects of the disclosure, methods for treating a neoplastic disorder are provided. In some embodiments, a method for treating a neoplastic disorder, comprises administering a cancer treatment, wherein the subject has been determined to be responsive to the cancer treatment by a method comprising: (a) selecting a subject for treatment with tislelizumab based on the presence of a gene expression signature (GES) in a tumor specimen from the subject, wherein the GES comprises one or more biomarkers chosen from one or more of: (i) a Microsatellite Instability-High (MSI-H) biomarker; (ii) a Deficient Mismatch Repair (dMMR) biomarker; and (b) classifying the subject as responsive to the cancer treatment by at least one measure of response as compared to a reference subject. In some embodiments, a reference subject does not have an MSI-H biomarker or a dMMR biomarker in a tumor specimen. In some embodiments, a cancer treatment comprises a therapeutically effective amount of tislelizumab.

[0024] In certain aspects of the disclosure, methods for treating a neoplastic disorder are provided. In some embodiments, a method for treating a neoplastic disorder comprises steps of: (a) selecting a subject for treatment with tislelizumab based on the presence of a gene expression signature (GES) in a tumor specimen from the subject, wherein the GES comprises one or more biomarkers chosen from one or more of: (i) a Microsatellite Instability-High (MSI-H) biomarker; and (ii) a Deficient Mismatch Repair (dMMR) biomarker; and (b) administering a therapeutically effective amount of tislelizumab to the subject. In some embodiments, treating is clinically effective or the subject is a responder to the treatment by at least one measure of response as compared to a reference subject. In some embodiments, a reference subject does not have an MSI-H biomarker or a dMMR biomarker in a tumor specimen.

[0025] In some embodiments, an MSI-H biomarker comprises presence of size shifts in at least two microsatellite markers. In some embodiments, at least five microsatellite markers are assessed for size shifts. In some embodiments, microsatellite markers are assessed for size shiftsusing polymerase chain reaction (PCR). In some embodiments, a dMMR biomarker comprises absence of at least one Mismatch Repair (MMR) protein in the tumor specimen. In some embodiments, a dMMR protein is selected from one, two, three, or more of MLH1, MSH2, MSH6, and PMS2 protein. In some embodiments, absence of at least one MMR protein is assessed using immunohistochemistry. In some embodiments, at least one measure of response is selected from one, two, three, four, five, six or more of overall survival (OS), progression-free survival (PFS), event- free survival, overall response rate, objective response rate, partial response, and duration of response. In some embodiments, at least one measure of response is tumor volume. In some embodiments, treating is clinically effective if a population of subjects has an OS rate at 24 months from treatment initiation of at least about 30% or more. In some embodiments, treating is clinically effective if a population of subjects has a PFS rate at 12 months from treatment initiation of at least about 50% or more. In some embodiments, treating is clinically effective if a population of subjects has an event-free survival rate at 12 months from treatment initiation of at least about 20% or more. In some embodiments, treating is clinically effective if the subject has at least about 15%, 20% or more probability of event-free survival at 12 months from treatment initiation. In some embodiments, a subject is susceptible to or suffering from a cancer selected from one, two, three, four, five, six, or more of colorectal cancer, gastric or gastroesophageal junction cancer, ampullary carcinoma, endometrial cancer, cervical cancer, ovarian cancer, small bowel adenocarcinoma, and pelvis clear cell carcinoma. In some embodiments, a subject was previously administered or delivered one or more cancer treatments, optionally wherein the one or more cancer treatments do not comprise tislelizumab. In some embodiments, a subject is administered or selected for treatment with one or more additional therapeutic agents. In some embodiments, one or more additional therapeutic agents comprises or are one or more chemotherapeutic agents. In some embodiments, one or more chemotherapeutic agents comprises or are one, two, three, or four of oxaliplatin, capecitabine, cisplatin, and 5 -fluorouracil.

[0026] In some embodiments, the anti-PD-1 antibody is administered at a dose from about 50 to 800 mg, optionally wherein the anti-PD-1 antibody is administered at 100 mg, 150 mg, 200, mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg. In some embodiments, the PD-1 antibody is administered every week, every 2weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks, preferably wherein the anti-PD-1 antibody is administered at 150 mg every two weeks, 300 mg every four weeks, or 400 mg every six weeks. In some embodiments, the cancer treatment comprises intravenous administration of tislelizumab. In some embodiments, the cancer treatment comprises intravenous administration of 200 mg tislelizumab every 3 weeks.

[0027] In some embodiments, the present disclosure relates to a method of treating a cancer in a subject, comprising administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises tislelizumab, and wherein a sample obtained from the subject has an immune-related gene expression signature (GES), wherein the immune-related GES comprises one or more of:(a) interferon signaling biomarkers,(b) macrophage regulation biomarkers,(c) T cell-related function biomarkers, and / or(d) an anti-viral response biomarker. In some embodiments, the immune-related GES comprises one or more biomarkers chosen from:(a) an anti-viral response biomarker chosen from one or both of IFIT1 and OAS2;(b) an interferon signaling biomarker chosen from one, two, or more of SP110, JAK2, and STAT1;(c) a macrophage regulation biomarker chosen from one or both of EPSTIl and SLAMF8; and(d) a T cell-related function biomarker chosen from one, two, three, or more of IL7R, CCL4, HLA.A, and SELPLG. In some embodiments, the cancer is esophageal squamous cell carcinoma (ESCC). In some embodiments, the cancer is a lung cancer. In some embodiments, the lung cancer is non-squamous non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is squamous non-small cell lung cancer (NSCLC). In some embodiments, the cancer is gastric or gastroesophageal junction cancer. In some embodiments, the cancer is unr esectable, recurrent, locally advanced, and / or metastatic. In some embodiments, the subject was previously administered one or more cancer treatments. In some embodiments, the method further comprises administering a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a platinum-based chemotherapy. In some embodiments, the platinum-based chemotherapy is carboplatin. In some embodiments, the method further comprises administering (a) carboplatin, and (b) paclitaxel or nab-paclitaxel. In some embodiments, the method further comprises administering pemetrexed and a platinum-based compound. In some embodiments, the method further comprises administering 5-fluorouracil. In some embodiments, the cancer is locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC), and the method further comprises administering pemetrexed and a platinumbased compound. In some embodiments, the cancer is locally advanced or metastatic squamous non-small cell lung cancer (NSCLC), and the method further comprises administering (a) carboplatin, and (b) paclitaxel or nab-paclitaxel. In some embodiments, the cancer is locally advanced or metastatic NSCLC, and the subject was previously administered one or more cancer treatments. In some embodiments, the cancer is unresectable, recurrent, locally advanced, or metastatic ESCC, and the subject was previously administered one or more cancer treatments. In some embodiments, the cancer is unresectable, recurrent, locally advanced, or metastatic gastric or gastroesophageal junction cancer, and the method further comprises administering a platinumbased compound and 5-fluorouracil.

[0028] In some embodiments, the cancer treatment comprises intravenous administration of tislelizumab. In some embodiments, the cancer treatment comprises intravenous administration of 200 mg tislelizumab every 3 weeks. In some embodiments, the anti-PD-1 antibody is administered at a dose from about 50 to 800 mg, optionally wherein the anti-PD-1 antibody is administered at 100 mg, 150 mg, 200, mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg. In some embodiments, the PD-1 antibody is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks, preferably wherein the anti-PD-1 antibody is administered at 150 mg every two weeks, 300 mg every four weeks, or 400 mg every six weeks. In some embodiments, the cancer treatment comprises intravenous administration of tislelizumab. In some embodiments, the cancer treatment comprises intravenous administration of 200 mg tislelizumab every 3 weeks.

[0029] In some embodiments, the pharmaceutical composition comprises comprising a histidine buffer, a surfactant and at least one stabilizer. In some embodiments, the surfactant is a polysorbate. In some embodiments, the stabilizer is trehalose. In some embodiments, thepharmaceutical composition comprises citric acid monohydrate, histidine, L-histidine hydrochloride monohydrate, polysorbate 20, sodium citrate, and trehalose.

[0030] In some embodiments, the subject is defined by a tumor area positivity (TAP) score of PD-L1 expression of at least about 1%, about 2%, about 5%, or about 10%.BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 A. Kaplan-Meier analysis of PFS in subjects with PD-L1 positive (PD-L1 >1% tumor cell expression) tumors treated with tislelizumab plus chemotherapy (T + Chemo; N = 143) or chemotherapy alone (Chemo; N = 70). The X axis depicts time in months since start of treatment; the Y axis depicts PFS as a percentage. At top center, median PFS in months and the associated 95% confidence interval (CI) for each treatment group (tislelizumab plus chemotherapy; chemotherapy alone) is displayed. At top right, hazard ratio (HR) and associated 95% CI and the p-value from a two-sided stratified Kaplan-Meier log-rank test are also shown.

[0032] Figure IB. Kaplan-Meier analysis of PFS in subjects with PD-L1 negative (PD-L1 < 1% tumor cell expression) tumors treated with tislelizumab plus chemotherapy (T + Chemo; N = 93) or chemotherapy alone (Chemo; N = 43). The X axis depicts time in months since start of treatment; the Y axis depicts PFS as a percentage. At top center, median PFS in months and the associated 95% confidence interval (CI) for each treatment group (tislelizumab plus chemotherapy; chemotherapy alone) is displayed. At top right, hazard ratio (HR) and associated 95% CI and the p-value from a two-sided stratified Kaplan-Meier log-rank test are also shown.

[0033] Figure 1C. Forest plot of PFS hazard ratios between subjects treated with tislelizumab plus chemotherapy (T + Chemo) or chemotherapy (Chemo) alone according to various PD-L1 expression cutoffs. Columns from left to right: cutoff of % tumor cell expression of PD-L1 for inclusion in subgroup; frequency (Freq) of PFS events in the subgroup (n) among total subjects in the subgroup (N); plot of hazard ratio (HR) with 95% confidence interval (CI); numerical HR and associated 95% CI; interaction p-value from testing the interaction effect between the two respective subgroups from the Cox model.

[0034] Figure 2A. Kaplan-Meier analysis of PFS in subjects with high tTMB (tTMB > 10 mutations / megabase) treated with tislelizumab plus chemotherapy (T + Chemo; N = 87) orchemotherapy alone (Chemo; N = 44). The X axis depicts time in months since start of treatment; the Y axis depicts PFS as a percentage. At top center, median PFS in months and the associated 95% confidence interval (CI) for each treatment group (tislelizumab plus chemotherapy; chemotherapy alone) is displayed. At top right, hazard ratio (HR) and associated 95% CI and the p-value from a two-sided stratified Kaplan-Meier log-rank test are also shown.

[0035] Figure 2B. Kaplan-Meier analysis of PFS in subjects with low tTMB (tTMB < 10 mutations / megabase) treated with tislelizumab plus chemotherapy (T + Chemo; N = 87) or chemotherapy alone (Chemo; N = 45). The X axis depicts time in months since start of treatment; the Y axis depicts PFS as a percentage. At top center, median PFS in months and the associated 95% confidence interval (CI) for each treatment group (tislelizumab plus chemotherapy; chemotherapy alone) is displayed. At top right, hazard ratio (HR) and associated 95% CI and the p-value from a two-sided stratified Kaplan-Meier log-rank test are also shown.

[0036] Figure 2C. Forest plot of PFS hazard ratios between subjects treated with tislelizumab plus chemotherapy (T + Chemo) or chemotherapy alone (Chemo) according to various tTMB cutoffs. Columns from left to right: cutoff of tTMB mutations / megabase for inclusion in subgroup; frequency (Freq) of subjects with PFS events in the subgroup (n) among total subjects in the subgroup (N); plot of hazard ratio (HR) with 95% confidence interval (CI); numerical HR and associated 95% CI; interaction p-value from testing the interaction effect between the two respective subgroups from the Cox model.

[0037] Figure 3 A. Kaplan-Meier analysis of PFS in subjects with high bTMB (bTMB > 6 mutations / megabase) treated with tislelizumab plus chemotherapy (T + Chemo; N = 48) or chemotherapy alone (Chemo; N = 14). The X axis depicts time in months since start of treatment; the Y axis depicts PFS as a percentage. At top center, median PFS in months and the associated 95% confidence interval (CI) for each treatment group (tislelizumab plus chemotherapy; chemotherapy alone) is displayed. At top right, hazard ratio (HR) and associated 95% CI and the p-value from a two-sided stratified Kaplan-Meier log-rank test are also shown.

[0038] Figure 3B. Kaplan-Meier analysis of PFS in subjects with low bTMB (bTMB < 6 mutations / megabase) treated with tislelizumab plus chemotherapy (T + Chemo; N = 33) or chemotherapy alone (Chemo; N = 16). The X axis depicts time in months since start oftreatment; the Y axis depicts PFS as a percentage. At top center, median PFS in months and the associated 95% confidence interval (CI) for each treatment group (tislelizumab plus chemotherapy; chemotherapy alone) is displayed. At top right, hazard ratio (HR) and associated 95% CI and the p-value from a two-sided stratified Kaplan-Meier log-rank test are also shown.

[0039] Figure 3C. Forest plot of PFS hazard ratios between subjects treated with tislelizumab plus chemotherapy (T + Chemo) or chemotherapy alone (Chemo) according to various bTMB cutoffs. Columns from left to right: cutoff of bTMB mutations / megabase for inclusion in subgroup; frequency (Freq) of subjects with PFS events in the subgroup (n) among total subjects in the subgroup (N); plot of hazard ratio (HR) with 95% confidence interval (CI); numerical HR and associated 95% CI; interaction p-value from testing the interaction effect between the two respective subgroups from the Cox model.

[0040] Figure 4. Forest plot of PFS hazard ratios between subjects treated with tislelizumab plus chemotherapy (T + Chemo) or chemotherapy alone (Chemo) according to genes comprising an immune-related GES. Columns from left to right: gene; plots of hazard ratio (HR) with 95% confidence interval (CI) for low expressors (< median; top plot for each gene) and high expressors (> median; bottom plot for each gene); numerical HR and associated 95% CI for low expressors (< median; top row of values for each gene) and high expressors (> median; bottom row of values for each gene); interaction p-value from testing the interaction effect between the two respective subgroups () from the Cox model.

[0041] Figure 5. Forest plot of PFS hazard ratios between subjects treated with tislelizumab plus chemotherapy (T + Chemo) or chemotherapy alone (Chemo) according to various gene signatures (immune-related GES (11 -gene GES); 18-gene T cell-inflamed signature (TIS); IMpower 131 T effector (Teff) signature; JAVELIN Renal 101 Immuno signature; 4-gene inflammation signature (4-gene GES)). Columns from left to right: gene signature; plots of hazard ratio (HR) with 95% confidence interval (CI) for low gene signature (< median; top plot for each gene signature) and high gene signature (> median; bottom plot for each gene signature); numerical HR and associated 95% CI for low gene signature (< median; top row of values for each gene signature) and high gene signature (> median GES; bottom row of values for each gene signature); interaction p-value from testing the interaction effect between the tworespective subgroups (low gene signature and high gene signature) from the Cox model.

[0042] Figure 6A. Kaplan-Meier analysis of PFS in subjects with high immune-related GES treated with tislelizumab plus chemotherapy (T + Chemo; N = 93) or chemotherapy alone (Chemo; N = 45). The X axis depicts time in months since start of treatment; the Y axis depicts PFS as a percentage. At top center, median PFS in months and the associated 95% confidence interval (CI) for each treatment group (tislelizumab plus chemotherapy; chemotherapy alone) is displayed. At top right, hazard ratio (HR) and associated 95% CI and the p-value from a two- sided stratified Kaplan-Meier log-rank test are also shown.

[0043] Figure 6B. Kaplan-Meier analysis of PFS in subjects with low immune-related GES treated with tislelizumab plus chemotherapy (T + Chemo; N = 91) or chemotherapy alone (Chemo; N = 46). The X axis depicts time in months since start of treatment; the Y axis depicts PFS as a percentage. At top center, median PFS in months and the associated 95% confidence interval (CI) for each treatment group (tislelizumab plus chemotherapy; chemotherapy alone) is displayed. At top right, hazard ratio (HR) and associated 95% CI and the p-value from a two- sided stratified Kaplan-Meier log-rank test are also shown.

[0044] Figure 7A. Kaplan-Meier analysis of PFS in subjects without one or more NRF2 activating mutations treated with tislelizumab plus chemotherapy (T + Chemo; N = 119) or chemotherapy alone (Chemo; N = 57). The X axis depicts time in months since start of treatment; the Y axis depicts PFS as a percentage. At top center, median PFS in months and the associated 95% confidence interval (CI) for each treatment group (tislelizumab plus chemotherapy; chemotherapy alone) is displayed. At top right, hazard ratio (HR) and associated 95% CI and the p-value from a two-sided stratified Kaplan-Meier log-rank test are also shown. NR, not reached.

[0045] Figure 7B. Kaplan-Meier analysis of PFS in subjects with one or more NRF2 activating mutations treated with tislelizumab plus chemotherapy (T + Chemo; N = 50) or chemotherapy alone (Chemo; N = 23). The X axis depicts time in months since start of treatment; the Y axis depicts PFS as a percentage. At top center, median PFS in months and the associated 95% confidence interval (CI) for each treatment group (tislelizumab plus chemotherapy; chemotherapy alone) is displayed. At top right, hazard ratio (HR) and associated95% CI and the p-value from a two-sided stratified Kaplan-Meier log-rank test are also shown.

[0046] Figure 8A. Kaplan-Meier analysis of PFS in subjects with low NRF2 pathway signature treated with tislelizumab plus chemotherapy (T + Chemo; N = 120) or chemotherapy alone (Chemo; N = 64). The X axis depicts time in months since start of treatment; the Y axis depicts PFS as a percentage. At top center, median PFS in months and the associated 95% confidence interval (CI) for each treatment group (tislelizumab plus chemotherapy; chemotherapy alone) is displayed. At top right, hazard ratio (HR) and associated 95% CI and the p-value from a two-sided stratified Kaplan-Meier log-rank test are also shown.

[0047] Figure 8B. Kaplan-Meier analysis of PFS in subjects with high NRF2 pathway signature treated with tislelizumab plus chemotherapy (T + Chemo; N = 64) or chemotherapy alone (Chemo; N = 27). The X axis depicts time in months since start of treatment; the Y axis depicts PFS as a percentage. At top center, median PFS in months and the associated 95% confidence interval (CI) for each treatment group (tislelizumab plus chemotherapy; chemotherapy alone) is displayed. At top right, hazard ratio (HR) and associated 95% CI and the p-value from a two-sided stratified Kaplan-Meier log-rank test are also shown.

[0048] Figure 9. Plot of NRF2 pathway signature scores in subjects without or with NRF2 pathway mutations. The X axis denotes NRF2 pathway mutation subgroup (without one or more mutations, NRF2WT, N = 140; with one or more mutations, NRF2MUT, N = 65); the Y axis depicts NRF2 pathway signature score, p < 0.001, two-sided Wilcoxon rank-sum test.

[0049] Figure 10A. Forest plot of PFS hazard ratios between subjects treated with tislelizumab plus chemotherapy (T + Chemo) or chemotherapy alone (Chemo) according to various groupings based on PD-L1 expression and NRF2 pathway signature. Columns from left to right: subgroup of subjects; frequency (Freq) of subjects with PFS events in the subgroup (n) among total subjects in the subgroup (N); plots of hazard ratio (HR) with 95% confidence interval (CI); numerical HR and associated 95% CI; p-value from the Cox model for treatment effect under each subgroup. PD-Llp0Sltlve(PD-L1 > 1% tumor cell expression); PD-L I "cgall c(PD-L1 <1% tumor cell expression); NRF2high(high NRF2 pathway signature); NRF2low(low NRF2 pathway signature).

[0050] Figure 10B. Forest plot of PFS hazard ratios between subjects treated withtislelizumab plus chemotherapy (T + Chemo) or chemotherapy alone (Chemo) according to various groupings based on tTMB and NRF2 pathway signature. Columns from left to right: subgroup of subjects; frequency (Freq) of subjects with PFS events in the subgroup (n) among total subjects in the subgroup (N); plots of hazard ratio (HR) with 95% confidence interval (CI); numerical HR and associated 95% CI; p-value from the Cox model for treatment effect under each subgroup. tTMBhlgh(> 10 mutations / megabase); tTMBlow(<10 mutations / megabase); NRF2hlgh(high NRF2 pathway signature); NRF2low(low NRF2 pathway signature).

[0051] Figure 10C. Forest plot of PFS hazard ratios between subjects treated with tislelizumab plus chemotherapy (T + Chemo) or chemotherapy alone (Chemo) according to various groupings based on GES and NRF2 pathway signature. Columns from left to right: subgroup of subjects; frequency (Freq) of subjects with PFS events in the subgroup (n) among total subjects in the subgroup (N); plots of hazard ratio (HR) with 95% confidence interval (CI); numerical HR and associated 95% CI; p-value from the Cox model for treatment effect under each subgroup. GEShlgh(high immune-related GES); GESlow(low immune-related GES);NRF2hlgh(high NRF2 pathway signature); NRF2low(low NRF2 pathway signature).

[0052] Figure 11A. Kaplan-Meier analysis of PFS in subjects with high immune-related GES treated with avelumab plus axitinib (N = 160) or sunitinib alone (N = 203). The X axis depicts time in months since start of treatment; the Y axis depicts PFS as a percentage. At top, median PFS in months and the associated 95% confidence interval (CI) for each treatment group (avelumab + axitinib; sunitinib) is displayed. Hazard ratio (HR) and associated 95% CI and the p-value from a two-sided stratified Kaplan-Meier log-rank test are also shown. NR, not reached.

[0053] Figure 1 IB. Kaplan-Meier analysis of PFS in subjects with low immune-related GES treated with avelumab plus axitinib (N = 194) or sunitinib alone (N = 169). The X axis depicts time in months since start of treatment; the Y axis depicts PFS as a percentage. At top, median PFS in months and the associated 95% confidence interval (CI) for each treatment group (avelumab + axitinib; sunitinib) is displayed. Hazard ratio (HR) and associated 95% CI and the p-value from a two-sided stratified Kaplan-Meier log-rank test are also shown.

[0054] Figure 12. Best percent change in sum of target tumor lesion diameters from baseline in subjects with histologically confirmed MSI-H / dMMR solid tumors treated with tislelizumab200 mg intravenously every three weeks until progressive disease, unacceptable toxicity, or withdrawal of consent. Data presented is for efficacy evaluable population, which included all subjects who received any dose of tislelizumab and had measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) vl.l at baseline. Each vertical bar represents one subject. CRC = colorectal cancer; G / GEJC = gastric or gastroesophageal junction cancer.

[0055] Figure 13 A. Kaplan-Meier analysis of progression-free survival (PFS) in subjects with histologically confirmed MSI-H / dMMR solid tumors treated with tislelizumab 200 mg intravenously every three weeks until progressive disease, unacceptable toxicity, or withdrawal of consent. Data presented is for efficacy evaluable population, which included all subjects who received any dose of tislelizumab and had measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) vl.l at baseline. Inset displays median months as estimated by the Kaplan-Meier method with 95% confidence intervals estimated using the method of Brookmeyer and Crowley. Bottom displays number of patients at risk by cancer type starting from 0 months at left and increasing in 1 month intervals towards the right. CRC = colorectal cancer; G / GEJC = gastric or gastroesophageal junction cancer; Other = endometrial cancer, small bowel adenocarcinoma, ampullary carcinoma, cervical cancer, ovarian cancer, or pelvis clear cell carcinoma; NR = not reached.

[0056] Figure 13B. Kaplan-Meier analysis of overall survival (OS) in subjects with histologically confirmed MSI-H / dMMR solid tumors treated with tislelizumab 200 mg intravenously every three weeks until progressive disease, unacceptable toxicity, or withdrawal of consent. Data presented is for efficacy evaluable population, which included all subjects who received any dose of tislelizumab and had measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) vl.l at baseline. Inset displays median months as estimated by the Kaplan-Meier method with 95% confidence intervals estimated using the method of Brookmeyer and Crowley. Bottom displays number of patients at risk by cancer type starting from 0 months at left and increasing in 1 month intervals towards the right. CRC = colorectal cancer; G / GEJC = gastric or gastroesophageal junction cancer; Other = endometrial cancer, small bowel adenocarcinoma, ampullary carcinoma, cervical cancer, ovarian cancer, or pelvis clear cell carcinoma; NR = not reached.

[0057] Figure 14A. Kaplan-Meier analysis of progression-free survival (PFS) in subjects with HER2-negative locally advanced unresectable or metastatic GC / GEJC treated with tislelizumab plus chemotherapy or placebo plus chemotherapy. The X axis depicts time in months since start of treatment; the Y axis depicts PFS as a percentage. At top right, events, median PFS in months with 95% confidence interval (CI), and stratified hazard ratio (HR) with 95% CI and long-rank test p-value (one sided) are shown. Log-rank model was stratified by region (east Asia vs other regions), PD-L1 expression, and presence of peritoneal metastasis. Bottom displays number of patients at risk by treatment starting from 0 months at left and increasing in 2 month intervals towards the right.

