Methods and compositions for cancer immunotherapy

Abstract

The present invention provides diagnostic methods, therapeutic methods, and compositions for the treatment of cancer. The compositions and methods described herein can be used, for example, to identify patients with cancer who may benefit from treatment with a PD-L1 axis-binding antagonist and to treat such patients accordingly. Using the compositions and methods of the present disclosure, it can be determined that if a patient, e.g., a human cancer patient, exhibits elevated expression levels of any of the biomarkers disclosed herein, the patient is likely to benefit from treatment with a PD-L1 axis-binding antagonist. Exemplary PD-L1 axis-binding antagonists that can be used in combination with the compositions and methods of the present disclosure are PD-L1 binding antagonists, such as anti-PD-L1 antibodies and antigen-binding fragments thereof, including atezolizumab, and PD-1 binding antagonists, such as anti-PD-1 antibodies and antigen-binding fragments thereof.

Description

Technical field

[0001] sequence listing The present application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy was created on June 11, 2021, is named 50474-171WO2_Sequence Listing_8.11.21_ST25, and is 398,463 bytes in size.

[0002] Cross-reference to related applications This application claims the priority benefit of US Provisional Patent Application No. 63 / 038,559, filed Jun. 12, 2020, the entire contents of which are hereby incorporated by reference.

[0003] Field of Invention The present invention relates to diagnostic and therapeutic methods for the treatment of cancer using PD-L1 axis binding antagonists. Also provided are related kits and compositions. [Background technology]

[0004] Cancer remains one of the deadliest threats to human health. Approximately 1.3 million new patients are diagnosed with cancer each year in the United States, making it the second leading cause of death after heart disease and accounting for approximately one in four deaths. It is also projected that cancer could overtake cardiovascular disease as the leading cause of death within five years. Solid tumors are responsible for the majority of these deaths.

[0005] Human studies with immune checkpoint inhibitors have shown promise in harnessing the immune system to suppress and eradicate tumor growth. Programmed death 1 (PD-1) receptor and its ligand Programmed death-ligand 1 (PD-L1) suppress immune system responses during chronic infections, pregnancy, tissue allografts, autoimmune diseases and cancer is an immune checkpoint protein involved in PD-L1 regulates immune responses by binding to the inhibitory receptor PD-1, which is expressed on the surface of T cells, B cells, and monocytes. PD-L1 also negatively regulates T cell function by interacting with another receptor, B7-1. Formation of PD-L1 / PD-1 and PD-L1 / B7-1 complexes negatively regulates T-cell receptor signaling and subsequently down-regulates T-cell activation and anti-tumor immune activity. bring about inhibitions.

[0006] Although advances in the treatment of certain cancers have been significant, the 5-year overall survival rate for all cancers has improved by only about 10% over the past 20 years. Malignant solid tumors in particular metastasize and grow rapidly in an uncontrolled manner, making their timely detection and treatment extremely difficult.

[0007] Despite significant advances in the treatment of cancer, there remains a need for improved diagnostic and therapeutic methods and cancer treatments. [Outline of the Invention]

[0008] The present disclosure provides cancer (e.g., lung cancer (e.g., non-small cell lung cancer (NSCLC)), endometrial cancer, colon adenocarcinoma, renal cell carcinoma, bladder cancer (e.g., urothelial carcinoma (UC)). The present invention provides therapeutic and diagnostic methods and compositions for treating individuals with renal cancer (eg, renal cell carcinoma (RCC)), and breast cancer (eg, triple-negative breast cancer (TNBC)).

[0009] In one aspect, the invention features a method of identifying an individual with cancer who may benefit from treatment comprising a PD-L1 axis binding antagonist, the method comprising, in a sample derived from the individual, the genes CD79A, Exceeding reference immune score expression levels of 2 or more genes, including determining expression levels of 2 or more of CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB12 Immune Score expression levels of one or more genes identify an individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0010] In another aspect, the invention features a method of selecting a therapy for an individual with cancer, comprising determining in a sample from the individual the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK , TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1, wherein the immune score expression level of the two or more genes exceeds the reference immune score expression level of the two or more genes. identifies individuals as likely to benefit from a treatment comprising a PD-L1 axis binding antagonist.