[0058] Figure 14B. Kaplan-Meier analysis of overall survival (OS) in subjects with HER2- negative locally advanced unresectable or metastatic GC / GEJC treated with tislelizumab plus chemotherapy or placebo plus chemotherapy. The X axis depicts time in months since start of treatment; the Y axis depicts OS as a percentage. At top right, events, median PFS in months with 95% confidence interval (CI), and stratified hazard ratio (HR) with 95% CI and long-rank test p-value (one sided) are shown. Log-rank model was stratified by region (east Asia vs other regions), PD-L1 expression, and presence of peritoneal metastasis. Bottom displays number of patients at risk by treatment starting from 0 months at left and increasing in 2 month intervals towards the right.

[0059] Figure 15A. Kaplan-Meier analysis of progression-free survival (PFS) in subjects with HER2-negative locally advanced unresectable or metastatic GC / GEJC with a PD-L1 score >5% treated with tislelizumab plus chemotherapy or placebo plus chemotherapy. The X axis depicts time in months since start of treatment; the Y axis depicts PFS as a percentage. At top right, events, median PFS in months with 95% confidence interval (CI), and stratified hazard ratio (HR) with 95% CI and long-rank test p-value (one sided) are shown. Log-rank model was stratified by region (east Asia vs other regions) and presence of peritoneal metastasis. Bottom displays number of patients at risk by treatment starting from 0 months at left and increasing in 2 month intervals towards the right.

[0060] Figure 15B. Kaplan-Meier analysis of overall survival (OS) in subjects with HER2- negative locally advanced unresectable or metastatic GC / GEJC with a PD-L1 score >5% treated 1with tislelizumab plus chemotherapy or placebo plus chemotherapy. The X axis depicts time in months since start of treatment; the Y axis depicts OS as a percentage. At top right, events, median PFS in months with 95% confidence interval (CI), and stratified hazard ratio (HR) with 95% CI and long-rank test p-value (one sided) are shown. Log-rank model was stratified by region (east Asia vs other regions) and presence of peritoneal metastasis. Bottom displays number of patients at risk by treatment starting from 0 months at left and increasing in 2 month intervals towards the right.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0061] As described herein, the present disclosure provides the insight that particular biomarkers and gene expression signatures (GESs) may be predictive of responsiveness of a subject to a cancer treatment. In some embodiments, the present disclosure provides an immune- related GES, wherein the level of the immune-related GES may indicate whether a subject having a cancer may be responsive to a cancer treatment. In some embodiments, an immune- related GES may comprise one or more biomarkers selected from one, two, three, or more of an anti-viral response biomarker, an interferon signaling biomarker, a macrophage regulation biomarker, and a T cell-related function biomarker. In some embodiments, an immune-related GES comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more biomarkers selected from IFIT1, OAS2, SP110, JAK2, STAT1, EPSTI1, SLAMF8, IL7R, CCL4, HLA.A, and SELPLG. Among other things, the present disclosure provides the insight that an immune-related GES may be predictive of responsiveness of a subject to a cancer treatment comprising a pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor, or a pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor and one or more pharmaceutical compositions comprising one or more therapeutic agents.

[0062] Among other things, the present disclosure provides the insight that an immune- related GES may be used to classify subjects as responsive to a cancer treatment. In some embodiments, the present disclosure provides methods wherein subjects are classified as responsive to a cancer treatment if a sample from the subject comprises an elevated level of an immune-related GES as compared to a threshold level of the immune-related GES. Among other things, the present disclosure provides methods for selecting a subject for treatment withtislelizumab based on the presence of an immune-related GES and administering a therapeutically effective amount of tislelizumab to the subject.Cancer Treatments

[0063] Various cancer treatments are known in the art can be used with provided technologies (e.g., methods) described herein. In some embodiments, a cancer treatment comprises or is a therapeutic agent, e.g., a chemotherapeutic agent, an affinity agent (e.g., an antibody or antigen binding portion thereof). In some embodiments, a cancer treatment comprises one or more therapeutic agents. In some embodiments, a cancer treatment comprises one or more pharmaceutical compositions comprising one or more therapeutic agents. In some embodiments, a cancer treatment comprises or is a chemotherapy. In some embodiments, a cancer treatment comprises or is a radiotherapy. In some embodiments, a cancer treatment comprises or is a hormone therapy. In some embodiments, a cancer treatment comprises or is a stem cell therapy. In some embodiments, a cancer treatment comprises or is one or more therapies, e.g., chemotherapy, radiotherapy, hormone therapy, a stem cell therapy.PD-1 or PD-L1 Inhibitors

[0064] Programmed death protein 1 (PD-1) reportedly acts as an immune checkpoint by inhibiting adaptive and innate immune responses upon binding with, e.g., PD-L1 (Han Y., et al. Am J Cancer Res. 2020 Mar l;10(3):727-742). Immune cells, particularly T cells, reportedly exhibit PD-1 expression, whereas a bind partner, programmed death-ligand 1 (PD-L1) can be found expressed on some immune cells as well as epithelial cells. Tumor cells have been reported to express elevated levels of PD-L1 as a mechanism to avoid anti-tumor immune responses and such expression has been correlated with poor outcomes (Ohaegbulam K. C., et al., Trends Mol Med. 2015 Jan;21(l):24-33). Without wishing to be bound by any theory, inhibition of PD-1 and / or PD-L1 may act as an anti-tumor therapy.

[0065] A variety of PD-1 and PD-L1 inhibitors have been developed as potential therapeutics for usage in cancer treatment (Gong J., et al., J Immunother Cancer. 2018 Jan 23;6(1):8; Liu J., et al., Front Pharmacol. 2021 Sep 1;12:731798). In some embodiments, a cancer may be treated by inhibition of PD-1 and / or PD-L1. In some embodiments, a cancer may be treated by inhibitionof PD-1. In some embodiments, a cancer may be treated by inhibition of PD-L1. In some embodiments, a cancer may be treated by administration of a PD-1 inhibitor. In some embodiments, a cancer may be treated by administration of a PD-L1 inhibitor. Various PD-1 and PD-L1 inhibitors known in the art can be used with provided technologies (e.g., methods) described herein.

[0066] In some embodiments, a PD-1 or PD-L1 inhibitor comprises a PD-1 inhibitor. In some embodiments, a PD-1 inhibitor comprises or is an anti-PD-1 antibody or antigen binding fragment thereof. In some embodiments, a PD-1 inhibitor comprises or is an anti-PD-1 monoclonal antibody or antigen binding fragment thereof. In some embodiments, a PD-1 inhibitor comprises or is an anti-PD-1 humanized antibody or antigen binding fragment thereof. In some embodiments, a PD-1 inhibitor comprises or is an anti-PD-1 humanized monoclonal antibody or antigen binding fragment thereof. In some embodiments, a PD-1 inhibitor comprises or is tislelizumab. In some embodiments, an anti-PD-1 antibody or antigen binding fragment thereof comprises or is tislelizumab. Tislelizumab is described, for example, in WO 2015 / 035606, US 8,735,553, US 9,217,034, US 9,834,606, US 9,988,450, US 11,186,637, US 11,673,951, etc. Various additional anti-PD-1 antibodies (e.g., cemiplimab, nivolumab, pembrolizumab) are known in the art and are described, for example, in Ai L., et al., Drug Des Devel Ther. 2020 Sep 8;14:3625-3649 and Liu J., et al., Front Pharmacol. 2021 Sep 1;12:731798.

[0067] In some embodiments, a PD-1 or PD-L1 inhibitor comprises or is a PD-L1 inhibitor. In some embodiments, a PD-L1 inhibitor comprises or is an anti-PD-Ll antibody or antigen binding fragment thereof. In some embodiments, a PD-L1 inhibitor comprises or is an anti-PD- Ll monoclonal antibody or antigen binding fragment thereof. In some embodiments, a PD-L1 inhibitor comprises or is an anti-PD-Ll humanized antibody or antigen binding fragment thereof. In some embodiments, a PD-L1 inhibitor comprises or is an anti-PD-Ll humanized monoclonal antibody or antigen binding fragment thereof. Various anti-PD-Ll antibodies (e.g., atezolizumab, avelumab, durvalumab) are known in the art and are described, for example, in Ai L., et al., Drug Des Devel Ther. 2020 Sep 8;14:3625-3649 and Liu J., et al., Front Pharmacol. 2021 Sep 1;12:731798.Antibodies

[0068] Various antibodies known in the art can be used with provided technologies (e.g., methods) described herein. In some embodiments, an antibody comprises or is a monoclonal antibody. In some embodiments, an antibody comprises or is a bispecific antibody. In some embodiments, an antibody comprises or is a conjugated antibody. In some embodiments, an antibody comprises or is an antibody-drug conjugate (ADC). In some embodiments, an antibody comprises or is a radiolabeled antibody.

[0069] In some embodiments, an antibody may specifically be any of the following nonlimiting antibodies: rituximab, palivizumab, infliximab, trastuzumab, alemtuzumab, adalimumab, ibritumomab tiuxetan, omalizumab, cetuximab, bevacizumab, natalizumab, panitumumab, ranibizumab, certolizumab pegol, ustekinumab, canakinumab, golimumab, ofatumumab, tocilizumab, denosumab, belimumab, ipilimumab, brentuximab vedotin, pertuzumab, trastuzumab emtansine, obinutuzumab, siltuximab, ramucirumab, vedolizumab, blinatumomab, nivolumab, pembrolizumab, idarucizumab, necitumumab, dinutuximab, secukinumab, mepolizumab, alirocumab, evolocumab, daratumumab, elotuzumab, ixekizumab, reslizumab, olaratumab, bezlotoxumab, atezolizumab, obiltoxaximab, inotuzumab ozogamicin, brodalumab, guselkumab, dupilumab, sarilumab, avelumab, ocrelizumab, emicizumab, benralizumab, gemtuzumab ozogamicin, durvalumab, burosumab, lanadelumab, mogamulizumab, erenumab, galcanezumab, tildrakizumab, cemiplimab, emapalumab, fremanezumab, ibalizumab, moxetumomab pasudodox, ravulizumab, romosozumab, risankizumab, polatuzumab vedotin, brolucizumab, isatuximab, enfortumab vedotin, trastuzumab deruxtecan, sacituzumab govitecan, iodine tositumomab, tafasitamab, loncastuximab tesirine, dostarlimab, tislelizumab, amivantamab, naxitamab, and / or any antigen-binding fragment thereof, and / or any combination thereof. See, e.g., Zahavi, D. and Weiner, L. Antibodies (Basel). 2020 Jul 20;9(3):34.Chemotherapeutic Agents

[0070] Various chemotherapeutic agents known in the art can be used with provided technologies (e.g., methods) described herein.

[0071] In some embodiments, a chemotherapeutic agent comprises or is an alkylating agent. In some embodiments, a chemotherapeutic agent comprises or is an antimetabolite. In some embodiments, a chemotherapeutic agent comprises or is a plant alkaloid. In some embodiments, a chemotherapeutic agent comprises or is an antibiotic. In some embodiments, a chemotherapeutic agent comprises or is an anti-microtubule agent. In some embodiments, a chemotherapeutic agent comprises or is a topoisomerase inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a DNA replication inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a DNA synthesis inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a RNA synthesis inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a nucleoside analogue. In some embodiments, a chemotherapeutic agent comprises or is a taxane. In some embodiments, a chemotherapeutic agent comprises or is a proteasome inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a mTOR inhibitor. In some embodiments, a chemotherapeutic agent comprises or is kinase inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a tyrosine kinase inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a VEGFR inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a HER2 inhibitor. In some embodiments, a chemotherapeutic agent comprises or is an EGFR inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a JAK inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a Bcr-Abl kinase inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a PDGFR inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a retinoid. In some embodiments, a chemotherapeutic agent comprises or is a platinum-based compound. In some embodiments, a chemotherapeutic agent comprises or is a histone deacetylase inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a cytoskeletal disruptor. In some embodiments, a chemotherapeutic agent comprises or is an anthracycline.

[0072] In some embodiments, a chemotherapeutic agent may specifically be any of the following non-limiting chemotherapeutic agents: chlorambucil, cyclophosphamide, thiotepa, busulfan, actinomycin D, doxorubicin, mitomycin, mitoxantrone, bleomycin, methotrexate, 5- fluorouracil, vinorelbine, vinblastine, dacarbazine, mustine, vincristine, prednisolone, etoposide, cisplatin, carboplatin, paclitaxel, docetaxel, epirubicin, capecitabine, folinic acid, oxaliplatin,gemcitabine, ifosfamide, mechlorethamine, melphalan, carmustine, semustine, fotemustine, streptozotocin, temozolomide, thiotepa, mytomycin, diaziquone, procarbazine, hexamethylmelamine, mitozolomide, N-nitroso-N-methylurea, lomustine, nelarabine, cladribine, clofarabine, pentostatin, fludarabine, azacitidine, decitabine, mercaptopurine, thioguanine, cytarabine, gemcitabine, pemetrexed, teniposide, irinotecan, topotecan, belotecan, exatecan, camptothecin, novobiocin, merbarone, aclarubicin, mitomycin C, pirarubicin, carmofur, tegafur, tioguanine, pentostatin, raltitrexed, hydroxycarbamide, valrubicin, cabazitaxel, bendamustine, altretamine, bortezomib, ixabepilone, everolimus, temsirolimus, panobinostat, entinostat, romidepsin, vorinostat, zabadinostat, larotaxel, tesetaxel, prednisone, erlotinib, gefitinib, imatinib, vemurafenib, vismodegib, sunitinib, sorafenib, vandetanib, ruxolitinib, regorafenib, ponatinib, pazopanib, nilotinib, lapatinib, dastinib, crizotinib, bosutinib, axitinib, afatinib, alitretinoin, bexarotene, isotretinoin, tretinoin, tamibarotene, anagrelide, lenalidomide, pomalidomide, and idarubicin, and derivatives thereof.

[0073] In some embodiments, a chemotherapeutic agent comprises or is paclitaxel. In some embodiments, paclitaxel is in one or more forms. In some embodiments, a form comprises or is solvent-based paclitaxel. In some embodiments, a form comprises or is protein-bound paclitaxel. In some embodiments, a form comprises or is nanoparticle albumin-bound (nab) paclitaxel. In some embodiments, a chemotherapeutic agent comprises or is protein-bound paclitaxel. In some embodiments, a chemotherapeutic agent comprises or is solvent-based paclitaxel. In some embodiments, a chemotherapeutic agent comprises or is nab-paclitaxel. In some embodiments, a chemotherapeutic agent comprises or is docetaxel.

[0074] In some embodiments, a chemotherapeutic agent comprises or is carboplatin. In some embodiments, a chemotherapeutic agent comprises or is cisplatin. In some embodiments, a chemotherapeutic agent comprises or is nedaplatin. In some embodiments, a chemotherapeutic agent comprises or is oxaliplatin.

[0075] Other compounds that are effective in treating cancer, that are suitable for use with the provided technologies (e.g., methods) of the present disclosure, are known in the art and are described, for example, in Anand U., et al. Gene Dis. 2022 Mar 18;10(4):1367-1401; Huang C., et al. Biomedicine (Taipei). 2017 Dec;7(4):23; Amjad M. T., et al., StatsPearls, 2023 Feb 27.Biomarkers

[0076] In some embodiments, a biomarker is a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a mRNA), or a protein encoded thereby (e.g., a polypeptide, etc.) from a species. In some embodiments, a biomarker is a nucleic acid, a characteristic portion of a nucleic acid, or a variant of a nucleic acid. In some embodiments, a biomarker is a DNA or RNA, a characteristic portion of a DNA or RNA, or a variant of a DNA or RNA. In some embodiments, a biomarker is a polypeptide, a characteristic portion of a polypeptide, or a variant of a polypeptide. In some embodiments, a biomarker is a protein, a characteristic portion of a protein, or a variant of a protein. In some embodiments, a biomarker is a fragment (e.g., a fragment comprising a characteristic portion thereof) of a nucleic acid, a polypeptide, or a protein. In some embodiments, a polypeptide, protein, or fragment thereof is a modified form of said polypeptide, protein, or fragment thereof. In some embodiments, a modified form comprises one or more modifications. In some embodiments, one or more modifications are phosphorylation, glycosylation, lipidation, methylation, sulphonation, glutathionylation, acetylation, cysteinylation, ubquitination, nitrosylation, amidation, hydroxylation, succinylation, SUMOylation, oxidation, etc. In some embodiments, a biomarker has one or more different isoforms.

[0077] Exemplary biomarkers for use with technologies provided herein are briefly described below. In some embodiments, a biomarker is an immune-related GES biomarker. In some embodiments, an immune-related GES biomarker is IFIT1, OAS2, SP110, JAK2, STAT1, EPSTI1, SLAMF8, IL7R, CCL4, HLA.A, or SELPLG. In some embodiments, a biomarker, e.g., an immune-related GES biomarker, is an anti-viral response biomarker. In some embodiments, an anti-viral response biomarker is IFIT1 or OAS2. In some embodiments, a biomarker, e.g., an immune-related GES biomarker, is an interferon signaling biomarker. In some embodiments, an interferon signaling biomarker is SP110, JAK2, or STATE In some embodiments, a biomarker, e.g., an immune-related GES biomarker, is a macrophage regulation biomarker. In some embodiments, a macrophage regulation biomarker is EPSTI1 or SLAMF8. In some embodiments, a biomarker, e.g., an immune-related GES biomarker, is a T cell-related function biomarker. In some embodiments, a T cell-related function biomarker is IL7R, CCL4, HLA.A, or SELPLG. In some embodiments, a biomarker is a NRF2 pathway signature biomarker.IFIT1

[0078] In some embodiments, a biomarker is or comprises IFIT1. In some embodiments, an anti-viral response biomarker is or comprises IFIT1. In some embodiments, an immune-related GES biomarker is or comprises IFIT1. In some embodiments, IFIT1 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., an IFIT1 mRNA), or a protein encoded thereby (e.g., an IFIT1 polypeptide) from a species, which may be known as G10P1, IFI56, IFNAI1, ISG56, interferon-induced protein with tetratricopeptide repeats 1, interferon- induced 56 kDa protein, IFI-56K, etc. Various IFIT1 sequences including variants thereof are readily available to those of skill in the art, including, e.g., reference human IFIT1 mRNA sequences available under NCBI Reference Sequence Nos. NM_001548.5,NM_001270927.2, NM 001270928.2, NM_001270929.2, and NM_001270930.2, reference human IFIT1 polypeptide sequences available under NCBI Reference Sequence Nos.NP_001539.3, NP 001257856.1, NP 001257857.1, NP 001257858.1, and NP_001257859.1.

[0079] The IFIT1 gene has been reported to contain two exons and localize to chromosome 10q23 in humans (Fensterl, V. and Sen, G. C. J Interferon Cytokine Res. 2011 Jan;31(l):71-8). Further, interferon-stimulated response elements (ISRE) have been identified in the upstream portion of the gene, which appear to provide a mechanism for upregulation of IFIT1 upon interferon type 1 stimulation. Additional studies have also suggested a variety of other potential mechanisms of IFIT1 induction, including by signaling initiated upon viral infection and / or detection of pathogen-associated molecular patterns (PAMPs) (Diamond, M. S., and Farzan, M. Nat Rev Immunol. 2013 Jan;13(l):46-57). IFIT1 protein reportedly acts as an interferon-induced antiviral RNA-binding protein which binds to single-stranded RNA that lacks a 5’ cap with 2’-O- methylation and / or displays a 5 ’-triphosphate group as part of the 5’ cap (Diamond, M. S.Cytokine Growth Factor Rev. 2014 Oct;25(5): 543-50). Binding by IFIT1 reportedly prevents the translation of these RNAs by blocking the binding of RNA translation machinery. Accordingly, studies indicate that IFIT1 acts as an inhibitor of viral translation as part of the antiviral immune response.

[0080] Various technologies, e.g., assays, probes, antibodies, etc., have also been reported and can be utilized for detection of IFIT1. In some embodiments, detection of IFIT1, acharacteristic fragment of IFIT1, and / or a variant of IFIT1 is used as a portion of an immune- related GES. In some embodiments, IFIT1 is detected in a sample. In some embodiments, IFIT1 nucleic acids are detected in a sample. In some embodiments, IFIT1 polypeptides are detected in a sample. In some embodiments, IFIT1 is detected using one or more anti-IFITl agents, e.g., an anti-IFITl probe, an anti-IFITl antibody or antigen binding fragment thereof, etc. In some embodiments, IFIT1 is detected using one or more technologies described herein. In some embodiments, detection of IFIT1 is used in a method described herein, e.g., a method of determining responsiveness to a cancer treatment, a method of treating, etc.OAS2

[0081] In some embodiments, a biomarker is or comprises OAS2. In some embodiments, an anti-viral response biomarker is or comprises OAS2. In some embodiments, an immune-related GES biomarker is or comprises OAS2. In some embodiments, OAS2 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., an OAS2 mRNA), or a protein encoded thereby (e.g., an OAS2 polypeptide), etc.) from a species, which may be known as 2’ -5 ’-oligoadenylate synthetase 2, 2’-5’-olgioadenylate synthase, etc. Various OAS2 sequences including variants thereof are readily available to those of skill in the art, including, e.g., reference human OAS2 gene sequence available under NCBI Reference Sequence No. NG_029692.1, reference human OAS2 mRNA sequences available under NCBI Reference Sequence Nos. NM_002535.3, NM_016817.3, and NM_001032731.2, reference human IFIT1 polypeptide sequences available under NCBI Reference Sequence Nos. NP_002526.2, NP_058197.2, and NP_001027903.1.

[0082] The OAS2 gene has been reported to comprise a total of 12 exons, comprising 5 repeated exons (A-E) and two additional C-terminal exons (Justesen, J., et al. Cell Mol Life Sci. 2000 Oct; 57(11): 1593-612). The two sets of 5 repeated exons reportedly each encode an 2’-5’- oligoadenylate synthetase (OAS) domain; however, in OAS2, one OAS domain is catalytically active whereas the other OAS domain is catalytically inactive (Sadler, A. J. and Williams, B. R. G. Nat Rev Immunol. 2008 Jul;8(7):559-68). OAS2 and the other members of the OAS family (OAS1, OAS3, OASL) have been theorized to act as part of the interferon-induced antiviral response. Particularly, studies have shown that OAS2 is activated by double-stranded RNA(dsRNA) of an intermediate length, with a minimum length of about 35 bp (Koul, A., et al. Biochem Cell Biol. 2020 Feb;98(l):70-82). Binding of dsRNA by OAS2 reportedly stimulates the synthesis of 2’-5’-oligoadenylates, which then leads to the activation of RNaseL that acts to degrade viral RNAs, e.g., viral ssRNAs, as well as cellular RNAs to promote the antiviral response (Schwartz, S. L. and Conn, G. L. Wiley Interdiscip Rev RNA. 2019 Jul;10(4):el534).

[0083] Various technologies, e.g., assays, probes, antibodies, etc., have also been reported and can be utilized for detection of OAS2. In some embodiments, detection of OAS2, a characteristic fragment of OAS2, and / or a variant of OAS2 is used as a portion of an immune- related GES. In some embodiments, OAS2 is detected in a sample. In some embodiments, OAS2 nucleic acids are detected in a sample. In some embodiments, OAS2 polypeptides are detected in a sample. In some embodiments, OAS2 is detected using one or more anti-OAS2 agents, e.g., an anti-OAS2 probe, an anti-OAS2 antibody or antigen binding fragment thereof, etc. In some embodiments, OAS2 is detected using one or more technologies described herein. In some embodiments, detection of OAS2 is used in a method described herein, e.g., a method of determining responsiveness to a cancer treatment, a method of treating, etc.SP110

[0084] In some embodiments, a biomarker is or comprises SP110. In some embodiments, an interferon signaling biomarker is or comprises SP110. In some embodiments, an immune-related GES biomarker is or comprises SP110. In some embodiments, SP110 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a SP110 mRNA), or a protein encoded thereby (e.g., a SP110 polypeptide), etc.) from a species, which may be known as IFI41, IFI75, Spl 10 nuclear body protein, interferon- induced protein 41 / 75, speckled 110 kDa, transcriptional coactivator Spl 10, etc. Various SP110 sequences including variants thereof are readily available to those of skill in the art, including, e.g., reference human SP110 gene sequence available under NCBI Reference Sequence No. NG_008295.1; reference human SP110 mRNA sequences available under NCBI Reference Sequence Nos. NM_080424.4, NM_004509.5, NM 004510.4, NM_001185015.2, NM_001378442.1, NM_001378443.1, NM_001378444.1, NM 001378445.1, NM_001378446.1, and NM 001378447.1; reference human SP110 polypeptide sequences available under NCBI Reference Sequence Nos.NP_536349.3, NP_004500.4, NP_004501.4, NP_001171944.1, NP_001365371.1,NP 001365372.1, NP 001365373.1, NP 001365374.1, NP 001365375.1, andNP 001365376.1.

[0085] At least three isoforms of SP110 have been reported, which include the A, B, and C isoforms (Fraschilla, I. and Jeffrey, K. L. Treds Immunol. 2020 Jul;41(7): 572-585). The full- length isoform SP110-C reportedly comprises a number of functional domains, including a caspase activation and recruitment domain (CARD), a SAND (SplOO, Aire, NucP41 / 75, DEAF- 1 shared) domain, a plant homeodomain (PHD), and a bromodomain (BRD) (Fraschilla, I. and Jeffrey, K. L. Trends Immunol. 2020 Jul;41(7):572-585). Meanwhile, the SP110-A isoform reportedly differs by containing a truncated BRD and the SP110-B isoform reportedly does not contain the PHD or BRD. Due to the particular domains contained, the SP110 protein has been hypothesized to interact with chromatin by binding to DNA, detecting histone methylation status, and multimerize. Various disease-associated mutations have been reported in SP110, including those associated with susceptibility to tuberculosis and development of veno-occlusive disease with immunodeficiency (VODI) (Tosh, K., et al. Proc Natl Acad Sci USA. 2006 Jul 5;103(27): 10364-10368; Wang, T. et al. Clin Immunol. 2012 Nov; 145(2): 102-7).

[0086] Various technologies, e.g., assays, probes, antibodies, etc., have also been reported and can be utilized for detection of SP110. In some embodiments, detection of SP110, a characteristic fragment of SP110, and / or a variant of SP110 is used as a portion of an immune- related GES. In some embodiments, SP110 is detected in a sample. In some embodiments, SP110 nucleic acids are detected in a sample. In some embodiments, SP110 polypeptides are detected in a sample. In some embodiments, SP110 is detected using one or more anti-SPl 10 agents, e.g., an anti-SPl 10 probe, an anti-SPl 10 antibody or antigen binding fragment thereof, etc. In some embodiments, SP110 is detected using one or more technologies described herein. In some embodiments, detection of SP110 is used in a method described herein, e.g., a method of determining responsiveness to a cancer treatment, a method of treating, etc.JAK2

[0087] In some embodiments, a biomarker is or comprises JAK2. In some embodiments, an interferon signaling biomarker is or comprises JAK2. In some embodiments, an immune-related GES biomarker is or comprises JAK2. In some embodiments, JAK2 refers to a gene or a geneproduct thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a JAK2 mRNA), or a protein encoded thereby (e.g., a JAK2 polypeptide), etc.) from a species, which may be known as JTK10, tyrosine-protein kinase JAK2, Janus kinase 2, etc. Various JAK2 sequences including variants thereof are readily available to those of skill in the art, including, e.g., reference human JAK2 gene sequence available under NCBI Reference Sequence No. NG_009904; reference human JAK2 mRNA sequences available under NCBI Reference Sequence Nos. NM 004972.4, NM_001322194.2, NM_001322195.2, NM_001322196.2, NM_001322198.2, NM_001322199.2, and NM_001322204.2; reference human JAK2 polypeptide sequences available under NCBI Reference Sequence Nos. NP_004963.1, NP 001309123.1, NP 001309124.1, NP 001309125.1, NP 001309127.1, NP 001309128.1, and NP_001309133.1.

[0088] JAK2 reportedly belongs to a family of non-receptor protein tyrosine kinases, which also includes JAK1, JAK3, and TYK2. Janus kinase (JAK) proteins have been reported to comprise four main domains, which include, from N- to C-terminal, a FERM (4.1, ezrin, radixin, moesin) domain, a SH2-like domain, a pseudokinase domain, and a tyrosine kinase domain (Ferrao, R. and Lupardus, P. J. Front Endocrinol (Lausanne). 2017 Apr 18;8: 71 ). Upon binding of cytokines to cytokine receptors, the JAK proteins reportedly are activated and phosphorylate the cytokine receptors - leading to the binding of STAT family proteins, which are themselves then phosphorylated, dimerized, and translocated to the nucleus (O’Shea, J. J., et al. N Engl J Med. 2013 Jan 10;368(2):161-70). Accordingly, studies have indicated that JAK2 may play a role in signaling for various immune responses and cellular growth and development. Furthermore, JAK2 dysregulation and / or mutation has been implicated in the mechanisms of various diseases, disorders, and conditions including autoimmune diseases and various cancers (O’Shea, J. J., et al. N Engl J Med. 2013 Jan 10;368(2):161-70).

[0089] Various technologies, e.g., assays, probes, antibodies, etc., have also been reported and can be utilized for detection of JAK2. In some embodiments, detection of JAK2, a characteristic fragment of JAK2, and / or a variant of JAK2 is used as a portion of an immune- related GES. In some embodiments, JAK2 is detected in a sample. In some embodiments, JAK2 nucleic acids are detected in a sample. In some embodiments, JAK2 polypeptides are detected in a sample. In some embodiments, JAK2 is detected using one or more anti-JAK2 agents, e.g., ananti-JAK2 probe, an anti-JAK2 antibody or antigen binding fragment thereof, etc. In some embodiments, JAK2 is detected using one or more technologies described herein. In some embodiments, detection of JAK2 is used in a method described herein, e.g., a method of determining responsiveness to a cancer treatment, a method of treating, etc.STAT1

[0090] In some embodiments, a biomarker is or comprises STAT1. In some embodiments, an interferon signaling biomarker is or comprises STAT1. In some embodiments, an immune- related GES biomarker is or comprises STATE In some embodiments, STAT1 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a STAT1 mRNA), or a protein encoded thereby (e.g., a STAT1 polypeptide), etc.) from a species, which may be known as STAT91, signal transducer and activator of transcription 1, transcription factor ISGF-3 components p91 / p84, etc. Various STAT1 sequences including variants thereof are readily available to those of skill in the art, including, e.g., reference human STAT1 gene sequence available under NCBI Reference Sequence No. NG_008294; reference human STAT1 mRNA sequences available under NCBI Reference Sequence Nos. NM_007315.4, NMJ39266.3, NM_001384880.1, NM 001384881.1, NM_001384882.1, NM_001384883.1, NM 001384884.1, NM_001384885.1, NM_001384886.1, NM 001384887.1, NM_001384888.1, NM_001384889.1, NM_001384890.1, and NM 001384891.1; reference human STAT1 polypeptide sequences available under NCBI Reference Sequence Nos.NP 009330.1, NP_644671.1, NP 001371809.1, NP 001371810.1, NP 001371811.1, NP 001371810.1, NP 001371812.1, NP 001371813.1, NP 001371814.1, NP 001371815.1, NP 001371816.1, NP 001371817.1, NP 001371818.1, NP 001371819.1, and NP_001371820.1.

[0091] STAT1 is reportedly a component of the JAK-STAT signaling pathway, interacts with JAK2 as part of the pathway, and participates in the modulation of transcription of a variety of genes (Ramana, C. V., et al. Oncogene. 2000 May 15;19(21):2619-27; Stark, G. R. and Darnell Jr., J. E. Immunity. 2012 Apr 20;36(4):503-14). Particularly, STAT1 has been reported to be involved in controlling interferon-dependent transcriptional activity through involvement in the JAK-STAT signaling pathway - with STAT1 becoming tyrosine phosphorylated followingIFN-alpha and IFN-gamma activation (Darnell Jr., J. E., et al. Science. 1994 Jun 3;264(5164): 1415-21). Further, unphosphorylated STAT1 has been indicated by studies to also prolong the expression of some interferon-induced genes (Cheon, H. and Stark, G. R. Proc Natl Acad Sci USA. 2009 Jun 9;106(23):9373-8).

[0092] Various technologies, e.g., assays, probes, antibodies, etc., have also been reported and can be utilized for detection of STATE In some embodiments, detection of STAT1, a characteristic fragment of STAT1, and / or a variant of STAT1 is used as a portion of an immune- related GES. In some embodiments, STAT1 is detected in a sample. In some embodiments, STAT1 nucleic acids are detected in a sample. In some embodiments, STAT1 polypeptides are detected in a sample. In some embodiments, STAT1 is detected using one or more anti-STATl agents, e.g., an anti-STATl probe, an anti-STATl antibody or antigen binding fragment thereof, etc. In some embodiments, STAT1 is detected using one or more technologies described herein. In some embodiments, detection of STAT1 is used in a method described herein, e.g., a method of determining responsiveness to a cancer treatment, a method of treating, etc.EPSTI1

[0093] In some embodiments, a biomarker is or comprises EPSTI1. In some embodiments, a macrophage regulation biomarker is or comprises EPSTU. In some embodiments, an immune- related GES biomarker is or comprises EPSTI1. In some embodiments, EPSTI1 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., an EPSTI1 mRNA), or a protein encoded thereby (e.g., an EPSTI1 polypeptide), etc.) from a species, which may be known as BRESI1, epithelial-stromal interaction protein 1, etc. Various EPSTI1 sequences including variants thereof are readily available to those of skill in the art, including, e.g., reference human EPSTI1 gene sequence available under NCBI Reference Sequence No. NG_051573.2; reference human EPSTU mRNA sequences available under NCBI Reference Sequence Nos. NM 033255.5, NM_001002264.4, NM_001330543.2, and NM_001331228.2; reference human EPSTU polypeptide sequences available under NCBI Reference Sequence Nos. NP_150280.1, NP_001002264.1, NP_001317472.1, and NP_001318157.1.

[0094] Originally identified by a study of upregulated genes in human breast cancer, EPSTIl reportedly is found on chromosome 13ql 3.3 and encodes a protein of about 307 amino acids in length (Nielsen, H. L., et al. Genomics. 2002 May;79(5):703-10). Further studies have reported a role for EPSTIl in immune functioning as an interferon-stimulated gene (ISG) and thus, in promoting antiviral activity and inflammation (Kim, Y., et al. Biochem Biophys Res Commun. 2018 Feb 5;496(2):778-783; Meng, X., et al. Mediators Inflamm. 2015;2015:716315).Moreover, EPSTIl reportedly may play a role in the regulation of apoptosis (Capdevila- Busquets, E., et al. PLoS One. 2015 Jan 15;10(l)e0115352).

[0095] Various technologies, e.g., assays, probes, antibodies, etc., have also been reported and can be utilized for detection of EPSTIl. In some embodiments, detection of EPSTIl, a characteristic fragment of EPSTIl, and / or a variant of EPSTIl is used as a portion of an immune-related GES. In some embodiments, EPSTIl is detected in a sample. In some embodiments, EPSTIl nucleic acids are detected in a sample. In some embodiments, EPSTIl polypeptides are detected in a sample. In some embodiments, STAT1 is detected using one or more anti-EPSTIl agents, e.g., an anti-EPSTIl probe, an anti-EPSTIl antibody or antigen binding fragment thereof, etc. In some embodiments, EPSTIl is detected using one or more technologies described herein. In some embodiments, detection of EPSTIl is used in a method described herein, e.g., a method of determining responsiveness to a cancer treatment, a method of treating, etc.SLAMF8

[0096] In some embodiments, a biomarker is or comprises SLAMF8. In some embodiments, a macrophage regulation biomarker is or comprises SLAMF8. In some embodiments, an immune-related GES biomarker is or comprises SLAMF8. In some embodiments, SLAMF8 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a SLAMF8 mRNA), or a protein encoded thereby (e.g., a SLAMF8 polypeptide), etc.) from a species, which may be known as BLAME, CD353, SLAM family member 8, B- lymphocyte activator macrophage expressed, BCM-like membrane protein, etc. Various SLAMF8 sequences including variants thereof are readily available to those of skill in the art, including, e.g., reference human SLAMF8 mRNA sequences available under NCBI Reference31Sequence Nos. NM_020125.3 and NM_001330741.2; reference human SLAMF8 polypeptide sequences available under NCBI Reference Sequence Nos. NP_064510.1 and NP_001317670.1.

[0097] SLAMF8 reportedly is one member of the signaling lymphocytic activation molecule (SLAM) family of receptors which act to facilitate various immune responses (Kingsbury, G. A., et al. J Immunol. 2001 May l;166(9):5675-90; Veillette, A. Cold Spring Harb Perspect Biol. 2010 Mar;2(3):a002469). Expression of SLAMF8 has been reported to be upregulated in macrophages upon stimulation with interferon gamma or contacting with bacteria (Wang, G., et al. J Immunol. 2012 Jun 15;188(12):5829-32). Further, studies have reported a role for SLAMF8 in decreasing production of reactive oxygen species (ROS) R negatively regulate the inflammatory response (Wang, G, et al. PLoS One. 2015 Mar 23;10(3):e0121968). Recent studies have also implicated SLAMF8 expression as having a potential role in cancer, e.g., lymphoma (Sugimoto, A., et al., Sci Rep. 2020 Feb 13; 10(l):2505).

[0098] Various technologies, e.g., assays, probes, antibodies, etc., have also been reported and can be utilized for detection of SLAMF8. In some embodiments, detection of SLAMF8, a characteristic fragment of SLAMF8, and / or a variant of SLAMF8 is used as a portion of an immune-related GES. In some embodiments, SLAMF8 is detected in a sample. In some embodiments, SLAMF8 nucleic acids are detected in a sample. In some embodiments, SLAMF8 polypeptides are detected in a sample. In some embodiments, SLAMF8 is detected using one or more anti-SLAMF8 agents, e.g., an anti-SLAMF8 probe, an anti-SLAMF8 antibody or antigen binding fragment thereof, etc. In some embodiments, SLAMF8 is detected using one or more technologies described herein. In some embodiments, detection of SLAMF8 is used in a method described herein, e.g., a method of determining responsiveness to a cancer treatment, a method of treating, etc.IL7R

[0099] In some embodiments, a biomarker is or comprises IL7R. In some embodiments, a T cell-related function biomarker is or comprises IL7R. In some embodiments, an immune-related GES biomarker is or comprises IL7R. In some embodiments, IL7R refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a IL7R mRNA), or a protein encoded thereby (e.g., a IL7R polypeptide), etc.) from a species, which may be knownas CD 127, IL-7R, IL7Ralpha, IL-7Ralpha, interleukin 7 receptor, interleukin-7 receptor subunit alpha, etc. Various IL7R sequences including variants thereof are readily available to those of skill in the art, including, e.g., reference human IL7R gene sequence available under NCBI Reference Sequence No. NG_009567.1; reference human IL7R mRNA sequences available under NCBI Reference Sequence No. NM_002185.5 and NM_001410734.1; reference human IL7R polypeptide sequences available under NCBI Reference Sequence No. NP 002176.2 and NP_001397663.1.

[0100] The IL7R gene reportedly comprises eight exons localized to chromosome 5 and which may encode multiple proteins, which vary due to alternative splicing and include at least both a transmembrane form and a soluble form (Goodwin, R. G, et al. Cell. 1990 Mar 23;60(6):941-51). As a transmembrane protein, IL7R reportedly acts as a receptor for IL-7 and participates in cellular signaling and modulation of gene transcription through the JAK-STAT and PI3K / AKT signaling pathways (Mazzucchelli, R. and Durum, S. K. Nat Rev Immunol. 2007 Feb;7(2): 144-54). The signaling mediated by IL7R reportedly is involved in regulation of a various cellular functions including survival, proliferation, and differentiation (Palmer, M. J., et al. Cell Mol Immunol. 2008 Apr;5(2): 79-89). In particular, studies suggest that IL7R participates in the proliferation of T cells and conversion of naive T cells into memoryphenotype cells (Sprent, J. and Surh, C. D. Nat Immunol. 2011 Jun; 12(6):478-84).Additionally, mutations in IL7R have been reported to be associated with a variety of diseases, including multiple sclerosis, various cancers, and severe combined immunodeficiency (SCID) (Campos, L. W., et al. Cancers (Basel). 2019 Dec 5;11(12): 1952).

[0101] Various technologies, e.g., assays, probes, antibodies, etc., have also been reported and can be utilized for detection of IL7R. In some embodiments, detection of IL7R, a characteristic fragment of IL7R, and / or a variant of IL7R is used as a portion of an immune- related GES. In some embodiments, IL7R is detected in a sample. In some embodiments, IL7R nucleic acids are detected in a sample. In some embodiments, IL7R polypeptides are detected in a sample. In some embodiments, IL7R is detected using one or more anti-IL7R agents, e.g., an anti-IL7R probe, an anti-IL7R antibody or antigen binding fragment thereof, etc. In some embodiments, IL7R is detected using one or more technologies described herein. In someembodiments, detection of IL7R is used in a method described herein, e.g., a method of determining responsiveness to a cancer treatment, a method of treating, etc.CCL4

[0102] In some embodiments, a biomarker is or comprises CCL4. In some embodiments, a T cell-related function biomarker is or comprises CCL4. In some embodiments, an immune- related GES biomarker is or comprises CCL4. In some embodiments, CCL4 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a CCL4 mRNA), or a protein encoded thereby (e.g., a CCL4 polypeptide), etc.) from a species, which may be known as lymphocyte activation gene 1 (LAG1), MIP1B, SCYA4, ACT2, C-C motif chemokine ligand 4, G-26 T-lymphocyte-secreted protein, HC21, macrophage inflammatory protein 1-beta, small-inducible cytokine A4, T-cell activation protein 2, etc. Various CCL4 sequences including variants thereof are readily available to those of skill in the art, including, e.g., reference human CCL4 gene sequence available under NCBI Reference Sequence No. NG_033066.2; reference human CCL4 mRNA sequences available under NCBI Reference Sequence No. NM_002984.4; reference human CCL4 polypeptide sequences available under NCBI Reference Sequence No. NP_002975.1.

[0103] The CCL4 gene is reportedly localized to chromosome 17 (alongside related chemokine genes), comprises three exons, and shares sequence similarities to other chemokines, e.g. CCL3 (Liang, W. G, et al. J Mol Biol. 2015 Mar 27;427(6 Pt B): 1345-1358). CCL4 is reportedly produced by a variety of cells, including macrophages and lymphocytes, and functions as a chemokine (Maurer, M. and von Stebut, E. Int J Biochem Cell Biol. 2004 Oct;36(10): 1882- 6). The presence of CCL4 is reported to act in the recruitment of various immune cells, e.g., natural killer cells, to a site of interest, e.g., inflamed tissue (Menten, P., et al. Cytokine Growth Factor Rev. 2002 Dec;13(6):455-81). The antigen-specific interaction of dendritic cells and CD4 positive T cells has been described as producing CCL4, which reportedly acts to attract CD8 positive T cells to the site of such interaction (Castellino, F., et al. Nature. 2006 Apr 13;440(7086):890-5). Further, CCL4 has been implicated by some studies as having a role in some cancers (Hu, G, et al. Int J Med Sci. 2018 Jul 30; 15(11): 1179- 1186; Lien, M., et al. Oncotarget, 2017 May 9;8(19):31424-31434).

[0104] Various technologies, e.g., assays, probes, antibodies, etc., have also been reported and can be utilized for detection of CCL4. In some embodiments, detection of CCL4, a characteristic fragment of CCL4, and / or a variant of CCL4 is used as a portion of an immune- related GES. In some embodiments, CCL4 is detected in a sample. In some embodiments, CCL4 nucleic acids are detected in a sample. In some embodiments, CCL4 polypeptides are detected in a sample. In some embodiments, CCL4 is detected using one or more anti-CCL4 agents, e.g., an anti-CCL4 probe, an anti-CCL4 antibody or antigen binding fragment thereof, etc. In some embodiments, CCL4 is detected using one or more technologies described herein. In some embodiments, detection of CCL4 is used in a method described herein, e.g., a method of determining responsiveness to a cancer treatment, a method of treating, etc.HLA.A

[0105] In some embodiments, a biomarker is or comprises HLA.A. In some embodiments, a T cell-related function biomarker is or comprises HLA.A. In some embodiments, an immune- related GES biomarker is or comprises HLA.A. In some embodiments, HLA.A refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., an HLA.A mRNA), or a protein encoded thereby (e.g., an HLA.A polypeptide), etc.) from a species, which may be known as HLAA, HLA-A, major histocompatibility complex class I A, human leukocyte antigen A, HLA class I histocompatibility antigen A, etc. Various HLA.A sequences including variants thereof are readily available to those of skill in the art, including, e.g., reference human HLA.A gene sequence available under NCBI Reference Sequence No. NG_029217.3; reference human HLA.A mRNA sequences available under NCBI Reference Sequence Nos. NM_002116.8 and NM_001242758.1; reference human HLA.A polypeptide sequences available under NCBI Reference Sequence Nos. NP_001229687.1 and NP_002107.3.

[0106] HLA-A is reportedly one of the antigen-presenting major histocompatibility complex class la (MHCIa) molecules, which also includes HLA-B and HLA-C. As such a molecule, HLA-A reportedly associates with beta-2-microglobulin (02M) to present endogenous peptides to cytotoxic CD8 positive T cells (Krensky, A. M. Kidney Int Suppl. 1997 Mar;58:S2-7).Eurther, myriad HLA-A alleles have been reported and such high variation has been suggested to aid in immune functioning due to the diversity of the possible antigens that may be encountered(Robinson, J., et al. Nucleic Acids Res. 2015 Jan;43 (Database issue):D423-31). On the other hand, numerous diseases, particularly autoimmune diseases, have been associated with the HLA genes, e.g., HLA-A (Trowsdale, J. T. and Knight, J. C. Annu Rev Genomics Humn Genet. 2013;14:301-23).

[0107] Various technologies, e.g., assays, probes, antibodies, etc., have also been reported and can be utilized for detection of HLA. A. In some embodiments, detection of HLA. A, a characteristic fragment of HLA. A, and / or a variant of HLA. A is used as a portion of an immune- related GES. In some embodiments, HLA. A is detected in a sample. In some embodiments, HLA. A nucleic acids are detected in a sample. In some embodiments, HLA. A polypeptides are detected in a sample. In some embodiments, HLA. A is detected using one or more anti-HLA.A agents, e.g., an anti-HLA.A probe, an anti-HLA.A antibody or antigen binding fragment thereof, etc. In some embodiments, HLA. A is detected using one or more technologies described herein. In some embodiments, detection of HLA.A is used in a method described herein, e.g., a method of determining responsiveness to a cancer treatment, a method of treating, etc.SELPLG

[0108] In some embodiments, a biomarker is or comprises SELPLG. In some embodiments, a T cell-related function biomarker is or comprises SELPLG. In some embodiments, an immune-related GES biomarker is or comprises SELPLG. In some embodiments, SELPLG refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a SELPLG mRNA), or a protein encoded thereby (e.g., a SELPLG polypeptide), etc.) from a species, which may be known as CD 162, PSGL-1, P-sel ectin glycoprotein ligand 1, selectin P ligand, etc. Various SELPLG sequences including variants thereof are readily available to those of skill in the art, including, e.g., reference human SELPLG mRNA sequences available under NCBI Reference Sequence Nos. NM_003006.4 and NM_001206609.2; reference human SELPLG polypeptide sequences available under NCBI Reference Sequence Nos. NP 002997.2 and NP_001193538.1.

[0109] SELPLG reportedly encodes the transmembrane PSGL-1 protein, which homodimerizes and acts a receptor for E-, L-, and P-selectin (Goetz, D. J., et al. J Cell Biol. 1997 Apr 21;137(2):509-19; Spertini, O., et al. J Cell Biol. 1996 Oct;135(2):523-31). Studies haveindicated a role for SELPLG in immune cell migration as well as immune checkpoint regulation (Tinoco, R., et al. Trends Immunol. 2017 May;38(5):323-335). Particularly, SELPLG reportedly allows for interaction between immune cells, e.g., T cells and endothelial cells to allow for capture, rolling, and migration across the endothelium (Zarbock, A., et al., J Leukoc Biol. 2009 Nov;86(5): 1119-24). Further, interactions mediated by SELPLG reportedly provide for cellular signaling that leads to modulation of gene expression, cytokine secretion, etc. (Tinoco, R., et al. Trends Immunol. 2017 May;38(5):323-335). Accordingly, SELPLG has been implicated as a potential critical immune-related receptor.

[0110] Various technologies, e.g., assays, probes, antibodies, etc., have also been reported and can be utilized for detection of SELPLG. In some embodiments, detection of SELPLG, a characteristic fragment of SELPLG, and / or a variant of SELPLG is used as a portion of an immune-related GES. In some embodiments, SELPLG is detected in a sample. In some embodiments, SELPLG nucleic acids are detected in a sample. In some embodiments, SELPLG polypeptides are detected in a sample. In some embodiments, SELPLG is detected using one or more anti-SELPLG agents, e.g., an anti-SELPLG probe, an anti-SELPLG antibody or antigen binding fragment thereof, etc. In some embodiments, SELPLG is detected using one or more technologies described herein. In some embodiments, detection of SELPLG is used in a method described herein, e.g., a method of determining responsiveness to a cancer treatment, a method of treating, etc.NRF2 Pathway Signature Biomarkers

[0111] In some embodiments, a biomarker is or comprises a NRF2 pathway signature biomarker. In some embodiments, a biomarker is or comprises G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1A, ABCG2, or ABCC2. In some embodiments, a NRF2 pathway signature biomarker is or comprises G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1 A, ABCG2, or ABCC2. In some embodiments, G6PD refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a G6PD mRNA), or a protein encoded thereby (e.g., a G6PD polypeptide), etc.) from a species, which may be known as G6PD1, glucose-6-phosphate dehydrogenase, etc. In someembodiments, TGFB2 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a TGFB2 mRNA), or a protein encoded thereby (e.g., a TGFB2 polypeptide), etc.) from a species, which may be known as TGF-beta 2, transforming growth factor beta 2, etc. In some embodiments, TFRC refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a TFRC mRNA), or a protein encoded thereby (e.g., a TFRC polypeptide), etc.) from a species, which may be known as TRFR, CD71, transferrin receptor protein 1, etc. In some embodiments, SPP1 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a SPP1 mRNA), or a protein encoded thereby (e.g., a SPP1 polypeptide), etc.) from a species, which may be known as OPN, BNSP, BSPI, ETA-1, secreted phosphoprotein 1, bone sialoprotein 1, etc. In some embodiments, SERPINE1 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a SERPINEl mRNA), or a protein encoded thereby (e.g., a SERPINEl polypeptide), etc.) from a species, which may be known as PAI1, PLANH1, serpin family E member 1 , plasminogen activator inhibitor 1 , etc. In some embodiments, RRM2 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a RRM2 mRNA), or a protein encoded thereby (e.g., a RRM2 polypeptide), etc.) from a species, which may be known as RR2, ribonucleotide reductase regulatory subunit M2, ribonucleotide reductase small subunit, etc. In some embodiments, NEIL3 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a NEIL3 mRNA), a protein encoded thereby (e.g., a NEIL3 polypeptide), etc.) from a species, which may be known as FGP2, FPG2, NEI3, ZGRF3, nei like DNA glycosylase 3 (NEIL3), endonuclease 8-like 3, DNA glycosylase FPG2, etc. In some embodiments, MCM10 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a MCM10 mRNA), or a protein encoded thereby (e.g., a MCM10 polypeptide), etc.) from a species, which may be known as PRO2249, mini chromosome maintenance 10 replication initiation factor, etc. In some embodiments, IDH1 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a IDH1 mRNA), or a protein encoded thereby (e.g., a IDH1 polypeptide), etc.) from a species, which may be known as PICD, IDPC, isocitrate dehydrogenase (NADP(+)) 1, cytosolic NADP-isocitrate dehydrogenase, etc. In some embodiments, HM0X1 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g.,DNA, RNA, etc.), a transcript (e.g., a HM0X1 mRNA), or a protein encoded thereby (e.g., a HM0X1 polypeptide), etc.) from a species, which may be known as HO-1, HM0X1D, heme oxygenase 1, etc. In some embodiments, CXCR7 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a CXCR7 mRNA), or a protein encoded thereby (e.g., a CXCR7 polypeptide), etc.) from a species, which may be known as ACKR3, GPR159, atypical chemokine receptor 3, C-X-C chemokine receptor type 7, G-protein coupled receptor 159, etc. In some embodiments, CES1 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a CES1 mRNA), or a protein encoded thereby (e.g., a CES1 polypeptide), etc.) from a species, which may be known as CES2, SES1, hCE-1, ACAT, CEH, carboxylesterase 1, liver carboxylesterase 1, acyl-coenzyme A: cholesterol acyltransferase, cholesteryl ester hydrolase, etc. In some embodiments, CCND3 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a CCND3 mRNA), or a protein encoded thereby (e.g., a CCND3 polypeptide), etc.) from a species, which may be known as cyclin D3, Gl / S-specific cyclin-D3, etc. In some embodiments, ASF1 A refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a ASF1A mRNA), or a protein encoded thereby (e.g., a ASF1 A polypeptide), etc.) from a species, which may be known as CGI-98, HSPC146, CIA, anti-silencing function 1 A histone chaperone, CCG1 -interacting factor A, etc. In some embodiments, ABCG2 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a ABCG2 mRNA), or a protein encoded thereby (e.g., a ABCG2 polypeptide), etc.) from a species, which may be known as MXR, ABCP, BCRP, BCRP1, CDw388, ATP binding cassette subfamily G member 2, broad substrate specificity ATP-binding cassette transporter, breast cancer resistance protein, mitoxantrone resistance-associated protein, etc. In some embodiments, ABCC2 refers to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a ABCC2 mRNA), or a protein encoded thereby (e.g., a ABCC2 polypeptide), etc.) from a species, which may be known as CMOAT, CM0AT1, CMRP, MRP2, ATP binding cassette subfamily C member 2, canalicular multidrug resistance protein, canalicular multispecific organic anion transporter 1, multidrug resistance-associated protein 2, etc. Various G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7,CES1, CCND3, ASF1 A, ABCG2, and ABCC2 sequences including variants thereof are readily available to those of skill in the art.

[0112] Various technologies, e.g., assays, probes, antibodies, etc., have also been reported and can be utilized for detection of G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1A, ABCG2, and / or ABCC2. In some embodiments, detection of G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1 A, ABCG2, and / or ABCC2; a characteristic fragment of G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1A, ABCG2, and / or ABCC2; and / or a variant of G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1A, ABCG2, and / or ABCC2 is used as a portion of a NRF2 pathway signature. In some embodiments, G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1A, ABCG2, and / or ABCC2 is detected in a sample. In some embodiments, G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1A, ABCG2, and / or ABCC2 nucleic acids are detected in a sample. In some embodiments, G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1 A, ABCG2, and / or ABCC2 polypeptides are detected in a sample. In some embodiments, G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1A, ABCG2, and / or ABCC2 is detected using one or more agents, e.g., a probe, an antibody or antigen binding fragment thereof, etc. In some embodiments, G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1A, ABCG2, and / or ABCC2 is detected using one or more technologies described herein. In some embodiments, detection of G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1 A, ABCG2, and / or ABCC2 is used in a method described herein, e.g., a method of determining responsiveness to a cancer treatment, a method of treating, etc.

[0113] Additional NRF2 pathway signature biomarkers have been described in the art, including those in Romero, R., et al. Nat Med. 2017 Nov;23(l l):1362-1368. In some embodiments, a biomarker is or comprises TXNRD1, TKT, SRXN1, NQO1, GCLC, G6PD,FTH1, EPHX1, DDC, CBR3, UIP1, UCHL1, TXN, TSPAN7, TRIM16, TM4SF20, TGFB2, TFRC, TALD01, SQSTM1, SPP1, SPANXB1, SPANXA1, SORD, SLC7A11, SLC6A6, SLC38A6, SFN, SERPINE1, RRM2, PRDX1, PPAT, POPDC3, PIR, PGD, PCK2, PBEF1, PA2G4, P2RY6, OSGIN1, NRCAM, NR0B1, NQO2, NLN, NFE2L2, NEIL3, NCF2, MSC, MGST1, MEGF9, MEI, MCM10, MARS, MAP2, MAFG, LTB4DH, LRP8, LRP12, LOC644799, LOC642252, KIAA0319, IDH1, HTATIP2, HSPA1B, HRB, HM0X1, HGD, GSR, GPX2, GPC1, GLA, GCLM, GALNT13, FZD7, FAM55C, F2RL2, DOCKIO, DKFZP762E1312, DGKG, DEGS1, CYP4F11, CXCR7, CPLX2, CLN5, CES1, CDKN2B, CCND3, CCDC77, CBR1, CAMKK1, CIS, C16ORF28, C14ORF149, BLVRB, ASPH, ASNS, ASF1A, ALDH3A2, ALDH3A1, AKR1C3, AKR1C1, AKR1B10, ADAM23, ABHD4, ABCG2, ABCC2, ABCC1, and / or ABCB6. In some embodiments, a NRF2 pathway signature biomarker is or comprises TXNRD1, TKT, SRXN1, NQO1, GCLC, G6PD, FTH1, EPHX1, DDC, CBR3, UIP1, UCHL1, TXN, TSPAN7, TRIM16, TM4SF20, TGFB2, TFRC, TALDO1, SQSTM1, SPP1, SPANXB1, SPANXA1, SORD, SLC7A11, SLC6A6, SLC38A6, SFN, SERPINE1, RRM2, PRDX1, PPAT, POPDC3, PIR, PGD, PCK2, PBEF1, PA2G4, P2RY6, OSGIN1, NRCAM, NR0B1, NQO2, NLN, NFE2L2, NEIL3, NCF2, MSC, MGST1, MEGF9, MEI, MCM10, MARS, MAP2, MAFG, LTB4DH, LRP8, LRP12, LOC644799, LOC642252, KIAA0319, IDH1, HTATIP2, HSPA1B, HRB, HM0X1, HGD, GSR, GPX2, GPC1, GLA, GCLM, GALNT13, FZD7, FAM55C, F2RL2, DOCKIO, DKFZP762E1312, DGKG, DEGS1, CYP4F11, CXCR7, CPLX2, CLN5, CES1, CDKN2B, CCND3, CCDC77, CBR1, CAMKK1, CIS, C16ORF28, C14ORF149, BLVRB, ASPH, ASNS, ASF1A, ALDH3A2, ALDH3A1, AKR1C3, AKR1C1, AKR1B10, ADAM23, ABHD4, ABCG2, ABCC2, ABCC1, and / or ABCB6.MSI-H

[0114] In some embodiments, a biomarker is or comprises a Microsatellite Instability-High (MSI-H) biomarker. In some embodiments, a gene expression signature comprises an MSI-H biomarker. Microsatellite instability-high (MSI-H) is a biomarker reportedly used to classify tumors, e.g., solid tumors (See, e.g., Lorenzi, M. et al. J Oncology. 2020 Mar 9). Presence of MSI-H or classification of a tumor as MSI-H is reportedly based on the presence of size shifts in various genetic loci. These size shifts may be detected at genetic loci which comprisemicrosatellite markers. Detection of the size shifts is reportedly conducted using polymerase chain reaction (PCR) and a panel of microsatellite markers. In some embodiments, a microsatellite marker comprises a repeated sequence of 1, 2, 3, 4, 5 or 6 nucleotides. In some embodiments, a microsatellite marker comprises a mononucleotide repeat. In some embodiments, a microsatellite marker comprises a dinucleotide repeat. Size shifts of microsatellite markers are reportedly indicative of underlying loss of microsatellite DNA in cells, e.g., tumor cells and correlates with enhanced mutation rates in cells.

[0115] Various genetic loci, e.g., microsatellite markers may be used to determine whether a tumor or a sample thereof, e.g., a tumor specimen, comprises an MSI-H biomarker or classifies as MSI-H. In some embodiments, a microsatellite marker is or comprises BAT-25, BAT-26, CAT-25, D2S123, D5S346, D17S250, NR-21, NR-24, or MONO-27 (See, e.g., Lorenzi, M. et al. J Oncology. 2020 Mar 9; Li, Y. et al. Front Oncol. 2022 Jun 28; 12: 897548). Assessment of MSI-H biomarker in a sample, e.g., a tumor specimen, may involves five or more microsatellite markers, wherein the sample is determined to comprise a MSI-H biomarker when two or more microsatellite markers comprise size shifts. In some embodiments, a panel of microsatellite markers comprises at least five microsatellite markers. In some embodiments, a panel of microsatellite markers comprises five or more microsatellite markers. In some embodiments, a panel of microsatellite markers comprises five or more microsatellite markers selected from BAT-25, BAT-26, CAT-25, D2S123, D5S346, D17S250, NR-21, NR-24, and MONO-27. In some embodiments, a panel of microsatellite markers comprises BAT-25, BAT-26, CAT-25, NR-24, and MONO-27. In some embodiments, a panel of microsatellite markers comprises BAT-25, BAT-26, D2S123, D5S346, and D17S250. In some embodiments, a panel of microsatellite markers comprises BAT-25, BAT-26, NR-21, NR-24, and MONO-27. In some embodiments, an MSI-H biomarker comprises presence of size shifts in at least two microsatellite markers. In some embodiments, an MSI-H biomarker comprises presence of size shifts in at least two microsatellite markers of a panel of five or more microsatellite markers. In some embodiments, a tumor is classified as MSI-H if size shifts in at least two microsatellite markers are present in a sample from the tumor. In some embodiments, a tumor is classified as MSI-H if size shifts in at least two microsatellite markers are detected by, e.g., PCR in a sample from the tumor. In some embodiments, an MSI-H biomarker is present in a sample if size shiftsin at least two microsatellite markers are present in the sample. In some embodiments, an MSI- H biomarker is present in a sample if size shifts in at least two microsatellite markers are detected by, e.g., PCR, in the sample. In some embodiments, a size shift is a change of 1, 2, 3, 4, 5 or more base pairs in length. In some embodiments, a size shift is a change of 2 or more base pairs in length. In some embodiments, a size shift is a change of 3 or more base pairs in length. In some embodiments, a size shift is a change of 4 or more base pairs in length. In some embodiments, a size shift is a change of 5 or more base pairs in length. dMMR

[0116] In some embodiments, a biomarker is or comprises Deficient Mismatch Repair (dMMR) biomarker. In some embodiments, a gene expression signature comprises a dMMR biomarker. Mismatch repair deficient (dMMR) is a biomarker reportedly used to classify tumors, e.g., solid tumors (See, e.g., Lorenzi, M. et al. J Oncology. 2020 Mar 9). Presence of dMMR or classification of a tumor as dMMR is reportedly based on the absence of at least one MMR protein in a sample, e.g., a tumor specimen, as detected by an assessment of the sample using, e.g., immunohistochemistry. In some embodiments, a sample, e.g., a tumor specimen, is assessed using immunohistochemistry. In some embodiments, a sample, e.g., a tumor specimen, is assessed for presence or absence of one or more MMR proteins.

[0117] Various MMR proteins can be used to determine whether a tumor or a sample thereof, e.g., a tumor specimen, comprises a dMMR biomarker or classifies as dMMR. The standard suite of MMR proteins reportedly used to determine presence of dMMR comprises MLH1, MSH2, MSH6, and PMS2 (See, e.g., Funkhouser Jr, W. K. et al. J Mol Diagn. 2012 Mar-Apr; 14(2): 91 -103). MLH1, MSH2, MSH6, and PMS2 proteins have been reported to be required for functional human DNA mismatch repair, and thus, absence of one of these proteins leads to malfunctioning of the DNA mismatch repair process. In some embodiments, an MMR protein is MLH1, MSH2, MSH6, or PMS2. In some embodiments, a tumor is classified as dMMR if at least one MMR protein is absent in a sample from the tumor. In some embodiments, a tumor is classified as dMMR if at least one of MLH1, MSH2, MSH6, or PMS2 is absent in sample from the tumor. In some embodiments, a tumor is classified as dMMR if at least one MMR protein is not detected by, e.g., immunohistochemistry, in a sample from the tumor. Insome embodiments, a tumor is classified as dMMR if at least one of MLH1, MSH2, MSH6, or PMS2 is not detected by, e.g., immunohistochemistry, in a sample from the tumor. In some embodiments, a dMMR biomarker is present in a sample if at least one MMR protein is absent in the sample. In some embodiments, a dMMR biomarker is present in a sample if at least one of MLH1, MSH2, MSH6, or PMS2 proteins is absent in the sample. In some embodiments, a dMMR biomarker is present in a sample if at least one MMR protein is not detected by, e.g., immunohistochemistry in the sample. In some embodiments, a dMMR biomarker is present in a sample if at least one of MLH1, MSH2, MSH6, or PMS2 proteins is not detected by, e.g., immunohistochemistry, in the sample.Gene Expression Signatures

[0118] Gene expression signatures (GES) can comprise one or more biomarkers (e.g., genes) with a shared pattern of expression (e.g., levels of transcripts (e.g., mRNA) and / or levels of gene products (e.g., polypeptides, proteins). A GES may be used to identify, categorize, analyze, etc. various biological samples. Various GES may be used with provided technologies (e.g., methods, etc.) described herein. In some embodiments, a GES is an immune- related GES. In some embodiments, a GES is a pathway signature, e.g., a NRF2 pathway signature.

[0119] In some embodiments, a GES comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more biomarkers. In some embodiments, a GES comprises 1 or more biomarkers. In some embodiments, a GES comprises 2 or more biomarkers. In some embodiments, a GES comprises 3 or more biomarkers. In some embodiments, a GES comprises 4 or more biomarkers. In some embodiments, a GES comprises 5 or more biomarkers. In some embodiments, a GES comprises 6 or more biomarkers. In some embodiments, a GES comprises 6 or more biomarkers. In some embodiments, a GES comprises 7 or more biomarkers. In some embodiments, a GES comprises 8 or more biomarkers. In some embodiments, a GES comprises 9 or more biomarkers. In some embodiments, a GES comprises 10 or more biomarkers. In some embodiments, a GES comprises 11 or more biomarkers. In some embodiments, a GES comprises 12 or more biomarkers. In some embodiments, a GES comprises 13 or more biomarkers. In someembodiments, a GES comprises 14 or more biomarkers. In some embodiments, a GES comprises 15 or more biomarkers. In some embodiments, a GES comprises 16 or more biomarkers. In some embodiments, a GES comprises 17 or more biomarkers. In some embodiments, a GES comprises 18 or more biomarkers. In some embodiments, a GES comprises 19 or more biomarkers. In some embodiments, a GES comprises 20 or more biomarkers. In some embodiments, a GES comprises 1 biomarker. In some embodiments, a GES comprises 2 biomarkers. In some embodiments, a GES comprises 3 biomarkers. In some embodiments, a GES comprises 4 biomarkers. In some embodiments, a GES comprises 5 biomarkers. In some embodiments, a GES comprises 6 biomarkers. In some embodiments, a GES comprises 6 biomarkers. In some embodiments, a GES comprises 7 biomarkers. In some embodiments, a GES comprises 8 biomarkers. In some embodiments, a GES comprises 9 biomarkers. In some embodiments, a GES comprises 10 biomarkers. In some embodiments, a GES comprises 11 biomarkers. In some embodiments, a GES comprises 12 biomarkers. In some embodiments, a GES comprises 13 biomarkers. In some embodiments, a GES comprises 14 biomarkers. In some embodiments, a GES comprises 15 biomarkers. In some embodiments, a GES comprises 16 biomarkers. In some embodiments, a GES comprises 17 biomarkers. In some embodiments, a GES comprises 18 biomarkers. In some embodiments, a GES comprises 19 biomarkers. In some embodiments, a GES comprises 20 biomarkers.

[0120] In some embodiments, an immune-related GES comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more biomarkers. In some embodiments, an immune-related GES comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more biomarkers. In some embodiments, an immune-related GES comprises 1 or more biomarkers. In some embodiments, an immune- related GES comprises 2 or more biomarkers. In some embodiments, an immune-related GES comprises 3 or more biomarkers. In some embodiments, an immune-related GES comprises 4 or more biomarkers. In some embodiments, an immune-related GES comprises 5 or more biomarkers. In some embodiments, an immune-related GES comprises 6 or more biomarkers. In some embodiments, an immune-related GES comprises 6 or more biomarkers. In some embodiments, an immune-related GES comprises 7 or more biomarkers. In some embodiments, an immune-related GES comprises 8 or more biomarkers. In some embodiments, an immune-related GES comprises 9 or more biomarkers. In some embodiments, an immune-related GES comprises 10 or more biomarkers. In some embodiments, an immune-related GES comprises 11 or more biomarkers. In some embodiments, an immune-related GES comprises 12 or more biomarkers. In some embodiments, an immune-related GES comprises 13 or more biomarkers. In some embodiments, an immune- related GES comprises 14 or more biomarkers. In some embodiments, an immune-related GES comprises 15 or more biomarkers. In some embodiments, an immune-related GES comprises 1 biomarker. In some embodiments, an immune-related GES comprises 2 biomarkers. In some embodiments, an immune-related GES comprises 3 biomarkers. In some embodiments, an immune-related GES comprises 4 biomarkers. In some embodiments, an immune-related GES comprises 5 biomarkers. In some embodiments, an immune-related GES comprises 6 biomarkers. In some embodiments, an immune-related GES comprises 6 biomarkers. In some embodiments, an immune-related GES comprises 7 biomarkers. In some embodiments, an immune-related GES comprises 8 biomarkers. In some embodiments, an immune-related GES comprises 9 biomarkers. In some embodiments, an immune- related GES comprises 10 biomarkers. In some embodiments, an immune-related GES comprises 11 biomarkers. In some embodiments, an immune-related GES comprises 12 biomarkers. In some embodiments, an immune-related GES comprises 13 biomarkers. In some embodiments, an immune-related GES comprises 14 biomarkers. In some embodiments, an immune-related GES comprises 15 biomarkers.

[0121] In some embodiments, an immune-related GES comprises one or more anti-viral biomarkers. In some embodiments, an immune-related GES comprises one or more biomarkers selected from IFIT1 and OAS2. In some embodiments, an immune-related GES comprises one, two, or more interferon signaling biomarkers. In some embodiments, an immune-related GES comprises one, two, or more biomarkers selected from SP110, JAK2, and STAT1. In some embodiments, an immune-related GES comprises one or more macrophage regulation biomarkers. In some embodiments, an immune-related GES comprises one or more biomarkers selected from EPSTI1 and SLAMF8. In some embodiments, an immune-related GES comprises one, two, three, or more T cell-related function biomarkers. In some embodiments, an immune- related GES comprises one, two, three, or more biomarkers selected from IL7R, CCL4, HLA.A, and SELPLG. In some embodiments, an immune-related GES comprises one or morebiomarkers selected from one, two, three, or more of an anti-viral response biomarker, an interferon signaling biomarker, a macrophage regulation biomarker, and a T cell-related function biomarker. In some embodiments, an immune-related GES comprises one or more biomarkers selected from one, two, three, or more of an anti-viral response biomarker selected from one or both of IFIT1 and OAS2; an interferon signaling biomarker selected from one, two, or more of SP110, JAK2, and STAT1; a macrophage regulation biomarker selected from one or both of EPSTI1 and SLAMF8; and a T cell-related function biomarker selected from one, two, three, or more of IL7R, CCL4, HLA.A, and SELPLG. In some embodiments, an immune-related GES comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more biomarkers selected from IFIT1, OAS2, SP110, JAK2, STAT1, EPSTI1, SLAMF8, IL7R, CCL4, HLA.A, and SELPLG. In some embodiments, an immune related GES comprises IFIT1, OAS2, SP110, JAK2, STAT1, EPSTI1, SLAMF8, IL7R, CCL4, HLA.A, and SELPLG biomarkers.

[0122] In some embodiments, a NRF2 pathway signature comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 1 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 2 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 3 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 4 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 5 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 6 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 6 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 7 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 8 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 9 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 10 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 11 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 12 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 13 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 14 or more biomarkers. In someembodiments, a NRF2 pathway signature comprises 15 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 16 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 17 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 18 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 19 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 20 or more biomarkers. In some embodiments, a NRF2 pathway signature comprises 1 biomarker. In some embodiments, a NRF2 pathway signature comprises 2 biomarkers. In some embodiments, a NRF2 pathway signature comprises 3 biomarkers. In some embodiments, a NRF2 pathway signature comprises 4 biomarkers. In some embodiments, a NRF2 pathway signature comprises 5 biomarkers. In some embodiments, a NRF2 pathway signature comprises 6 biomarkers. In some embodiments, a NRF2 pathway signature comprises 6 biomarkers. In some embodiments, a NRF2 pathway signature comprises 7 biomarkers. In some embodiments, a NRF2 pathway signature comprises 8 biomarkers. In some embodiments, a NRF2 pathway signature comprises 9 biomarkers. In some embodiments, a NRF2 pathway signature comprises 10 biomarkers. In some embodiments, a NRF2 pathway signature comprises 11 biomarkers. In some embodiments, a NRF2 pathway signature comprises 12 biomarkers. In some embodiments, a NRF2 pathway signature comprises 13 biomarkers. In some embodiments, a NRF2 pathway signature comprises 14 biomarkers. In some embodiments, a NRF2 pathway signature comprises 15 biomarkers. In some embodiments, a NRF2 pathway signature comprises 16 biomarkers. In some embodiments, a NRF2 pathway signature comprises 17 biomarkers. In some embodiments, a NRF2 pathway signature comprises 18 biomarkers. In some embodiments, a NRF2 pathway signature comprises 19 biomarkers. In some embodiments, a NRF2 pathway signature comprises 20 biomarkers.

[0123] In some embodiments, a NRF2 pathway signature comprises one or more NRF2 pathway signature biomarkers as described herein. In some embodiments, a NRF2 pathway signature comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more biomarkers selected from G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1 A, ABCG2, and ABCC2. In some embodiments, a NRF2pathway signature comprises G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1A, ABCG2, and ABCC2.

[0124] In some embodiments, a GES comprises an MSI-H biomarker or a dMMR biomarker. In some embodiments, a GES comprises an MSI-H biomarker and a dMMR biomarker. In some embodiments, an MSI-H biomarker is an MSI-H biomarker described herein. In some embodiments, a dMMR biomarker is a dMMR biomarker described herein.Threshold Levels

[0125] Provided technologies (e.g., methods, etc.) may use various threshold levels in the classification of a subject as responsive to a cancer treatment. Threshold levels are generally useful for categorizing a sample from a subject, classifying a subject, stratifying a population of subjects, etc. to direct treatment of a disease, disorder, or condition, e.g., cancer. For example, a threshold level may be a value measured in an assay that defines the dividing line between two subsets of a population. In some embodiments, a value equal to or higher than a threshold level defines one subset of a population and a value lower than a threshold level defines one subset of a population.

[0126] A threshold level may comprise a predetermined level of one or more measurements, e.g., resulting from an assay. In some embodiments, a threshold level is a predetermined average level. In some embodiments, a threshold level is a predetermined mean or median level. In some embodiments, a threshold level is a predetermined mean level. In some embodiments, a threshold level is a predetermined median level. In some embodiments, a threshold level is a predetermined average level of a population of samples provided or obtained from a population of subjects. In some embodiments, a threshold level is a predetermined mean or median level of a population of samples provided or obtained from a population of subjects. In some embodiments, a threshold level is a predetermined mean level of a population of samples provided or obtained from a population of subjects. In some embodiments, a threshold level is a predetermined median level of a population of samples provided or obtained from a population of subjects. In some embodiments, a population of subjects is a population of healthy subjects. In some embodiments, a population of subjects is a population of subjects diagnosed with a disease, disorder, or condition. In some embodiments, a population of subjects is a population ofsubjects diagnosed with a benign tumor. In some embodiments, a population of subjects is a population of subjects diagnosed with a malignant tumor. In some embodiments, a population of subjects is a population of subjects diagnosed with a cancer.

[0127] A threshold level may comprise a level of one or more measurements, e.g., resulting from an assay of a second sample. In some embodiments, a second sample is a reference sample. In some embodiments, a second sample is provided or obtained from a subject prior to administration of a treatment, e.g., a cancer treatment. In some embodiments, a second sample is provided or obtained from a subject after administration of at least one treatment, e.g., cancer treatment. In some embodiments, a second sample is provided or obtained from a subject after administration of 1, 2, 3, 4, 5, or more treatments, e.g., cancer treatments. In some embodiments, a second sample is provided or obtained from a second subject. In some embodiments, a second subject is a healthy subject. In some embodiments, a second subject is a subject diagnosed with a disease, disorder, or condition. In some embodiments, a second subject is a subject diagnosed with a benign tumor In some embodiments, a second subject is a healthy subject or a subject diagnosed with a benign tumor. In some embodiments, a second subject is a subject diagnosed with a malignant tumor. In some embodiments, a second subject is a subject diagnosed with a cancer.

[0128] In some embodiments, a threshold level is a threshold level of a GES. In some embodiments, a threshold level of a GES is a predetermined average level of a GES. In some embodiments, a threshold level of a GES is a predetermined mean or median level of a GES. In some embodiments, a threshold level of a GES is a predetermined mean level of a GES. In some embodiments, a threshold level of a GES is a predetermined median level of a GES. In some embodiments, a threshold level of a GES is a predetermined average level of a GES of a population of samples provided or obtained from a population of subjects. In some embodiments, a threshold level of a GES is a predetermined mean or median level of a GES of a population of samples provided or obtained from a population of subjects. In some embodiments, a threshold level of a GES is a predetermined mean level of a GES of a population of samples provided or obtained from a population of subjects. In some embodiments, a threshold level of a GES is a predetermined median level of a GES of a population of samples provided or obtained from a population of subjects.

[0129] In some embodiments, a threshold level is a threshold level of an immune-related GES. In some embodiments, a threshold level of an immune-related GES is a predetermined average level of an immune-related GES. In some embodiments, a threshold level of an immune-related GES is a predetermined mean or median level of an immune- related GES. In some embodiments, a threshold level of an immune-related GES is a predetermined mean level of an immune-related GES. In some embodiments, a threshold level of an immune-related GES is a predetermined median level of an immune-related GES. In some embodiments, a threshold level of an immune-related GES is a predetermined average level of an immune-related GES of a population of samples provided or obtained from a population of subjects. In some embodiments, a threshold level of an immune-related GES is a predetermined mean or median level of an immune-related GES of a population of samples provided or obtained from a population of subjects. In some embodiments, a threshold level of an immune-related GES is a predetermined mean level of an immune-related GES of a population of samples provided or obtained from a population of subjects. In some embodiments, a threshold level of an immune- related GES is a predetermined median level of an immune-related GES of a population of samples provided or obtained from a population of subjects.

[0130] In some embodiments, a threshold level is a threshold level of a NRF2 pathway signature. In some embodiments, a threshold level of a NRF2 pathway signature is a predetermined average level of a NRF2 pathway signature. In some embodiments, a threshold level of a NRF2 pathway signature is a predetermined mean or median level of a NRF2 pathway signature. In some embodiments, a threshold level of a NRF2 pathway signature is a predetermined mean level of a NRF2 pathway signature. In some embodiments, a threshold level of a NRF2 pathway signature is a predetermined median level of a NRF2 pathway signature. In some embodiments, a threshold level of a NRF2 pathway signature is a predetermined average level of a NRF2 pathway signature of a population of samples provided or obtained from a population of subjects. In some embodiments, a threshold level of a NRF2 pathway signature is a predetermined mean or median level of a NRF2 pathway signature of a population of samples provided or obtained from a population of subjects. In some embodiments, a threshold level of a NRF2 pathway signature is a predetermined mean level of a NRF2 pathway signature of a population of samples provided or obtained from a population ofsubjects. In some embodiments, a threshold level of a NRF2 pathway signature is a predetermined median level of a NRF2 pathway signature of a population of samples provided or obtained from a population of subjects.

[0131] In some embodiments, a threshold level is a weighted expression level. In some embodiments, a threshold level is a weighted expression level of a GES. In some embodiments, a threshold level is a weighted expression level of an immune-related GES. In some embodiments, a threshold level is a weighted expression level of a NRF2 pathway signature.

[0132] In some embodiments, a threshold level is used to classify a subject as responsive to a treatment, e.g., a cancer treatment. In some embodiments, a threshold level is used in a method to classify a subject as responsive to a treatment, e.g., a cancer treatment. In some embodiments, a subject is classified as responsive to a treatment, e.g., a cancer treatment, when a sample provided or obtained from the subject exhibits an elevated level of, e.g., a GES relative to a threshold level of, e.g., the GES. In some embodiments, an elevated level of a GES is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or more higher than a threshold level of the GES. In some embodiments, an elevated level of a GES is at least about 25%, 50%, or 75% higher than a threshold level of the GES. In some embodiments, an elevated level of a GES is at least about 25% higher than a threshold level of the GES. In some embodiments, an elevated level of a GES is at least about 50% higher than a threshold level of the GES. In some embodiments, an elevated of a GES is at least about 75% higher than a threshold level of the GES. In some embodiments, a subject is classified as responsive to a cancer treatment when a sample provided or obtained from the subject exhibits an elevated level of an immune-related GES relative to a threshold level of the immune-related GES. In some embodiments, an elevated level of an immune-related GES is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or more higher than a threshold level of the immune-related GES. In some embodiments, an elevated level of an immune-related GES is at least about 25%, 50%, or 75% higher than a threshold level of the immune-related GES. In some embodiments, an elevated level of an immune-related GES is at least about 25% higher than a threshold level of the immune-related GES. In some embodiments, an elevated level of an immune-related GES is at least about 50% higher than a threshold level of the immune-relatedGES. In some embodiments, an elevated of an immune-related GES is at least about 75% higher than a threshold level of the immune-related GES.Cancers

[0133] Provided technologies (e.g., methods, etc.) may be used in treatment of any cancer or tumor as described herein. In some embodiments, a cancer comprises or is a PD-L1 positive cancer. In some embodiments, a tumor comprises or is a PD-L1 positive tumor. In some embodiments, a cancer comprises or is an advanced stage cancer. In some embodiments, a tumor comprises or is a solid tumor. In some embodiments, a cancer comprises or is a lung cancer. In some embodiments, a lung cancer comprises or is a non-small cell lung cancer (NSCLC). In some embodiments, NSCLC comprises or is lung squamous cell carcinoma (LUSC). In some embodiments, NSCLC comprises or is lung adenocarcinoma (LU AD). In some embodiments, a cancer comprises or is a liver cancer. In some embodiments, a liver cancer comprises or is hepatocellular carcinoma (HCC). In some embodiments, a cancer comprises or is a head and neck cancer. In some embodiments, a head and neck cancer comprises or is a head and neck squamous cell carcinoma. In some embodiments, a cancer comprises or is a nasopharynx cancer. In some embodiments, a nasopharynx cancer comprises or is nasopharyngeal carcinoma (NCC). In some embodiments, a cancer comprises or is an esophageal cancer. In some embodiments, an esophageal cancer comprises or is an esophageal squamous cell carcinoma (ESCC). In some embodiments, a cancer comprises or is a gastric cancer. In some embodiments, a cancer comprises or is a colorectal cancer. In some embodiments, a cancer comprises or is a skin cancer. In some embodiments, a skin cancer comprises or is a melanoma. In some embodiments, a cancer comprises or is an ovarian cancer. In some embodiments, a cancer comprises or is an urothelial bladder cancer. In some embodiments, a cancer comprises or is a kidney cancer. In some embodiments, a cancer comprises or is a renal cell carcinoma.

[0134] In some embodiments, a cancer comprises or is a colorectal cancer (CRC). In some embodiments, a cancer comprises or is a gastric or gastroesophageal junction cancer (G / GEJC). In some embodiments, a cancer comprises or is a gastric or gastroesophageal junction adenocarcinoma. In some embodiments, a cancer comprises or is a gastric cancer. In someembodiments, a cancer is a gastroesophageal junction cancer. In some embodiments, a cancer is an ampullary carcinoma. In some embodiments, a cancer is an endometrial cancer. In some embodiments, a cancer is a cervical cancer. In some embodiments, a cancer is an ovarian cancer. In some embodiments, a cancer is a small bowel adenocarcinoma. In some embodiments, a cancer is a pelvis clear cell carcinoma.

[0135] In some embodiments, a cancer is a HER2-negative cancer. In some embodiments, a cancer is a HER2-negative gastric or gastroesophageal junction adenocarcinoma. In some embodiments, a cancer is a HER2-negative gastric or gastroesophageal junction cancer.

[0136] In some embodiments, a cancer may specifically be of any of the following nonlimiting histological types: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; Paget’s disease, mammary; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma with squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; androblastoma, malignant; sertoli cell carcinoma; Leydig cell tumor, malignant; lipid cell tumor, malignant; paraganglioma, malignant; extramammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; melanoma;malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malig melanoma in giant pigmented nevus; epithelioid cell melanoma; blue nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant; choriocarcinoma; mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma, malignant; Kaposi sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; Ewing sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma; Hodgkin’s disease; Hodgkin’s lymphoma; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other specified non-Hodgkin’s lymphomas; malignant histiocytosis; myeloma; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; hairy cell leukemia; lung adenocarcinoma; lung squamous cell carcinoma; soft tissue sarcoma; bone sarcoma; nasopharyngeal carcinoma; bronchioloalveolar carcinoma; esophageal squamous cell carcinoma; head and neck squamous cell carcinoma; bronchogenic carcinoma; pelvis clear cell carcinoma ampullary carcinoma; gastroesophageal cancer; gastroesophageal adenocarcinoma; colorectal cancer; cervical cancer; ovarian cancer; endometrial cancer; small bowel adenocarcinoma; gastric cancer; gastric adenocarcinoma; and / or renal cell carcinoma.

[0137] In some embodiments, a cancer is a lung cancer. In some embodiments, a cancer is a kidney cancer. In some embodiments, a cancer is a breast cancer. In some embodiments, a cancer is a gastric cancer. In some embodiments, a cancer is a brain cancer. In some embodiments, a cancer is a skin cancer. In some embodiments, a cancer is a hypopharyngeal cancer. In some embodiments, a cancer is a prostate cancer. In some embodiments, a cancer is a bladder cancer. In some embodiments, a cancer is a gallbladder cancer. In some embodiments, a cancer is a cervical cancer. In some embodiments, a cancer is a thyroid cancer. In some embodiments, a cancer is a liver cancer. In some embodiments, a cancer is an ovarian cancer. In some embodiments, a cancer is a uterine cancer. In some embodiments, a cancer is a nasopharyngeal cancer. In some embodiments, a cancer is a colorectal cancer. In some embodiments, a cancer is a pancreatic cancer. In some embodiments, a cancer is an endometrial cancer. In some embodiments, a cancer is an oropharyngeal cancer. In some embodiments, a cancer is an esophageal cancer. In some embodiments, a cancer is a retinal cancer. In some embodiments, a cancer is a gastrointestinal cancer. In some embodiments, a cancer is a testicular cancer. In some embodiments, a cancer is a laryngeal cancer. In some embodiments, a cancer is an oral cavity cancer. In some embodiments, a cancer is a mouth cancer. In some embodiments, a cancer is nasal cavity cancer. In some embodiments, a cancer is a head and neck cancer. In some embodiments, a cancer is a parathyroid cancer. In some embodiments, a cancer is a peritoneal cancer. In some embodiments, a cancer is a rectal cancer. In some embodiments, a cancer is a colon cancer. In some embodiments, a cancer is a salivary gland cancer. In some embodiments, a cancer is a stomach cancer. In some embodiments, a cancer is a small intestine cancer. In some embodiments, a cancer is a vaginal cancer. In some embodiments, a cancer is a vulvar cancer. In some embodiments, a cancer is a tracheobronchial cancer. In some embodiments, a cancer is an anal cancer. In some embodiments, a cancer is a transitional cell cancer. In some embodiments, a cancer is a renal cell cancer. In some embodiments, a cancer is a small cell lung cancer. In some embodiments, a cancer is a penile cancer. In some embodiments, a cancer is a paranasal sinus cancer. In some embodiments, a cancer is a nonsmall cell lung cancer. In some embodiments, a cancer is a lip cancer. In some embodiments, a cancer is a hepatocellular cancer. In some embodiments, a cancer is a fallopian tube cancer. Insome embodiments, a cancer is an eye cancer. In some embodiments, a cancer is a bile duct cancer. In some embodiments, a cancer is a bone cancer.

[0138] In some embodiments, a cancer or tumor is resistant to a cancer treatment, e.g., a cancer treatment described herein. In some embodiments, a tumor is locally advanced. In some embodiments, a tumor is unresectable. In some embodiments, a tumor is locally advanced unresectable. In some embodiments, a tumor is metastatic.Response to Treatments

[0139] Provided technologies (e.g., methods, etc.) may be used to classify subjects as responsive to cancer treatments described herein. In some embodiments, responsive to a cancer treatment may comprise a modulation of one or more clinical assessments. In some embodiments, responsive to a cancer treatment may comprise an increased likelihood of a modulation of one or more clinical assessments. In some embodiments, a modulation comprises an increase or decrease, depending on the clinical assessment and which direction indicates a clinical benefit to a subject.

[0140] In some embodiments, a clinical assessment comprises or is progression free survival (PFS). In some embodiments, PFS is the time from treatment assignment to the first objectively documented disease progression, or death from any cause, whichever occurs first, as determined, e.g., using clinical guidelines, e.g., response evaluation criteria in solid tumors (RECIST) vl.l. In some embodiments, a clinical assessment comprises or is overall survival (OS). In some embodiments, OS is the time from treatment assignment to death from any cause. In some embodiments, a clinical assessment comprises or is objective response rate (ORR). In some embodiments, ORR is the proportion of patients who had a complete response (CR) or partial response (PR) as assessed, e.g., using clinical guidelines, e.g., RECIST vl.l. In some embodiments, a clinical assessment comprises or is duration of response (DOR). In some embodiments, DOR is measured from the time measurement criteria are first met for CR or PR (whichever is first recorded) until the first time that recurrent or progressive disease is objectively documented as determined, e.g., using clinical guidelines, e.g., RECIST vl.l. In some embodiments, a clinical assessment comprises or is health-related quality of life (HRQoL). In some embodiments, HRQoL is determined, e.g., using a clinical questionnaire, e.g., EuropeanOrganization for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13) or European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Various additional clinical questionnaires useful for, e.g., determination of, e.g., HRQoL are known or available to those skilled in the art. In some embodiments, a clinical assessment comprises or is time-to-response (TTR). In some embodiments, TTR is the time from treatment assignment to the time measurement criteria are first met for CR or PR. In some embodiments, a clinical assessment comprises or is tumor size. Various additional clinical assessments useful for, e.g., determination of, e.g., a subject’s responsiveness to a cancer treatment are known or available to those skilled in the art. Further, various additional clinical guidelines useful for, e.g. determination of, e.g., disease progression are known or available to those skilled in the art.

[0141] In some embodiments, a subject is classified as responsive to a cancer treatment when a sample provided or obtained from the subject exhibits an elevated level of a GES relative to a threshold level of the GES. In some embodiments, a subject is classified as responsive to a cancer treatment when a sample provided or obtained from the subject exhibits an elevated level of an immune-related GES relative to a threshold level of the immune-related GES. In some embodiments, a subject is administered a cancer treatment if the subject is classified as responsive to the cancer treatment.

[0142] In some embodiments, a measure of response is or comprises one or more clinical assessments as described herein. In some embodiments, a measure of response is or comprises overall survival (OS). In some embodiments, a measure of response is or comprises progression- free survival (PFS). In some embodiments, a measure of response is or comprises event-free survival. In some embodiments, a measure of response is or comprises overall response rate. In some embodiments, a measure of response is or comprises objective response rate. In some embodiments, a measure of response is or comprises partial response. In some embodiments, a measure of response is or comprises duration of response. In some embodiments, a measure of response is or comprises tumor volume.

[0143] In some embodiments, a measure of response is used to classify a subject as a responder to a treatment, e.g., a treatment described herein. In some embodiments, at least onemeasure of response is used to classify a subject as a responder to a treatment, e.g., a treatment described herein. In some embodiments, one or more measures of response is used to classify a subject as a responder to a treatment. In some embodiments, a subject is a responder to a treatment, e.g., a treatment described herein, by at least one measure of response as compared to a reference subject. In some embodiments, a reference subject does not have an MSI-H biomarker in a sample, e.g., a tumor specimen from the reference subject. In some embodiments, a reference subject does not have a dMMR biomarker in a sample, e.g., a tumor specimen from the reference subject. In some embodiments, a reference subject does not have an MSI-H or a dMMR biomarker in a sample, e.g., a tumor specimen from the reference subject. In some embodiments, a reference subject does not have an MSI-H and a dMMR biomarker in a sample, e.g., a tumor specimen from the reference subject.Methods

[0144] Among other things, the present disclosure provides methods, including, e.g., methods of determining responsiveness of a subject to a treatment and methods of treating a subject. In some embodiments, the present disclosure provides methods of determining responsiveness of a subject having a cancer to a cancer treatment. In some embodiments, the present disclosure provides methods of treating a subject having cancer.

[0145] In some embodiments, the present disclosure provides a method comprising steps of (a) providing or obtaining a sample from a subject having cancer; (b) testing for or detecting a GES in the sample; (c) comparing a level of the GES in the sample to a threshold level of the GES; and (d) classifying the subject as responsive to a cancer treatment when the sample exhibits an elevated level of the GES relative to the threshold level of the GES. In some embodiments, the present disclosure provides a method comprising steps of (a) providing or obtaining a sample from a subject having cancer; (b) testing for or detecting an immune-related GES in the sample; (c) comparing a level of the immune-related GES in the sample to a threshold level of the immune-related GES; and (d) classifying the subject as responsive to a cancer treatment when the sample exhibits an elevated level of the immune-related GES relative to the threshold level of the immune- related GES. In some embodiments, a GES is a GES as described herein. In some embodiments, an immune-related GES is an immune-related GES asdescribed herein. In some embodiments, a method further comprises administering the cancer treatment to the subject if the subject is classified as responsive to the cancer treatment.

[0146] In some embodiments, the present disclosure provides a method of determining responsiveness of a subject having a disease, disorder, or condition to a treatment. In some embodiments, the present disclosure provides a method of determining responsiveness of a subject having cancer to a cancer treatment. In some embodiments, the present disclosure provides a method of determining responsiveness of a subject diagnosed with a cancer to a cancer treatment. In some embodiments, a method of determining responsiveness of a subject having a cancer to a cancer treatment comprises (a) providing or obtaining a sample from a subject having cancer; (b) testing for or detecting a GES in the sample; (c) comparing a level of the GES in the sample to a threshold level of the GES; and (d) classifying the subject as responsive to a cancer treatment when the sample exhibits an elevated level of the GES relative to the threshold level of the GES. In some embodiments, a method of determining responsiveness of a subject having a cancer to a cancer treatment comprises (a) providing or obtaining a sample from a subject having cancer; (b) testing for or detecting an immune-related GES in the sample; (c) comparing a level of the immune-related GES in the sample to a threshold level of the immune-related GES; and (d) classifying the subject as responsive to a cancer treatment when the sample exhibits an elevated level of the immune-related GES relative to the threshold level of the immune- related GES. In some embodiments, a GES is a GES as described herein. In some embodiments, an immune-related GES is an immune-related GES as described herein. In some embodiments, a method of determining responsiveness of a subject having a cancer to a cancer treatment further comprises administering the cancer treatment to the subject if the subject is classified as responsive to the cancer treatment.

[0147] In some embodiments, the present disclosure provides a method of treating a subject. In some embodiments, the present disclosure provides a method of treating a subject having a disease, disorder, or condition. In some embodiments, the present disclosure provides a method of treating a subject having cancer. In some embodiments, the present disclosure provides a method of treating a subject diagnosed with a cancer. In some embodiments, a method of treating a subject having cancer comprises (a) providing or obtaining a sample from the subject; (b) testing for or detecting a GES in the sample; (c) comparing a level of the GES in the sampleto a threshold level of the GES; (d) classifying the subject as responsive to a cancer treatment when the sample exhibits an elevated level of the GES relative to threshold level of the GES; and (e) administering the cancer treatment to the subject if the subject is classified as responsive to the cancer treatment. In some embodiments, a method of treating a subject having cancer comprises (a) providing or obtaining a sample from the subject; (b) testing for or detecting an immune-related GES in the sample; (c) comparing a level of the immune-related GES in the sample to a threshold level of the immune- related GES; (d) classifying the subject as responsive to a cancer treatment when the sample exhibits an elevated level of the immune-related GES relative to threshold level of the immune-related GES; and (e) administering the cancer treatment to the subject if the subject is classified as responsive to the cancer treatment. In some embodiments, a method of treating a subject diagnosed with a cancer comprises (a) providing or obtaining a sample from the subject; (b) testing for or detecting a GES in the sample; (c) comparing a level of the GES in the sample to a threshold level of the GES; (d) classifying the subject as responsive to a cancer treatment when the sample exhibits an elevated level of the GES relative to threshold level of the GES; and (e) administering the cancer treatment to the subject if the subject is classified as responsive to the cancer treatment. In some embodiments, a method of treating a subject diagnosed with a cancer comprises (a) providing or obtaining a sample from the subject; (b) testing for or detecting an immune-related GES in the sample; (c) comparing a level of the immune-related GES in the sample to a threshold level of the immune- related GES; (d) classifying the subject as responsive to a cancer treatment when the sample exhibits an elevated level of the immune-related GES relative to threshold level of the immune- related GES; and (e) administering the cancer treatment to the subject if the subject is classified as responsive to the cancer treatment. In some embodiments, a GES is a GES as described herein. In some embodiments, an immune-related GES is an immune-related GES as described herein.

[0148] In some embodiments, a method of treating a subject having a disease, disorder, or condition comprises administering a treatment. In some embodiments, a method of treating a subject having cancer comprises administering a cancer treatment. In some embodiments, a method of treating a subject diagnosed with a cancer comprises administering a cancer treatment.

[0149] In some embodiments, a subject has been determined to be responsive to a treatment. In some embodiments, a subject has been determined to be responsive to a cancer treatment. In some embodiments, a subject has been determined to be responsive to a cancer treatment by a method comprising (a) providing or obtaining a sample from the subject; (b) testing for or detecting a GES in the sample; (c) comparing a level of the GES in the sample to a threshold level of the GES; and (d) classifying the subject as responsive to the cancer treatment when the sample exhibits an elevated level of the GES relative to threshold level of the GES. In some embodiments, a subject has been determined to be responsive to a cancer treatment by a method comprising (a) providing or obtaining a sample from the subject; (b) testing for or detecting an immune-related GES in the sample; (c) comparing a level of the immune-related GES in the sample to a threshold level of the immune- related GES; and (d) classifying the subject as responsive to the cancer treatment when the sample exhibits an elevated level of the immune- related GES relative to the threshold level of the immune-related GES. In some embodiments, a GES is a GES as described herein. In some embodiments, an immune-related GES is an immune-related GES as described herein.

[0150] In some embodiments, a method (e.g., a method of testing for or detecting, a method of treating) further comprises testing for or detecting a NRF2 pathway signature in a sample provided or obtained from the subject. In some embodiments, a method (e.g., a method of testing for or detecting, a method of treating) further comprises testing for or detecting a NRF2 pathway signature in a sample provided or obtained from the subject and comparing a level of the NRF2 pathway signature in the sample to a threshold level of the NRF pathway signature. In some embodiments, a NRF2 pathway signature is a NRF2 pathway signature as described herein.

[0151] In some embodiments, a method (e.g., a method of testing for or detecting, a method of treating) further comprises testing for or detecting one or more activating NRF2 pathway mutations in a sample provided or obtained from the subject. In some embodiments, one or more activating NRF2 pathway mutations comprise or are one, two, or more of (i) one or more gain of function mutations in NFE2L2; (ii) one or more loss of function mutations in KEAP1; (iii) one or more loss of function mutations in CUL3.

[0152] In some embodiments, the present disclosure provides a method comprising steps of (a) selecting a subject for treatment with a cancer treatment based on the presence of a GES in a sample and (b) administering a therapeutically effective amount of the cancer treatment to the subject. In some embodiments, the present disclosure provides a method comprising steps of (a) selecting a subject for treatment with a cancer treatment based on the presence of an immune- related GES in a sample and (b) administering a therapeutically effective amount of the cancer treatment to the subject. In some embodiments, the present disclosure provides a method comprising steps of (a) selecting a subject for treatment with a PD-1 or PD-L1 inhibitor based on the presence of an immune-related GES in a sample and (b) administering a therapeutically effective amount of the PD-1 or PD-L1 inhibitor to the subject. In some embodiments, the present disclosure provides a method comprising steps of (a) selecting a subject for treatment with a PD-1 inhibitor based on the presence of an immune-related GES in a sample and (b) administering a therapeutically effective amount of the PD-1 inhibitor to the subject. In some embodiments, the present disclosure provides a method comprising steps of (a) selecting a subject for treatment with a PD-L1 inhibitor based on the presence of an immune-related GES in a sample and (b) administering a therapeutically effective amount of the PD-L1 inhibitor to the subject. In some embodiments, the present disclosure provides a method comprising steps of (a) selecting a subject for treatment with tislelizumab based on the presence of an immune-related GES in a tumor specimen and (b) administering a therapeutically effective amount of tislelizumab to the subject. In some embodiments, a method further comprises administering one or more therapeutic agents to a subject. In some embodiments, a method further comprises administering one or more chemotherapeutic agents to a subject. In some embodiments, a method further comprises administering one or more pharmaceutical compositions comprising one or more therapeutic agents to a subject. In some embodiments, a method further comprises administering one or more pharmaceutical compositions comprising one or more chemotherapeutic agents to a subject. In some embodiments, one or more therapeutic agents comprise or are one or more therapeutic agents described herein. In some embodiments, one or more chemotherapeutic agents comprise or are one or more chemotherapeutic agents described herein. In some embodiments, a GES is a GES as described herein. In some embodiments, an immune-related GES is an immune-related GES as described herein.

[0153] In some embodiments, a subject was previously administered or delivered one or more cancer treatments, e.g., a cancer treatment described herein. In some embodiments, a subject was previously administered or delivered at least one cancer treatment, e.g., a cancer treatment described herein. In some embodiments, a subject is susceptible to or suffering from an unr esectable tumor. In some embodiments, a subject is susceptible to or suffering from a locally advanced tumor. In some embodiments, a subject is susceptible to or suffering from a locally advanced unresectable tumor. In some embodiments, a subject is susceptible to or suffering from a metastatic tumor.Pharmaceutical Composition

[0154] Provided herein are compositions, including pharmaceutical formulations, comprising therapeutic agents. In some embodiments, provided herein are compositions, including pharmaceutical formulations, comprising an anti-PD-1 antibody (e.g. tislelizumab) or an antigenbinding fragment thereof described herein. Also provided herein are compositions, including pharmaceutical formulations, comprising one or more chemotherapeutic drugs described herein.

[0155] Pharmaceutical formulations of any antibody as described herein are prepared by mixing such antibody or antigen-binding fragment having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3- pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG). In some embodiments, the surfactant is a polysorbate. Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Nos. US 7,871,607 and 2006 / 0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.

[0156] Exemplary lyophilized antibody formulations are described in US Patent No. 6,267,958. Aqueous antibody formulations include those described in US Patent No. 6,171,586 and W02006 / 044908, the latter formulations including a histidine-acetate buffer. In some embodiments, the formulations include a histidine-citric acid buffer. Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. The formulations to be used for in vivo administration are generally sterile. Sterility can be readily accomplished, e.g., by filtration through sterile filtration membranes.

[0157] In some embodiments, the pharmaceutical composition or formulation comprises a formulation buffer comprising histidine, acetate, citrate, succinate, phosphate, mixture of histidine and acetic acid, mixture of histidine and citric acid, salt or hydrate thereof, or any combination of them. In some embodiments, the formulation buffer comprises a histidine buffer that comprises histidine, histidine hydrochloride, L-histidine, L-histidine hydrochloride, L- histidine hydrochloride hydrate, L-histidine hydrochloride monohydrate, or a combination thereof. In some embodiments, the histidine buffer comprises L-histidine / L-histidine hydrochloride monohydrate buffer (His / His HC1). In some embodiments, the histidine buffer comprises histidine / L-histidine hydrochloride monohydrate buffer and citric acid monohydrate. In some embodiments, the concentration of the histidine buffer (e.g., L-histidine / L-histidine hydrochloride monohydrate) is between about 5 mM to about 30 mM. In some embodiments, the concentration of the histidine buffer (e.g., L-histidine / L-histidine hydrochloride monohydrate) is between about 5 mM to about 10 mM, between about 5 mM to about 15 mM,between about 5 mM to about 20 mM, between about 10 mM to about 15 mM, between about 10 mM to about 20 mM, between about 10 mM to about 25 mM, between about 15 mM to about 20 mM, between about 15 mM to about 25 mM, between about 15 mM to about 30 mM, between about 20 mM to about 25 mM, or between about 25 mM to about 30 mM. In some embodiments, the concentration of the histidine buffer (e.g., L-histidine / L-histidine hydrochloride monohydrate) is about 5 mM or more, about 10 mM or more, about 15 mM or more, about 20 mM or more, about 25 mM or more, about 30 mM or more. In some embodiments, the concentration of the histidine buffer (e.g., L-histidine / L-histidine hydrochloride monohydrate) is 1 OmM.

[0158] In some embodiments, the concentration of the histidine is about 5-15 mM, in a preferred embodiment the concentration of histidine is about 11 mM. In some embodiments, the concentration of the L-histidine hydrochloride monohydrate is about 1-5 mM, in a preferred embodiment the concentration of L-histidine hydrochloride monohydrate is about 4 mM. In some embodiments, the formulation comprises histidine at a concentration of about 5-15 mM, in a preferred embodiment the concentration of histidine is about 11 mM, and L-histidine hydrochloride monohydrate at a concentration of about 1-5 mM, in a preferred embodiment the concentration of L-histidine hydrochloride monohydrate is about 4 mM. In some embodiments, the formulation buffer is a mixture of histidine, L-histidine hydrochloride monohydrate, citric acid monohydrate, and sodium citrate; wherein the formulation comprises histidine at a concentration of about 5-15 mM, in a preferred embodiment the concentration of histidine is about 11 mM, and L-histidine hydrochloride monohydrate at a concentration of about 1-5 mM, in a preferred embodiment the concentration of L-histidine hydrochloride monohydrate is about 4 mM, wherein the citric acid monohydrate is at a concentration of about 1-5 mM, preferably 2 mM, and sodium citrate is present at a concentration of 15- 30 mM, preferably about 23 mM.

[0159] In some embodiments, the pharmaceutical composition or formulation comprises a stabilizer. In some embodiments, the stabilizer comprises trehalose, sucrose, sorbitol, mannitol, L-arginine hydrochloride, maltose, dextran, (2-hydroxypropyl)-b-cyclodextrin, sodium chloride, magnesium chloride, calcium chloride, sodium sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, or a combination thereof. In some embodiments, the stabilizer comprises trehalose, sucrose, L-arginine hydrochloride, sodium chloride, or a combination thereof. In someembodiments, the stabilizer is trehalose. In some embodiments the trehalose is a-trehalose dihydrate.

[0160] In some embodiments, the concentration of the stabilizer is between about 50 mM to about 300 mM. In some embodiments, the concentration of the stabilizer is between about 50 mM to about 100 mM, between about 50 mM to about 150 mM, between about 50 mM to about 200 mM, between about 100 mM to about 150 mM, between about 100 mM to about 200 mM, between about 100 mM to about 250 mM, between about 150 mM to about 200 mM, between about 150 mM to about 250 mM, or between about 150 mM to about 300 mM. In some embodiments, the concentration of the stabilizer is about 50 mM or more, about 60 mM or more, about 70 mM or more, about 80 mM or more, about 90 mM or more, about 100 mM or more, about 110 mM or more, about 120 mM or more, about 130 mM or more, about 140 mM or more, about 150 mM or more, about 160 mM or more, about 170 mM or more, about 180 mM or more, about 190 mM or more, about 200 mM or more, about 210 mM or more, about 220 mM or more, about 230 mM or more, about 240 mM or more, about 250 mM or more, about 260 mM or more, about 270 mM or more, about 280 mM or more, about 290 mM or more, or about 300 mM or more. In some embodiments, the concentration of the stabilizer is about 190 mM.

[0161] In some embodiments, the pharmaceutical composition or formulation comprises a non-ionic surfactant. In some embodiments, the non-ionic surfactant comprises polysorbate 80 (PS80), polysorbate 20 (PS20), poloxamerl88 (Pl 88), or a combination thereof. In some embodiments, the non-ionic surfactant is PS20. In some embodiment, the concentration of the non-ionic surfactant is between about 0.01% to about 1%. In some embodiments, the concentration of the non-ionic surfactant is between about 0.01% to about 0.03%, between about 0.01% to about 0.06%, between about 0.01% to about 0.09%, between about 0.03% to about 0.06%, between about 0.03% to about 0.09%, between about 0.03% to about 0.2%, between about 0.06% to about 0.09%, between about 0.06% to about 0.2%, between about 0.06% to about 0.5%, between about 0.09% to about 0.2%, between about 0.09% to about 0.5%, between about 0.09% to about 0.8%, between about 0.2% to about 0.5%, between about 0.2% to about 0.8%, between about 0.2% to about 1%, between about 0.5% to about 0.8%, between about 0.5% to about 1%, or between about 0.8% to about 1%. In some embodiments, the concentration of the non-ionic surfactant is about 0.01% or more, is about 0.02% or more, is about 0.03% or more, is1about 0.04% or more, is about 0.05% or more, is about 0.06% or more, is about 0.07% or more, is about 0.08% or more, is about 0.09% or more, is about 0.1% or more, is about 0.2% or more, is about 0.3% or more, is about 0.4% or more, is about 0.5% or more, is about 0.6% or more, is about 0.7% or more, is about 0.8% or more, is about 0.9% or more, or is about 1% or more. In some embodiments, the concentration of the non-ionic surfactant is 0.2%.

[0162] In some embodiments, the pharmaceutical composition or formulation comprises between about 1 mg / ml to about 10 mg / ml of the multi-specific antibody or antigen-binding fragment as disclosed herein. In some embodiments, the pharmaceutical composition or formulation comprises between about 1 mg / ml to about 2 mg / ml, between about 1 mg / ml to about 3 mg / ml, between about 1 mg / ml to about 4 mg / ml, between about 2 mg / ml to about 3 mg / ml, between about 2 mg / ml to about 4 mg / ml, between about 2 mg / ml to about 5 mg / ml, between about 3 mg / ml to about 4 mg / ml, between about 3 mg / ml to about 5 mg / ml, between about 3 mg / ml to about 6 mg / ml, between about 4 mg / ml to about 5 mg / ml, between about 4 mg / ml to about 6 mg / ml, between about 4 mg / ml to about 7 mg / ml, between about 5 mg / ml to about 6 mg / ml, between about 5 mg / ml to about 7 mg / ml, between about 5 mg / ml to about 8 mg / ml, between about 6 mg / ml to about 7 mg / ml, between about 6 mg / ml to about 8 mg / ml, between about 6 mg / ml to about 9 mg / ml, between about 7 mg / ml to about 8 mg / ml, between about 7 mg / ml to about 9 mg / ml, between about 7 mg / ml to about 10 mg / ml, between about 8 mg / ml to about 9 mg / ml, between about 8 mg / ml to about 10 mg / ml, or between about 9 mg / ml to about 10 mg / ml of the multi-specific antibody or antigen-binding fragment as disclosed herein. In some embodiments, the pharmaceutical composition or formulation comprises about 1 mg / ml or more, 2 mg / ml or more, 3 mg / ml or more, 4 mg / ml or more, 5 mg / ml or more, 6 mg / ml or more, 7 mg / ml or more, 8 mg / ml or more, 9 mg / ml or more, or 10 mg / ml or more of the multispecific antibody or antigen-binding fragment as disclosed herein. In some embodiments, the pharmaceutical composition or formulation comprises 10 mg / ml of the antibody (e.g., PD-1 antibody or tislelizumab) as disclosed herein.

[0163] In some embodiments, the pharmaceutical composition or formulation has a pH of between about 4.5 to about 7.5. In some embodiments, the pharmaceutical composition or formulation has a pH of between about 4.5 to about 5.0, between about 4.5 to about 5.5, between about 4.5 to about 6.0, between about 5.0 to about 5.5, between about 5.0 to about 6.0, betweenabout 5.0 to about 6.5, between about 5.5 to about 6.0, between about 5.5 to about 6.5, between about 5.5 to about 7.0, between about 6.0 to about 6.5, between about 6.0 to about 7.0, between about 6.0 to about 7.5, between about 6.5 to about 7.0, between about 6.5 to about 7.5, or between about 7.0 to about 7.5. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.5 or more, about 5.0 or more, about 5.5 or more, about 6.0 or more, about 6.5 or more, about 7.0 or more, or about 7.5 or more. In some embodiments, the pharmaceutical composition or formulation has a pH of 6.5.

[0164] In some embodiments, the antibody (e.g. PD-1 antibody or tislelizumab) is formulated in a pharmaceutical composition comprising a histidine buffer, a surfactant and a stabilizer. In some embodiments, the surfactant is a polysorbate. In some embodiments, the stabilizer is trehalose. In a particular embodiment, the PD-1 antibody (e.g. tislelizumab) is formulated in a pharmaceutical composition comprising citric acid monohydrate, histidine, L- histidine hydrochloride monohydrate, polysorbate 20, sodium citrate, and trehalose.

[0165] The term “pharmaceutical composition” refers to preparations with pharmaceutically acceptable excipients which are in such form as to permit the active ingredients to be effective, and which contains no additional components which are toxic to the subjects to which the composition would be administered. In some embodiments, a pharmaceutical composition may be formulated for administration in solid or liquid form, comprising, without limitation, a form adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces. In some aspects, the present disclosure provides compositions, e.g., pharmaceutically acceptable compositions, which include an anti -PD-1 antibody described herein, formulated together with at least one pharmaceutically acceptable excipient.

[0166] The term “pharmaceutically acceptable” refers to a molecule or composition that, when administered to a recipient, is not deleterious to the recipient thereof, or that any deleterious effect is outweighed by a benefit to the recipient thereof.

[0167] Some examples of materials which may serve as pharmaceutically acceptable carriers comprise: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0168] A “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible. The excipient can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g., by injection or infusion).

[0169] The compositions disclosed herein can be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusion solutions), dispersions or suspensions, liposomes, and suppositories. A suitable form depends on the intended mode of administration and therapeutic application. Typical suitable compositions are in the form of injectable or infusion solutions. One suitable mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In some embodiments, the antibody is administered by intravenous infusion or injection. In some embodiments, the antibody is administered by intramuscular or subcutaneous injection. In some embodiments, the antibody is administered by way of a syringe infusion system.

[0170] In some embodiments, the anti-PD-1 antibody is administered at a dose from about 50 to 800 mg, optionally wherein the anti-PD-1 antibody is administered at 100 mg, 150 mg, 200,mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg. In some embodiments, the PD-1 antibody is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks, preferably wherein the anti -PD-1 antibody is administered at 150 mg every two weeks, 300 mg every four weeks, or 400 mg every six weeks. In some embodiments, the cancer treatment comprises intravenous administration of tislelizumab. In some embodiments, the cancer treatment comprises intravenous administration of 200 mg tislelizumab every 3 weeks.Kits

[0171] The present disclosure, among other things, provides kits comprising anti-PD-1 antibodies or antigen-binding fragments thereof, and instructions for use and / or administration. In some embodiments, a kit comprises at least one anti-PD-1 antibody or antigen-binding fragment thereof, at least one chemotherapeutic agent, and a pharmaceutically acceptable carrier, and instructions for use and / or administration.

[0172] Also provided are kits for use in various methods disclosed herein. Instructions can comprise a description of administering of one or more pharmaceutical compositions described herein to a subject to achieve an intended activity in a subject. A kit may further comprise a description of selecting a human suitable for treatment based on identifying whether the human is in need of treatment.

[0173] Instructions generally include information as to dosage, dosing schedule, and route of administration for an intended treatment. Containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses. Instructions supplied in kits of the disclosure are typically written instructions on a label or package insert. A label or package insert may indicate that one or more pharmaceutical compositions described herein are used for treating, delaying the onset, and / or alleviating a disease, disorder or condition in a subject.

[0174] In some embodiments, kits provided herein are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging, and the like. Also contemplated are packages for use in combination with a specific device, such as an infusion device. A kit may have a sterile access port (for example, a container may be an intravenoussolution bag or a vial having a stopper pierce able by a hypodermic injection needle). A container may also have a sterile access port.

[0175] Kits can include additional components such as buffers and interpretive information. A kit can comprise a container and a label or one or more package inserts on or associated with a container. In some embodiment, the disclosure provides articles of manufacture comprising contents of kits described above.Definitions

[0176] Administering: As used herein, the term “administering” or “administration” typically refers to the administration of a composition to a subject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be parenteral. In some embodiments, administration may be intravenous. In some embodiments, administration may be oral. In some embodiments, administration may be via injection. In some embodiments, administration may be systemic. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., infusion, perfusion) for at least a selected period of time.

[0177] Affinity Agent: The term “affinity agent” as used herein refers to an entity that is or comprises a target-binding moiety as described herein, and therefore binds to a target of interest (e.g., molecular target of interest such as a biomarker or an epitope). In some embodiments, an affinity agent in accordance with the present disclosure binds specifically with a biomarker as described herein. In some embodiments, an affinity agent may be or comprise an antibody agent (e.g., an antibody or other entity that is or includes an antigen-binding portion thereof). Alternatively or additionally, in some embodiments, an affinity agent may selected from the group consisting of affimers, aptamers, lectins, and combinations thereof, and / or another bindingagent that may be considered a ligand. In some embodiments, a target (e.g., a biomarker target) of an affinity agent is or comprises one or more polypeptide, nucleic acid, carbohydrate, and / or lipid moieties and / or entities).

[0178] Agent: In general, the term “agent”, as used herein, is used to refer to an entity (e.g., for example, a lipid, metal, nucleic acid, polypeptide, polysaccharide, small molecule, etc., or complex, combination, mixture or system (e.g., cell, tissue, organism) thereof), or phenomenon (e.g., heat, electric current or field, magnetic force or field, etc.). In appropriate circumstances, as will be clear from context to those skilled in the art, the term may be utilized to refer to an entity that is or comprises a cell or organism, or a fraction, extract, or component thereof. Alternatively or additionally, as context will make clear, the term may be used to refer to a natural product in that it is found in and / or is obtained from nature. In some instances, again as will be clear from context, the term may be used to refer to one or more entities that is man-made in that it is designed, engineered, and / or produced through action of the hand of man and / or is not found in nature. In some embodiments, an agent may be utilized in isolated or pure form; in some embodiments, an agent may be utilized in crude form. In some embodiments, potential agents may be provided as collections or libraries, for example that may be screened to identify or characterize active agents within them. In some cases, the term “agent” may refer to a compound or entity that is or comprises a polymer; in some cases, the term may refer to a compound or entity that comprises one or more polymeric moieties. In some embodiments, the term “agent” may refer to a compound or entity that is not a polymer and / or is substantially free of any polymer and / or of one or more particular polymeric moieties. In some embodiments, the term may refer to a compound or entity that lacks or is substantially free of any polymeric moiety.

[0179] Associated: Two events or entities are “associated” with one another, as that term is used herein, if the presence, level and / or form of one is correlated with that of the other. For example, a particular biological phenomenon (e.g., expression of a specific biomarker) is considered to be associated with a disease, disorder, and / or condition (e.g., a cancer, a specific type of cancer), if its presence correlates with incidence of and / or susceptibility of the disease, disorder, and / or condition (e.g., across a relevant population).

[0180] Biomarker: The term “biomarker” typically refers to an entity, event, or characteristic whose presence, level, degree, type, and / or form, correlates with a particular biological event or state of interest, so that it is considered to be a “marker” of that event or state. To give but a few examples, in some embodiments, a biomarker may be or comprise a marker for a particular disease state, or for likelihood that a particular disease, disorder or condition may develop, occur, or reoccur. In some embodiments, a biomarker may be or comprise a marker for a particular disease or therapeutic outcome, or likelihood thereof. In some embodiments, a biomarker is predictive; in some embodiments, a biomarker is prognostic; in some embodiments, a biomarker is diagnostic, of the relevant biological event or state of interest. A biomarker may be or comprise an entity of any chemical class, and may be or comprise a combination of entities. For example, in some embodiments, a biomarker may be or comprise a nucleic acid, a polypeptide, a lipid, a carbohydrate, a small molecule, an inorganic agent (e.g., a metal or ion), or a combination thereof. In some embodiments, a biomarker is or comprises a portion of a particular molecule, complex, or structure; e.g., in some embodiments, a biomarker may be or comprise an epitope. In some embodiments, a biomarker is intracellular. In some embodiments, a biomarker is extracellular.

[0181] Cancer: The term “cancer” is used herein to generally refer to a disease or condition in which cells of a tissue of interest exhibit relatively abnormal, uncontrolled, and / or autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. In some embodiments, cancer may comprise cells that are precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and / or non-metastatic.

[0182] Detecting: The term “detecting” is used broadly herein to include appropriate means of determining the presence or absence of an entity of interest, e.g., a biomarker. Thus, “detecting” may include determining, measuring, assessing, or assaying the presence or absence, level, amount, and / or location of an entity of interest (e.g., a biomarker). In some embodiments, “detecting” includes determining, measuring, assessing, or quantifying a form of measurement indicative of an entity of interest (e.g., a biomarker). Quantitative and qualitative determinations, measurements or assessments are included, including semi-quantitative. Such determinations, measurements or assessments may be relative, for example when an entity of interest (e.g., a biomarker) or a form of measurement indicative thereof is being detected relative to a controlreference, or absolute. As such, the term “quantifying” when used in the context of quantifying an entity of interest (e.g., a biomarker) or a form of measurement indicative thereof can refer to absolute or to relative quantification. Absolute quantification may be accomplished by correlating a detected level of an entity of interest (e.g., a biomarker) or a form of measurement indicative thereof to known control standards (e.g., through generation of a standard curve). Alternatively, relative quantification can be accomplished by comparison of detected levels or amounts between two or more different entities of interest (e.g., two or more biomarkers, one or more biomarkers in two or more subjects, samples, and / or populations) to provide a relative quantification of each of the two or more different entities of interest, i.e., relative to each other.

[0183] Epitope: As used herein, the term “epitope” includes any moiety that is specifically recognized by an affinity agent (e.g., but not limited to, an antibody, affimer, and / or aptamer). In some embodiments, an epitope is comprised of a plurality of chemical atoms or groups on an antigen. In some embodiments, such chemical atoms or groups are surface-exposed when the antigen adopts a relevant three-dimensional conformation. In some embodiments, such chemical atoms or groups are physically near to each other in space when the antigen adopts such a conformation. In some embodiments, at least some such chemical atoms are groups are physically separated from one another when the antigen adopts an alternative conformation (e.g., is linearized).

[0184] In vitro: As used herein, the term “in vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within an organism (e.g., animal, plant and / or microbe).

[0185] In vivo: As used herein, the term “in vivo” refers to events that occur within an organism (e.g., animal, plant and / or microbe).

[0186] Nucleic acid: The term “nucleic acid”, as used herein, includes any nucleotides and polymers thereof. The term “polynucleotide”, as used herein, refers to a polymeric form of nucleotides of any length, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) or a combination thereof. These terms refer to the primary structure of the molecules and, thus, include double- and single-stranded DNA, and double- and single-stranded RNA. These terms include, as equivalents, analogs of either RNA or DNA comprising modified nucleotides and / ormodified polynucleotides, such as, though not limited to, methylated, protected and / or capped nucleotides or polynucleotides. The terms encompass poly- or oligo-ribonucleotides (RNA) and poly- or oligo-deoxyribonucleotides (DNA); RNA or DNA derived from N-glycosides or C- gly cosides of nucleobases and / or modified nucleobases; nucleic acids derived from sugars and / or modified sugars; and nucleic acids derived from phosphate bridges and / or modified internucleotidic linkages. The term encompasses nucleic acids containing any combinations of nucleobases, modified nucleobases, sugars, modified sugars, phosphate bridges or modified internucleotidic linkages. Examples include, and are not limited to, nucleic acids containing ribose moieties, nucleic acids containing deoxyribose moieties, nucleic acids containing both ribose and deoxyribose moieties, nucleic acids containing ribose and modified ribose moieties. Unless otherwise specified, the prefix poly- refers to a nucleic acid containing 2 to about 10,000 nucleotide monomer units and wherein the prefix oligo- refers to a nucleic acid containing 2 to about 200 nucleotide monomer units.

[0187] Polypeptide: The term “polypeptide”, as used herein, typically has its art-recognized meaning of a polymer of at least three amino acids or more. Those of ordinary skill in the art will appreciate that the term “polypeptide” is intended to be sufficiently general as to encompass not only polypeptides having a complete sequence recited herein, but also to encompass polypeptides that represent functional, biologically active, or characteristic fragments, portions or domains (e.g., fragments, portions, or domains retaining at least one activity) of such complete polypeptides. In some embodiments, polypeptides may contain L-amino acids, D-amino acids, or both and / or may contain any of a variety of amino acid modifications or analogs known in the art. Useful modifications include, e.g., terminal acetylation, amidation, glycosylation, lipidation, methylation, etc. In some embodiments, polypeptides may comprise natural amino acids, nonnatural amino acids, synthetic amino acids, and combinations thereof (e.g., may be or comprise peptidomimetics).

[0188] Reference: As used herein, “reference” describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence, or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing ordetermination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. In some embodiments, a reference or control in the context of a reference level of a target refers to a level of a target in a normal healthy subject or a population of normal healthy subjects. In some embodiments, a reference or control in the context of a reference level of a target refers to a level of a target in a subject prior to a treatment. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. In some embodiments, cell-line-derived extracellular vesicles are used as a reference or control. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0189] Sample: As used herein, the term “sample” typically refers to an aliquot of material obtained or derived from a source of interest. In some embodiments, a sample is obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest. In some embodiments, a source of interest may be or comprise a cell or an organism, such as an animal or human. In some embodiments, a sample may include blood; blood cells; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; cerebrospinal fluid; lymph; tissue biopsy specimens; surgical specimens; other body fluids, secretions, and / or excretions; and / or cells therefrom. In some embodiments, a source of interest is or comprises biological tissue or fluid. In some embodiments, a biological tissue or fluid may be or comprise amniotic fluid, aqueous humor, ascites, bile, bone marrow, blood, breast milk, cerebrospinal fluid, cerumen, chyle, chime, ejaculate, endolymph, exudate, feces, gastric acid, gastric juice, lymph, mucus, pericardial fluid, perilymph, peritoneal fluid, pleural fluid, pus, rheum, saliva, sebum, semen, serum, smegma, sputum, synovial fluid, sweat, tears, urine, vaginal secretions, vitreous humour, vomit, and / or combinations or component(s) thereof. In some embodiments, a biological fluid may be or comprise an intracellular fluid, an extracellular fluid, an intravesicular fluid (blood plasma), an interstitial fluid, a lymphatic fluid, and / or a transcellular fluid. In some embodiments, a biological tissue or sample may be obtained, for example, by aspirate, biopsy (e.g., fine needle or tissue biopsy), swab (e.g., oral, nasal, skin, or vaginal swab), scraping, surgery, washing or lavage (e.g., bronchoalveolar, ductal, nasal, ocular, oral, uterine, vaginal, or other washing or lavage). In some embodiments, a sample is or comprises a liquid biopsy. Insome embodiments, a sample is or comprises cells obtained from an individual. In some embodiments, a sample is or comprises a tumor specimen. In some embodiments, a sample is or comprises a tumor biopsy. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and / or by adding one or more agents to) a primary sample. For example, a sample is a preparation that is processed by using a semi-permeable membrane or an affinity-based method such antibody-based method to separate a biological entity of interest from other non-target entities. Such a “processed sample” may comprise, for example, in some embodiments extracellular vesicles, while, in some embodiments, nucleic acids and / or proteins, etc., extracted from a sample. In some embodiments, a processed sample can be obtained by subjecting a primary sample to one or more techniques such as amplification or reverse transcription of nucleic acid, isolation and / or purification of certain components, etc.

[0190] Subject: As used herein, the term “subject” or “test subject” refers to any organism to which a compound (e.g., an oligonucleotide) or composition is administered in accordance with the present disclosure e.g., for experimental, diagnostic, prophylactic and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, nonhuman primates, and humans; insects; worms; etc.) and plants. In some embodiments, a subject is a human. In some embodiments, a subject may be suffering from and / or susceptible to a disease, disorder, and / or condition. In some embodiments, a subject may be suffering from and / or susceptible to a cancer. In some embodiments, a subject displays one or more symptoms of a disease, disorder, and / or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and / or therapy is and / or has been administered.

[0191] Suffering from: An individual who is “suffering from” a disease, disorder, and / or condition has been diagnosed with and / or displays one or more symptoms of a disease, disorder, and / or condition.

[0192] Susceptible to: An individual who is “susceptible to” a disease, disorder, and / or condition is one who has a higher risk of developing the disease, disorder, and / or condition thandoes a member of the general public. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may not have been diagnosed with the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may not exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will develop the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will not develop the disease, disorder, and / or condition.

[0193] Therapeutically effective amount: As used herein, the term “therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of compound in a formulation to treat a disease, disorder, and / or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and / or reduces incidence of one or more symptoms or features of the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.

[0194] Threshold level: As used herein, “threshold level” refers to a level that is used as a reference to attain information on and / or classify the results of a measurement, for example, the results of a measurement attained in an assay. For example, in some embodiments, a threshold level (e.g., a cutoff) means a value measured in an assay that defines the dividing line between two subsets of a population (e.g., high immune-related GES versus low immune-related GES, high NRF2 pathway signature versus low NRF2 pathway signature). Thus, a value that is equalto or higher than the threshold level defines one subset of the population, and a value that is lower than the threshold level defines the other subset of the population. A threshold level can be determined based on one or more samples, e.g., control samples, or across a population of samples, e.g., control samples. A threshold level can be determined prior to, concurrently with, or after the measurement of interest is taken. In some embodiments, a threshold level is a median, e.g., a median level of a measurement in a population, e.g., a population of subjects and / or a population of samples.

[0195] Treat: As used herein, the term “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who is suffering from a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who is suffering from a cancer.

[0196] Wild-type: As used herein, the term “wild-type” has its art-understood meaning that refers to an entity having a structure and / or activity as found in nature in a “normal” (as contrasted with mutant, diseased, altered, etc.) state or context. Those of ordinary skill in the art will appreciate that wild type genes and polypeptides often exist in multiple different forms (e.g., alleles).EXAMPLES

[0197] Certain examples of provided technologies (methods, etc.) are presented herein.Those skilled in the art appreciate that many technologies can be utilized to assess the provided technologies in accordance with the present disclosure.Example 1. PD-L1 Expression and Tumor Mutational Burden were not Predictive of Responsiveness to Cancer Treatment comprising an Anti-PD-1 Antibody and Chemotherapy

[0198] Patients in the RATIONALE 307 (NCT03594747) study were examined for biomarkers indicative of responsiveness to treatment with an anti-PD-1 antibody, tislelizumab in combination with chemotherapy comprising paclitaxel and carboplatin. Briefly, patients in the RATIONALE 307 study were individuals with either locally advanced or metastatic lung squamous cell carcinoma (LUSC). Following initial randomization, patients were randomized to receive (i) tislelizumab plus paclitaxel and carboplatin, (ii) tislelizumab plus nab-paclitaxel and carboplatin, or (iii) paclitaxel and carboplatin. A total of 355 patients received one of the aforementioned treatments, with 238 receiving tislelizumab plus chemotherapy (i.e., paclitaxel and carboplatin or nab-paclitaxel and carboplatin) and 117 patients receiving chemotherapy (i.e., paclitaxel and carboplatin) alone. Patient samples (e.g., blood samples, tumor specimens) were collected and various assays (e.g., PD-L1 expression assay using immunohistochemistry, gene expression profiling using RNA sequencing) were used to evaluate biomarkers.

[0199] As shown in Figures 1A-C, PD-L1 expression did not significantly predict responsiveness to treatment with tislelizumab plus chemotherapy as measured by progression free survival (PFS). Although patients with PD-L1 positive (PD-L1 > 1% tumor cell expression) tumors did display a trend towards prolonged PFS, a significant interaction was not observed (p = 0.143). Less stringent PD-L1 expression cutoffs did not result in any increased likelihood of prolonged PFS. Similarly, neither tissue tumor mutational burden (tTMB) or blood tumor mutational burden (bTMB) significantly predicted responsiveness to treatment with tislelizumab plus chemotherapy as measured by PFS. As shown in Figures 2A-C, a cutoff of >10 mutations per megabase (mut / Mb) for tTMB only displayed a hazard ratio (HR) of 0.44 (interaction p = 0.463). As shown in Figures 3A-C, regardless of the cutoff used for bTMB, the prognostic value of the bTMB was not statistically significant (with interaction p > 0.2 for all cutoffs).Accordingly, usage of PD-L1 expression, tTMB, or bTMB did not demonstrate predictive value in determining responsiveness to treatment with tislelizumab plus chemotherapy.Example 2. An Immune-Related GES is Predicative of Responsiveness to Cancer Treatment comprising an Anti-PD-1 Antibody and Chemotherapy

[0200] Patients in the RATIONALE 307 (NCT03594747) study were examined for biomarkers indicative of responsiveness to treatment with an anti-PD-1 antibody, tislelizumab in combination with chemotherapy comprising paclitaxel and carboplatin. As described in Example 1, patient tumor specimens were collected and analyzed for gene expression using RNA sequencing.

[0201] Based on the gene expression profiles constructed from the patient tumor specimen sequencing, a total of 32 genes were identified as significantly associated with prolonged PFS upon treatment with tislelizumab in combination with paclitaxel and carboplatin as compared to treatment with only paclitaxel and carboplatin. From these 32 genes, a subset of 11 genes (IFIT1, OAS2, SP110, JAK2, STAT1, EPSTI1, SLAMF8, IL7R, CCL4 HLA.A, and SELPLG) were used as biomarkers to build an immune-related GES. The predictive value of these eleven biomarkers are displayed in Figure 4, with the most predictive (i.e., smallest interaction p value) biomarker listed at top. All eleven biomarkers exhibited an interaction p value of < 0.025 - indicating that patients with high (e.g., > median) expression of the gene displayed prolonged PFS as compared to those patients with low (e.g., < median) expression of the gene.

[0202] Patients who displayed a high level of the immune-related GES exhibited prolonged PFS when receiving tislelizumab plus chemotherapy as compared to those patients that were administered the chemotherapy alone (Figure 6A). On the other hand, those patients with a low level of the immune-related GES displayed limited differences in PFS whether receiving tislelizumab plus chemotherapy or chemotherapy alone (Figure 6B). Further, as shown in Figure 5, the immune-related GES demonstrated greater or comparable predictive effect of responsiveness to treatment with tislelizumab plus chemotherapy as compared to other previously published gene signatures, including an 18-gene T cell-inflamed signature (TIS), IMpower 131 T effector (Teff) signature, JAVELIN Renal 101 Immuno signature, and a 4-gene inflammation signature (4-gene GES). In some embodiments, an immune-related GES is predictive of responsiveness to a cancer treatment comprising, e.g., a PD-1 inhibitor (e.g., tislelizumab) and one or more therapeutic agents (e.g., paclitaxel and carboplatin). In some embodiments, a subject is classified as responsive to a cancer treatment if an elevated level of an immune-related GES is detected in a sample (e.g., a tumor specimen) from the subject as compared to a threshold level of the immune-related GES. In some embodiments, a subject with an elevated level of an immune-related GES exhibits prolonged PFS, or an increased likelihood of PFS, as compared to a reference subject.Example 3. NRF2 Pathway Mutations and a NRF Pathway Signature is Predicative of Resistance to Cancer Treatment comprising an Anti-PD-1 Antibody and Chemotherapy

[0203] Patients in the RATIONALE 307 (NCT03594747) study were examined for biomarkers indicative of responsiveness to treatment with an anti-PD-1 antibody, tislelizumab in combination with chemotherapy comprising paclitaxel and carboplatin. As described in Example 1, patient tumor specimens were collected and analyzed for gene expression using RNA sequencing.

[0204] Patient samples were analyzed for mutations in various oncogenic pathways, e.g., TP53, PI3K, cell-cycle, NRF2, and Wnt pathways. Mutations in the TP53, PI3K, or cell-cycle pathways were not predictive of PFS in patients treated with tislelizumab plus chemotherapy or chemotherapy alone. The absence of one or more activating mutations in the NRF2 pathway, e.g., gain of function mutations in NFE2L2 and / or loss of function mutations in KEAP1 and / or CUL3, were associated with responsiveness to treatment with tislelizumab plus chemotherapy as assessed by prolonged PFS as compared to treatment with chemotherapy alone, as shown in Figure 7A. Conversely, the presence of one or more activating mutations in the NRF2 pathway was associated with a lack of prolonged PFS for treatment with tislelizumab plus chemotherapy as compared to treatment with chemotherapy alone, as shown in Figure 7B. In some embodiments, one or more activating NRF2 pathway mutations are detected in a sample from the subject.

[0205] Tumor specimens from patients were also examined for a NRF2 pathway signature comprising G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HM0X1, CXCR7, CES1, CCND3, ASF1 A, ABCG2, and ABCC2. Patients with one or more activating mutations in the NRF2 pathway had a significantly higher level of the NRF2 pathway signature, as shown in Figure 9. Moreover, as depicted in Figures 8A-B, patients with a low level of the NRF2 pathway signature showed increased prolonged PFS benefit from treatmentwith tislelizumab plus chemotherapy as compared to patients with a high level of the NRF2 pathway signature.

[0206] Patients were further analyzed according to stratification based on the combination of (i) level of the NRF2 pathway signature and (ii) either PD-L1 expression level, tTMB, or level of an immune-related GES as described in Example 3. As shown in Figure 10A, a high level of NRF2 pathway signature was associated with lessened PFS benefit within patients with tumors positive for PD-L1 expression, and likewise, as shown in Figure 10B, a high level of NRF2 pathway signature was associated with lessened PFS benefit within patients with high tTMB. The immune-related GES was indicative of significant PFS benefit regardless of a high or low level of NRF2 pathway signature, as depicted in Figure 10C.Example 4. An Immune-Related GES is Predictive of Responsiveness to Cancer Treatment comprising an Anti-PD-Ll Antibody and an Anti-VEGFR Therapeutic

[0207] An immune-related GES comprising IFIT1, OAS2, SP110, JAK2, STAT1, EPSTI1, SLAMF8, IL7R, CCL4 HLA. A, and SELPLG biomarkers was examined in patients from the JAVELIN Renal 101 study. In the JAVELIN Renal 101 study, patients with a kidney cancer, renal cell carcinoma (RCC) were treated with either an anti-PD-Ll antibody, avelumab plus an anti-VEGFR therapeutic, axitinib or an anti-VEGFR therapeutic, sunitinib alone (NCT02684006; Motzer, R. J. et al. Nat Med. 2020 Nov;26(l 1): 1733-1741). Whole-transcriptome profiles, previously generated in the course of the JAVELIN Renal 101 study using RNA sequencing (RNA-seq) of tumor specimens obtained from the patients, were assessed for biomarkers including IFIT1, OAS2, SP110, JAK2, STAT1, EPSTI1, SLAMF8, IL7R, CCL4, HLA.A, and SELPLG to form an immune-related GES for each patient. Median immune-related GES of the population of examined patients was used as a threshold to group patients as either high immune- related GES (> median GES) or low immune-related GES (< median GES).

[0208] The progression free survival (PFS) of patients in each group (high immune-related GES, low immune-related GES) was examined according to treatment arm (avelumab plus axitinib versus sunitinib alone) using Kaplan-Meier analysis. A two-sided stratified Kaplan- Meier log-rank test was also performed between treatment arms for each group. As shown inFigures 11 A and 1 IB, patients with high immune-related GES displayed significantly greater benefit from treatment with avelumab plus axitinib versus sunitinib alone as compared to patients with low immune-related GES. The hazard ratio (HR) for treatment with avelumab plus axitinib versus sunitinib alone was 0.49 (p = 0.006) for patients with high immune-related GES as compared to 0.85 (p = 0.263) for patients with low immune-related GES. Accordingly, the analysis of PFS in patients with RCC confirmed that patients with high immune-related GES were more responsive to treatment with anti-PD-Ll antibody plus an anti -VEGFR therapeutic versus an anti -VEGFR therapeutic alone, as compared to patients with low immune-related GES. In some embodiments, an immune-related GES is predictive of responsiveness to a cancer treatment comprising, e.g., a PD-L1 inhibitor (e.g., an anti-PD-Ll antibody) and one or more therapeutic agents (e.g., an anti-VEGFR therapeutic). In some embodiments, a subject is classified as responsive to a cancer treatment if an elevated level of an immune-related GES is detected in a sample (e.g., a tumor specimen) from the subject as compared to a threshold level of the immune-related GES. In some embodiments, a subject with an elevated level of an immune-related GES exhibits prolonged PFS, or an increased likelihood of PFS, as compared to a reference subject.Example 5. Treatment of Subjects with Tumors comprising MSI-H and dMMR Biomarkers

[0209] Subjects with previously treated, locally advanced unr esectable or metastatic MSI-H / dMMR tumors were treated with tislelizumab monotherapy in a clinical study, RATIONALE- 209. In the RATIONALE-209 study, human adults with previously treated, locally advanced unresectable or metastatic histologically confirmed MSLH / dMMR solid tumors were enrolled and treated. MSI-H biomarker was confirmed by polymerase chain reaction (PCR) test-based confirmation of the presence of 2 or more altered mononucleotide repeat markers with 3 or more base pairs change in length. Enrolled subjects were suffering from colorectal cancer, endometrial cancer, gastric or gastroesophageal junction cancer, small bowel adenocarcinoma, ampullary carcinoma, cervical cancer, ovarian cancer, or pelvis clear cell carcinoma. A total of 80 subjects were part of the clinical study, and a total of 79 subjects had received prior anticancertherapy. Prior anticancer therapies administered to subjects included radiation, fluoropyrimidines, oxaliplatin, irinotecan, taxane, bevacizumab, carboplatin, cisplatin, cetuximab, apatinib, endostatin, ramucirumab, etc. All subjects received tislelizumab 200 mg intravenously every three weeks until progressive disease, unacceptable toxicity, or withdrawal of consent.

[0210] Throughout the clinical study, subjects were assessed using computed tomography or magnetic resonance imaging (MRI) to perform tumor imaging. Any subjects which received at least one dose of tislelizumab and had baseline measurable disease were included in statistical analyses as the efficacy- evaluable population. Overall survival and safety analyses utilized all subjects who received one or more doses of tislelizumab. Certain results are shown in Figure 12, Figure 13A, and Figure 13B.

[0211] As shown in Figure 12, a majority of subjects, in the efficacy-evaluable population, exhibited a reduction in total target lesion diameter during the course of the study. Further, a majority of subjects, in the efficacy- evaluable population, with colorectal cancer, endometrial cancer, cervical cancer, ovarian cancer, small bowel adenocarcinoma, gastric or gastroesophageal cancer, or pelvis clear cell carcinoma exhibited a reduction in total target lesion diameter during the course of the study. As shown in Figure 13A and Figure 13B, progression free survival rate at 12 months from start of treatment was approximately 59.8% for all cancer types, and overall survival rate at 12 months from start of treatment was approximately 76.9% for all cancer types.

[0212] In some embodiments, a subject with a tumor comprising a GES comprising an MSI- H biomarker and / or a dMMR biomarker is responsive to treatment with a cancer treatment comprising tislelizumab. In some embodiments, a subject with a tumor comprising a GES comprising an MSI-H biomarker and / or a dMMR biomarker is responsive to a treatment with a cancer treatment comprising tislelizumab. In some embodiments, a subject who has received a prior cancer treatment, e.g., a cancer treatment described herein, and with a tumor comprising a GES comprising an MSI-H biomarker and / or a dMMR biomarker is responsive to a treatment with a cancer treatment comprising tislelizumab.Example 6. Treatment of Subjects with HER2-negative Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

[0213] Subjects with HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal adenocarcinoma (G / GEJC) were treated with tislelizumab in combination with chemotherapy or placebo in combination with chemotherapy in a clinical study, RATIONALE 305. In the RATIONALE 305 study, human adults with HER2-negative locally advanced unresectable or metastatic G / GEJC were enrolled and treated. Subjects were randomized (1: 1) and stratified by region, PD-L1 expression, presence or absence of peritoneal metastases, and investigator’s choice of chemotherapy to receive tislelizumab 200 mg intravenously every three weeks in combination with the chemotherapy or matching placebo intravenously every three weeks in combination with the chemotherapy. Chemotherapy options included oxaliplatin and capecitabine or cisplatin and 5 -fluorouracil. Subjects were required to not have been previously treated with systemic therapy for advanced disease. PD-L1 expression was assessed by tumor area positivity scoring. Treatment continued until disease progression or unacceptable toxicity.

[0214] Throughout the clinical study, subjects were assessed using computed tomography or magnetic resonance imaging (MRI) to perform tumor imaging. Efficacy analyses were conducted in all randomized subjects with PD-L1 score >5% and in all randomized subjects. The overall survival (OS) and progression free survival (PFS) of subjects was examined according to treatment arm (tislelizumab plus chemotherapy versus placebo plus chemotherapy) using Kaplan-Meier analysis. Certain results are shown in Figure 14A, Figure 14B, Figure 15A, and Figure 15B.

[0215] As shown in Figure 14A and Figure 14B, in all randomized subjects, those who were administered tislelizumab in combination with chemotherapy displayed increased PFS and OS as compared to subjects who were administered placebo in combination with chemotherapy. The PFS hazard ratio (HR) for treatment with tislelizumab plus chemotherapy versus placebo plus chemotherapy was 0.78 (95% CI: 0.67, 0.90); the OS HR for treatment with tislelizumab plus chemotherapy versus placebo plus chemotherapy was 0.80 (95% CI: 0.70, 0.92; p=0.0011). Furthermore, as shown in Figure 15A and Figure 15B, in the population of subjects with a PD- L1 score >5%, those who were administered tislelizumab in combination with chemotherapyalso displayed increased PFS and OS as compared to subjects who were administered placebo in combination with chemotherapy. Accordingly, the analysis of subjects with HER2-negative locally advanced unresectable or metastatic G / GEJC confirmed that treatment of tislelizumab plus chemotherapy increased PFS and OS - in both all randomized subjects as well as the population of subjects with a PD-L1 score >5%.

[0216] Overall survival was also examined in the population of subjects with MSI-H and dMMR biomarkers (N=40). Of those subjects with MSI-H / dMMR tumors, 11 received tislelizumab plus chemotherapy and 14 received placebo plus chemotherapy. For the \ of subjects with MSI-H and dMMR biomarkers, the hazard ratio for overall survival - as analyzed using an unstratified Cox regression model with treatment as a covariate - was 0.66 (95% CI: 0.30, 1.43). Among the population of subjects with MSI-H / dMMR tumors and a PD-L1 score >5% (N=25), the corresponding hazard ratio for overall survival was 0.48 (95% CI: 0.18, 1.29). Accordingly, subjects with MSI-H / dMMR tumors demonstrated favorability for response to treatment with tislelizumab plus chemotherapy as opposed to chemotherapy alone (e.g., placebo plus chemotherapy). In some embodiments, a subject with a tumor comprising a GES comprising an MSI-H biomarker and / or a dMMR biomarker is responsive to treatment with a cancer treatment comprising tislelizumab. In some embodiments, a subject with a tumor comprising a GES comprising an MSI-H biomarker and / or a dMMR biomarker is responsive to a treatment with a cancer treatment comprising tislelizumab. In some embodiments, a subject who has received a prior cancer treatment, e.g., a cancer treatment described herein, and with a tumor comprising a GES comprising an MSI-H biomarker and / or a dMMR biomarker is responsive to a treatment with a cancer treatment comprising tislelizumab.Example 7. Efficacy and safety of tislelizumab + chemotherapy vs placebo + chemotherapy in HER2-negative advanced or metastatic gastric or gastroesophageal junction adenocarcinoma.

[0217] Methods. Adults with locally advanced, non-resectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative, untreated GC / GEJC were randomized (1 :1) to intravenous tislelizumab (TIS) 200 mg or PBO every 3 weeks plus investigator-chosen chemo (oxaliplatin + capecitabine or cisplatin + 5 -fluorouracil). The primary endpoint in the main studywas OS in all randomized patients and patients with PD-L1 TAP score >5% (PD-L1 positive). TAP score was evaluated in tumor tissues using the VENTANA PD-L1 (SP263) assay. Secondary endpoints included investigator-assessed progression-free survival (PFS), objective response rate (ORR), duration of response per Response Evaluation Criteria in Solid Tumors vl.l, and safety assessments.

[0218] Results. A total of 516 Chinese patients were randomized (TIS + chemo, n=259; PBO + chemo, n=257). The median age was 59.0 years and 69.4% were male. At study entry, 99.0% (511 / 516) of patients had metastatic disease, with >3 metastatic sites in 37.2% (192 / 516) of patients and peritoneal metastasis in 39.9% (206 / 516) of patients. 133 (51.4%) patients in the US + chemo group and 132 (51.4%) patients in the PBO + chemo group had PD-L1 TAP score >5% (PD-L1 positive analysis set). After a minimum follow-up of 27.5 months, TIS + chemo vs PBO + chemo resulted in a median OS of 15.7 months (95% CI: 13.9, 18.4) vs 13.0 months (95% CI: 11.9, 14.3), HR, 0.77; 95% CI: 0.63, 0.93 (Table 1). A PFS improvement was observed in the TIS + chemo group vs the PBO + chemo group (HR, 0.73; 95% CI: 0.60, 0.89). TIS + chemo also demonstrated an OS benefit vs PBO + chemo in patients with PD-L1 TAP score >5%, with a median OS of 18.4 months (95% CI: 14.1, 23.2) vs 12.5 months (95% CI: 10.5, 14.4), HR, 0.63; 95% CI: 0.48, 0.83 (Table). Additional main efficacy results are presented in Table 1.

[0219] Grade >3 treatment-related adverse events (TRAEs) related to TIS / PBO were similar between groups, occurring in 25.6% (66 / 258) of patients receiving TIS + chemo and 21.6% (55 / 255) of patients receiving PBO + chemo. TRAEs leading to discontinuation were reported in 17.4% vs 9.8% of patients in the TIS + chemo and the PBO + chemo groups, and TRAEs leading to death, excluding death due to disease under study, were reported in 1.6% and 0.8% of patients in the TIS + chemo and the PBO + chemo groups, respectively.Table 1: Efficacy Outcomes in the Chinese SubgroupaUnstratified.bInvestigator-evaluated. Data cutoff: 28 February 2023. CI, confidence interval; chemo, chemotherapy; DoR, duration of response; HR, hazard ratio; ORR, objective response rate; OS, overall survival; PBO, placebo; PD-L1, programmed deathligand 1; PFS, progression-free survival; FIS, tislelizumab.

[0220] Conclusions. In the subgroup of Chinese patients with advanced GC / GEJC from the RATIONALE-305 study, US + chemo demonstrated clinically meaningful improvements in OS, PFS, and ORR compared with PBO + chemo, with no new safety signals. These findings are consistent with published results in the overall study population.

[0221] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.

[0222] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scopeof the claimed technology. Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.

[0223] The present disclosure is not to be limited in terms of the particular embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, or compositions, which can of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0224] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0225] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

[0226] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[0227] Other embodiments are set forth in the following claims.

Claims

CLAIMS1. A method comprising steps of:(a) providing or obtaining a sample from a subject having cancer;(b) testing for or detecting an immune-related gene expression signature (GES) in the sample, wherein the immune-related GES comprises one or more biomarkers chosen from one, two, three, or more of:(i) an anti-viral response biomarker chosen from one or both of IFIT1 and OAS2:(ii) an interferon signaling biomarker chosen from one, two, or more of SP110, JAK2, and STATE,(iii) a macrophage regulation biomarker chosen from one or both of EPSTH and SI M 8’ and(iv) a T cell-related function biomarker chosen from one, two, three, or more of IL7R, CCL4, HI A A, and SELPLG,(c) comparing a level of the immune-related GES in the sample to a threshold level of the immune-related GES; and(d) classifying the subject as responsive to a cancer treatment when the sample exhibits an elevated level of the immune-related GES relative to the threshold level of the immune-related GES, wherein the cancer treatment comprises a pharmaceutical composition comprising a PD-1 or PD-Ll inhibitor.

2. A method of determining responsiveness of a subject having cancer to a cancer treatment comprising:(a) providing or obtaining a sample from the subject;(b) testing for or detecting an immune-related gene expression signature (GES) in the sample, wherein the immune-related GES comprises one or more biomarkers chosen from one, two, three, or more of:(i) an anti-viral response biomarker chosen from one or both of IFIT1 and ()AS2(ii) an interferon signaling biomarker chosen from one, two, or more of SP110, JAK2, and STATE,(iii) a macrophage regulation biomarker chosen from one or both of EPSTH and SLAMF8,- and(iv) a T cell-related function biomarker chosen from one, two, three, or more of IL7R, CCL4, HLA.A, and SELPLG,(c) comparing a level of the immune-related GES in the sample to a threshold level of the immune-related GES; and(d) classifying the subject as responsive to a cancer treatment when the sample exhibits an elevated level of the immune-related GES relative to the threshold level of the immune-related GES, wherein the cancer treatment comprises a pharmaceutical composition comprising a PD-1 or PD-Ll inhibitor.

3. The method of claim 1 or 2, further comprising administering the cancer treatment to the subject if the subject is classified as responsive to the cancer treatment.

4. A method of treating a subject having cancer comprising administering a cancer treatment, wherein the subject has been determined to be responsive to the cancer treatment by a method comprising:(a) providing or obtaining a sample from the subject;(b) testing for or detecting an immune-related gene expression signature (GES) in the sample, wherein the immune-related GES comprises one or more biomarkers chosen from one, two, three, or more of:(i) an anti-viral response biomarker chosen from one or both of IFIT1 and OAS2:(ii) an interferon signaling biomarker chosen from one, two, or more of SP110, JAK2, and STATE,(iii) a macrophage regulation biomarker chosen from one or both of EPSTH and SLAMF8,- and(iv) a T cell-related function biomarker chosen from one, two, three, or more of IL7R, CCL4, HLA.A, and SELPLG,(c) comparing a level of the immune-related GES in the sample to a threshold level of the immune-related GES; and(d) classifying the subject as responsive to the cancer treatment when the sample exhibits an elevated level of the immune-related GES relative to the threshold level of the immune-related GES, wherein the cancer treatment comprises a pharmaceutical composition comprising a PD-1 or PD-Ll inhibitor.

5. A method of treating a subject having cancer comprising:(a) providing or obtaining a sample from a subject having cancer;(b) testing for or detecting an immune-related gene expression signature (GES) in the sample, wherein the immune-related GES comprises one or more biomarkers chosen from one, two, three, or more of:(i) an anti-viral response biomarker chosen from one or both of IFIT1 and OAS2,'(ii) an interferon signaling biomarker chosen from one, two, or more of SP110, JAK2, and STAT ,(iii) a macrophage regulation biomarker chosen from one or both of EPSTH and SLAMF8,- and(iv) a T cell-related function biomarker chosen from one, two, three, or more of IL7R, CCL4, HLA.A, and SELPLG,(c) comparing a level of the immune-related GES in the sample to a threshold level of the immune-related GES;(d) classifying the subject as responsive to a cancer treatment when the sample exhibits an elevated level of the immune-related GES relative to the threshold level of the immune-related GES; and(e) administering the cancer treatment to the subject if the subject is classified as responsive to the cancer treatment,wherein the cancer treatment comprises a pharmaceutical composition comprising a PD-1 or PD-Ll inhibitor.

6. The method of any one of claims 1-5, wherein the cancer treatment further comprises one or more pharmaceutical compositions comprising one or more therapeutic agents.

7. The method of any one of claims 1 -6, wherein the threshold level of the immune-related GES is a predetermined mean or median level of the immune-related GES of a population of samples provided or obtained from a population of subjects.

8. The method of any one of claims 1-6, wherein the threshold level of the immune-related GES is a level of the immune-related GES in a second sample.

9. The method of any one of claims 1-8, further comprising testing for or detecting a NRF2 pathway signature in a sample provided or obtained from the subject, wherein the NRF2 pathway signature comprises one or more biomarkers chosen from one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more of G6PD, TGFB2, TFRC, SPP1, SERPINE1, RRM2, NEIL3, MCM10, IDH1, HMOX1, CXCR7, CES1, CCND3, ASF1A, ABCG2, and ABCC2.

10. The method of claim 9, further comprising comparing a level of the NRF2 pathway signature in the sample to a threshold level of the NRF2 pathway signature.

11. The method of any one of claims 1-10, further comprising testing for or detecting one or more activating NRF2 pathway mutations in a sample provided or obtained from the subject.

12. The method of claim 11 , wherein the one or more activating NRF2 pathway mutations comprise or are one, two, or more of:(i) one or more gain of function mutations in NFE2L2(ii) one or more loss of function mutations in KEAPP, or(iii) one or more loss of function mutations in CUL3.

13. The method of any one of claims 9-12, wherein the threshold level of the NRF2 pathway signature is a predetermined mean or median level of the NRF2 pathway signature of a population of samples provided or obtained from a population of subjects.

14. The method of claim 7 or 13, wherein the population of subjects is a population of healthy subjects.

15. The method of claim 7 or 13, wherein the population of subjects is a population of subjects diagnosed with a benign tumor.

16. The method of claim 7 or 13, wherein the population of subjects is a population of subjects diagnosed with the cancer.

17. The method of any one of claims 9-12, wherein the threshold level of the NRF2 pathway signature is a level of the NRF2 pathway signature in a second sample.

18. The method of claim 8 or 17, wherein the second sample is from the subject prior to administration of a cancer treatment.

19. The method of claim 8 or 17, wherein the second sample is from the subject after administration of at least one cancer treatment.

20. The method of claim 19, wherein at least once cancer treatment comprises 1, 2, 3, 4, 5, or more cancer treatments.

21. The method of claim 8 or 17, wherein the second sample is from a second subject.

22. The method of claim 21, wherein the second subject is a healthy subject or a subject diagnosed with a benign tumor.

23. The method of any one of 1-22, wherein the elevated level of the immune- related GES is at least about 25%, 50%, or 75% higher than the threshold level of the immune-related GES.

24. The method of any one of claims 1-23, wherein the cancer comprises or is a lung cancer.

25. The method of claim 24, wherein the lung cancer comprises or is non-small cell lung cancer (NSCLC).

26. The method of claim 25, wherein the NSCLC comprises or is lung squamous cell carcinoma (LUSC) or lung adenocarcinoma (LU AD).

27. The method of any one of claims 1-23, wherein the cancer comprises or is a liver cancer.

28. The method of claim 27, wherein the liver cancer comprises or is hepatocellular carcinoma (HCC).

29. The method of any one of claims 1-23, wherein the cancer comprises or is a head and neck cancer.

30. The method of claim 29, wherein the head and neck cancer comprises or is a head and neck squamous cell carcinoma (HNSCC).

31. The method of any one of claims 1-23, wherein the cancer comprises or is a nasopharynx cancer.

32. The method of claim 31, wherein the cancer comprises or is nasopharyngeal carcinoma (NPC).

33. The method of any one of claims 1-23, wherein the cancer comprises or is an esophageal cancer.

34. The method of claim 33, wherein the esophageal cancer comprises or is an esophageal squamous cell carcinoma (ESCC).

35. The method of any one of claims 1-23, wherein the cancer comprises or is a gastric cancer.

36. The method of any one of claims 1-23, wherein the cancer comprises or is a colorectal cancer.

37. The method of any one of claims 1-23, wherein the cancer comprises or is a skin cancer.

38. The method of claim 37, wherein the skin cancer comprises or is a melanoma.

39. The method of any one of claims 1-23, wherein the cancer comprises or is an ovarian cancer.

40. The method of any one of claims 1-23, wherein the cancer comprises or is an urothelial bladder cancer.

41. The method of any one of claims 1-23, wherein the cancer comprises or is a kidney cancer.

42. The method of claim 41, wherein the kidney cancer comprises or is a renal cell carcinoma (RCC).

43. The method of any one of claims 1-42, wherein the cancer is an advanced stage cancer.

44. The method of any one of claims 1-43, wherein responsive to the cancer treatment comprises prolonged progression free survival (PFS) as compared to a reference subject or an increased likelihood of prolonged PFS as compared to a reference subject.

45. The method of any one of claims 1-44, wherein responsive to the cancer treatment comprises increased objective response rate (ORR) as compared to a reference subject or an increased likelihood of increased ORR as compared to a reference subject.

46. The method of any one of claims 1-45, wherein responsive to the cancer treatment comprises increased duration of response (DOR) as compared to a reference subject or an increased likelihood of increased DOR as compared to a reference subject.

47. The method of any one of claims 44-46, wherein one, two, or more of PFS, ORR, or DOR is measured according to Response Evaluation Criteria in Solid Tumors (RECIST).

48. The method of any one of claims 1-47, wherein responsive to the cancer treatment comprises prolonged overall survival (OS) as compared to a reference subject or an increased likelihood of prolonged OS as compared to a reference subject.

49. The method of any one of claims 1 -47, wherein responsive to the cancer treatment comprises increased health-related quality of life (HRQoL) as compared to a reference subject or an increased likelihood of increased HRQoL as compared to a reference subject.

50. The method of claim 49, wherein HRQoL is measured using one or both of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13) or European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30).

51. The method of any one of claims 44-50, wherein the reference subject was administered the one or more pharmaceutical compositions comprising the one or more therapeutic agents.

52. The method of any one of claims 44-51, wherein the reference subject was administered the PD-1 or PD-Ll inhibitor.

53. The method of any one of claims 44-51, wherein the reference subject was not administered the PD- 1 or PD-Ll inhibitor.

54. The method of any one of claims 44-53, wherein the reference subject exhibits one, two, or more of:(i) a lower level of the immune-related GES as compared to the threshold level of the immune-related GES detected in a reference sample provided or obtained from the reference subject;(ii) an elevated level of the NRF2 pathway signature as compared to the threshold level of the NRF2 pathway signature detected in a reference sample provided or obtained from the reference subject; or(iii) one or more activating NRF2 pathway mutations detected in a reference sample provided or obtained from the reference subject.

55. The method of any one of claims 1-54, wherein the sample comprises or is a tumor specimen.

56. The method of any one of claims 1-55, wherein the sample comprises polynucleotides.

57. The method of claim 56, wherein the polynucleotides comprise one or both of DNA or RNA.

58. The method of claim 56 or 57, wherein the polynucleotides are tested for or detected by performing one, two, three, four, five, or more of quantitative PCR, reverse-transcription PCR, in situ hybridization, in vitro hybridization, microarray, or nucleic acid sequencing.

59. The method of claim 58, wherein nucleic acid sequencing comprises one or both of nextgeneration sequencing or whole-genome sequencing.

60. The method of any one of claims 1-59, wherein the PD-1 or PD-L1 inhibitor comprises or is a PD- 1 inhibitor.

61. The method of any one of claims 60, wherein the PD-1 inhibitor comprises or is an anti- PD-1 antibody or antigen-binding fragment thereof.

62. The method of claim 61, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises or is tislelizumab.

63. The method of any one of claims 1-59, wherein the PD-1 or PD-L1 inhibitor comprises or is a PD-L1 inhibitor.

64. The method of claim 63, wherein the PD-L1 inhibitor comprises or is an anti-PD-Ll antibody or antigen-binding fragment thereof.

65. The method of any one of claims 6-64, wherein the one or more therapeutic agents comprise or are one or both of:(i) one or more chemotherapeutic agents; or(ii) one or more antibodies or antigen-binding fragments thereof.

66. The method of claim 65, wherein the one or more chemotherapeutic agents comprise or are one or both of paclitaxel or carboplatin.

67. The method of claim 66, wherein paclitaxel is in one or more forms.

68. The method of claim 67, wherein the one or more forms comprises solvent-based paclitaxel.

69. The method of claim 67, wherein the one or more forms comprises nanoparticle albuminbound paclitaxel.

70. The method of claim 65, wherein the one or more chemotherapeutic agents comprise or are an anti-vascular endothelial growth factor receptor (VEGFR) therapeutic.

71. A method comprising steps of:(a) selecting a subject for treatment with tislelizumab based on the presence of an immune- related gene expression signature (GES) in a tumor specimen from the subject, wherein the immune-related GES comprises one or more biomarkers chosen from one, two, three, or more of:(i) an anti-viral response biomarker chosen from one or both of IFIT1 and OAS2:(ii) an interferon signaling biomarker chosen from one, two, or more of SP110, JAK2, and STATE,(iii) a macrophage regulation biomarker chosen from one or both of EPSTH and SI M 8’ and(iv) a T cell-related function biomarker chosen from one, two, three, or more of IL7R, CCL4, HI A A, and SELPLG, and(b) administering a therapeutically effective amount of tislelizumab to the subject.

72. The method of claim 71, further comprising administering one or more chemotherapeutic agents to the subject.

73. The method of any one of claims 71-72, wherein the subject exhibits prolonged progression free survival (PFS) as compared to a reference subject or an increased likelihood of prolonged PFS as compared to a reference subject.

74. The method of claim 73, wherein the reference subject does not have an immune- related GES in a tumor specimen.

75. The method of any one of claims 71-74, wherein the method increases one or both of overall survival (OS) or PFS of the subject.

76. The method of any one of claims 71-75, wherein the subject is refractory to chemotherapy.

77. A method comprising steps of:(a) selecting a subject for treatment with tislelizumab based on the presence of a gene expression signature (GES) in a tumor specimen from the subject, wherein the GES comprises one or more biomarkers chosen from one or more of:(i) a Microsatellite Instability-High (MSI-H) biomarker; and(ii) a Deficient Mismatch Repair (dMMR) biomarker; and(b) administering a therapeutically effective amount of tislelizumab to the subject; wherein treating is clinically effective or the subject is a responder to treatment by at least one measure of response as compared to a reference subject, wherein the reference subject does not have an MSI-H biomarker or a dMMR biomarker in a tumor specimen.

78. A method for treating a neoplastic disorder, comprising administering a cancer treatment, wherein the subject has been determined to be responsive to the cancer treatment by a method comprising:(a) selecting a subject for treatment with tislelizumab based on the presence of a gene expression signature (GES) in a tumor specimen from the subject, wherein the GES comprises one or more biomarkers chosen from one or more of:(i) a Microsatellite Instability-High (MSI-H) biomarker; and(ii) a Deficient Mismatch Repair (dMMR) biomarker; and(b) classifying the subject as responsive to the cancer treatment by at least one measure of response as compared to a reference subject, wherein the reference subject does not have an MSI-H biomarker or a dMMR biomarker in a tumor specimen; wherein the cancer treatment comprises a therapeutically effective amount of tislelizumab.

79. A method for treating a neoplastic disorder, comprising steps of:(a) selecting a subject for treatment with tislelizumab based on the presence of a gene expression signature (GES) in a tumor specimen from the subject, wherein the GES comprises one or more biomarkers chosen from one or more of:(i) a Microsatellite Instability-High (MSI-H) biomarker; and(ii) a Deficient Mismatch Repair (dMMR) biomarker; and(b) administering a therapeutically effective amount of tislelizumab to the subject;Wherein the treating is clinically effective or the subject is a responder to the treatment by at least one measure of response as compared to a reference subject, wherein the reference subject does not have an MSI-H biomarker or a dMMR biomarker in a tumor specimen.

80. The method of any one of claims 77-79, wherein the MSI-H biomarker comprises presence of size shifts in at least two microsatellite markers.

81. The method of claim 80, wherein at least five microsatellite markers are assessed for size shifts.

82. The method of any one of claims 80-81, wherein microsatellite markers are assessed for size shifts using polymerase chain reaction (PCR).

83. The method of any one of claims 77-82, wherein the dMMR biomarker comprises absence of at least one Mismatch Repair (MMR) protein in the tumor specimen.I l l84. The method of claim 83, wherein a dMMR protein is selected from one, two, three, or more of MLH1, MSH2, MSH6, and PMS2 protein.

85. The method of claim 83 or 84, wherein absence of at least one MMR protein is assessed using immunohistochemistry.

86. The method of any one of claims 77-85, wherein at least one measure of response is selected from one, two, three, four, five, six or more of overall survival (OS), progression-free survival (PFS), event- free survival, overall response rate, objective response rate, partial response, and duration of response.

87. The method of any one of claims 77-86, wherein at least one measure of response is tumor volume.

88. The method of any one of claims 77-87, wherein treating is clinically effective if a population of subjects has an OS rate at 24 months from treatment initiation of at least about 30% or more.

89. The method of any one of claims 77-88, wherein treating is clinically effective if a population of subjects has a PFS rate at 12 months from treatment initiation of at least about 50% or more.

90. The method of any one of claims 77-89, wherein treating is clinically effective if a population of subjects has an event-free survival rate at 12 months from treatment initiation of at least about 20% or more.

91. The method of any one of claims 77-90, wherein treating is clinically effective if the subject has at least about 15%, 20% or more probability of event-free survival at 12 months from treatment initiation.

92. The method of any one of claims 77-91, wherein the subject is susceptible to or suffering from a cancer selected from one, two, three, four, five, six, or more of colorectal cancer, gastric or gastroesophageal junction cancer, ampullary carcinoma, endometrial cancer, cervical cancer, ovarian cancer, small bowel adenocarcinoma, and pelvis clear cell carcinoma.

93. The method of any one of claims 77-92, wherein the subject was previously administered or delivered one or more cancer treatments, optionally wherein the one or more cancer treatments do not comprise tislelizumab.

94. The method of any one of claims 77-93, wherein the subject is administered or selected for treatment with one or more additional therapeutic agents.

95. The method of claim 94, wherein the one or more additional therapeutic agents comprises or are one or more chemotherapeutic agents.

96. The method of claim 95, wherein the one or more chemotherapeutic agents comprises or are one, two, three, or four of oxaliplatin, capecitabine, cisplatin, and 5 -fluorouracil.

97. The method of any one of claims 1-96, wherein the cancer treatment comprises tislelizumab, wherein the cancer is esophageal squamous cell carcinoma (ESCC), and wherein the subject was previously administered one or more cancer treatments.

98. The method of claim 97, wherein the ESCC is unresectable, recurrent, locally advanced, or metastatic.

99. The method of any one of claims 1-96, wherein the cancer treatment comprises tislelizumab, wherein the cancer is non-small cell lung cancer (NSCLC), and the method further comprises administering pemetrexed and a platinum-based compound.

100. The method of any one of claims 1-96, wherein the cancer treatment comprises tislelizumab, wherein the cancer is squamous non-small cell lung cancer (NSCLC), and the method further comprises administering (a) carboplatin, and (b) paclitaxel or nab-paclitaxel.

101. The method of any one of claims 1-96, wherein the cancer is gastric or gastroesophageal junction cancer, and the method further comprises administering platinum-based chemotherapy and 5 -fluorouracil.

102. The method of any one of claims 99 - 101, wherein the cancer is locally advanced or metastatic NSCLC, and the subject was previously administered one or more cancer treatments.

103. The method of any one of claims 1-102, wherein the anti-PD-1 antibody is administered at a dose from about 50 to 800 mg, optionally wherein the anti-PD-1 antibody is administered at 100 mg, 150 mg, 200, mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg.

104. The method of claim 103, wherein the PD-1 antibody is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks, preferably wherein the anti-PD-1 antibody is administered at 150 mg every two weeks, 300 mg every four weeks, or 400 mg every six weeks.

105. The method of any one of claims 1-104, wherein the cancer treatment comprises intravenous administration of tislelizumab.

106. The method of any one of claims 1-105, wherein the cancer treatment comprises intravenous administration of 200 mg tislelizumab every 3 weeks.

107. A pharmaceutical composition for use in the method according to any one of claims 1- 106, wherein the pharmaceutical composition comprises tislelizumab.

108. A method of treating a cancer in a subject, comprising administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises tislelizumab, andwherein a sample obtained from the subject has an immune- related gene expression signature (GES), wherein the immune-related GES comprises one or more of:(e) interferon signaling biomarkers,(f) macrophage regulation biomarkers,(g) T cell-related function biomarkers, and / or(h) an anti-viral response biomarker.

109. The method of claim 108, wherein the immune-related GES comprises one or more biomarkers chosen from:(a) an anti-viral response biomarker chosen from one or both of IFIT1 and OAS2;(b) an interferon signaling biomarker chosen from one, two, or more of SP110, JAK2, and STAT1;(c) a macrophage regulation biomarker chosen from one or both of EPSTIl and SLAMF8; and(d) a T cell-related function biomarker chosen from one, two, three, or more of IL7R, CCL4, HLA.A, and SELPLG.

110. The method of any one of claims 108 or 109, wherein the cancer is esophageal squamous cell carcinoma (ESCC).

111. The method of any one of claims 108 or 109, wherein the cancer is a lung cancer.

112. The method of any one of claims 108 or 109, wherein the lung cancer is non-squamous non-small cell lung cancer (NSCLC).

113. The method of any one of claims 108 or 109, wherein the lung cancer is squamous non- small cell lung cancer (NSCLC).

114. The method of any one of claims 108 or 109, wherein the cancer is gastric or gastroesophageal junction cancer.

115. The method of any one of claims 108 to 114, wherein the cancer is unresectable, recurrent, locally advanced, and / or metastatic.

116. The method of any one of claims 108 to 115, wherein the subject was previously administered one or more cancer treatments.

117. The method of any one of claims 108-116, wherein the method further comprises administering a chemotherapeutic agent.

118. The method of claim 117, wherein the chemotherapeutic agent is a platinum-based chemotherapy.

119. The method of claim 118, wherein the platinum- based chemotherapy is carboplatin.

120. The method of any one of claims 108-119, wherein the method further comprises administering (a) carboplatin, and (b) paclitaxel or nab-paclitaxel.

121. The method of any one of claims 108-120, wherein the method further comprises administering pemetrexed and a platinum-based compound.

122. The method of any one of claims 108-121, wherein the method further comprises administering 5-fluorouracil.

123. The method of claims 108 or 109, wherein the cancer is locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC), and the method further comprises administering pemetrexed and a platinum-based compound124. The method of claims 108 or 109, wherein the cancer is locally advanced or metastatic squamous non-small cell lung cancer (NSCLC), and the method further comprises administering (a) carboplatin, and (b) paclitaxel or nab-paclitaxel.

125. The method of claims 108 or 109, wherein the cancer is locally advanced or metastatic NSCLC, and the subject was previously administered one or more cancer treatments126. The method of claims 108 or 109, wherein the cancer is unresectable, recurrent, locally advanced, or metastatic ESCC, and the subject was previously administered one or more cancer treatments127. The method of claims 108 or 109, wherein the cancer is unresectable, recurrent, locally advanced, or metastatic gastric or gastroesophageal junction cancer, and the method further comprises administering a platinum-based compound and 5-fluorouracil.

128. The method of any one of claims 108-127, wherein the anti-PD-1 antibody is administered at a dose from about 50 to 800 mg, optionally wherein the anti-PD-1 antibody isadministered at 100 mg, 150 mg, 200, mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg129. The method of claim 128, wherein the PD-1 antibody is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks, preferably wherein the anti -PD-1 antibody is administered at 150 mg every two weeks, 300 mg every four weeks, or 400 mg every six weeks.

130. The method of any one of claims 108-129, wherein the cancer treatment comprises intravenous administration of tislelizumab.

131. The method of any one of claims 108-129, wherein the cancer treatment comprises intravenous administration of 200 mg tislelizumab every 3 weeks.

132. The method of any one of claims 1-131, wherein the pharmaceutical composition comprises comprising a histidine buffer, a surfactant and at least one stabilizer.

133. The method of claim 132, wherein the surfactant is a polysorbate.

134. The method of claim 132 or 133, wherein the stabilizer is trehalose.

135. The method of any one of claims 1-131, wherein the pharmaceutical composition comprises citric acid monohydrate, histidine, L-histidine hydrochloride monohydrate, polysorbate 20, sodium citrate, and trehalose.

136. The method of any one of claim 1-135, wherein the subject is defined by a tumor area positivity (TAP) score of PD-L1 expression of at least about 1%, about 2%, about 5%, or about 10%.

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