[0011] In some embodiments, the immune score expression levels of two or more genes in the sample are above the reference immune score expression levels, and the method further comprises administering to the individual an effective amount of a PD-L1 axis binding antagonist. include.

[0012] In another aspect, the invention features a method of treating an individual with cancer, comprising: (a) the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17 in a sample from the individual; , IGJ, IGLL5, RBPJ, and MZB1, wherein the immune score expression levels of the two or more genes in the sample are equal to the reference immune score of the two or more genes Determining the expression level, which is determined to be above the expression level; and (b) administering to the individual an effective amount of a PD-L1 axis binding antagonist.

[0013] In another aspect, the invention provides immune score expression levels of two or more of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 in a sample from an individual. is above a reference immune score expression level for two or more genes, the method comprising administering to the individual an effective amount of a PD-L1 axis binding antagonist including administering

[0014] In another aspect, the invention features a PD-L1 axis binding antagonist for use in a method of treating an individual with cancer, comprising: (a) the gene CD79A, in a sample from the individual; determining the expression levels of two or more of CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1, wherein the immunoscore expression levels of the two or more genes in the sample is above a reference immune score expression level for two or more genes; and (b) administering to the individual an effective amount of a PD-L1 axis binding antagonist. .

[0015] In another aspect, the invention provides reference immunization of two or more of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 in a sample from an individual. A PD-L1 axis binding antagonist for treating cancer in an individual determined to have two or more Immune Score expression levels above the Score expression level is featured.

[0016] In some embodiments, the Immunoscore reference expression level is the Immunoscore expression level of two or more genes in a reference population.

[0017] In some embodiments, the reference population is a population of individuals with cancer.

[0018] In some embodiments, the population of individuals is a first subset of individuals treated with a PD-L1 axis binding antagonist and a second subset of individuals treated with a therapy that does not include a PD-L1 axis binding antagonist. including.

[0019] In some embodiments, the reference Immune Score expression level is the individual's responsiveness to treatment with a PD-L1 axis binding antagonist and the reference Immune Score expression level for each of the first subset and the second subset of individuals. A significant segregation of individuals' responsiveness to treatment with a PD-L1 axis binding antagonist based on a significant difference between an overriding individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist. is significantly improved compared to an individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist.

[0020] In some embodiments, PD-L1 axis binding antagonist-free therapies include anti-tumor agents, chemotherapeutic agents, growth inhibitory agents, anti-angiogenic agents, radiotherapy, cytotoxic agents, or combinations thereof. .

[0021] In some embodiments, the PD-L1 axis binding antagonist-free therapy comprises a chemotherapeutic agent.

[0022] In some embodiments, the chemotherapeutic agent is docetaxel.

[0023] In some embodiments, responsiveness to treatment comprises prolonged OS, prolonged progression-free survival (PFS), or increased best overall response (BCOR).

[0024] In some embodiments, responsiveness to treatment comprises prolongation of OS.

[0025] In some embodiments, the reference immune score expression level is the median expression level of each of the two or more genes in the reference population.

[0026] In some embodiments, the gene comprises three or more of CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1.

[0027] In some embodiments, the genes comprise four or more of CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1.

[0028] In some embodiments, the genes comprise five or more of CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1.

[0029] In some embodiments, the genes comprise six or more of CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1.

[0030] In some embodiments, the genes comprise seven or more of CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1.

[0031] In some embodiments, the gene comprises CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1.

[0032] In another aspect, the invention features a method of identifying an individual with cancer who may benefit from treatment comprising a PD-L1 axis binding antagonist, the method comprising determining, in a sample derived from the individual, the gene CD79A , CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 above the reference immune score expression level of one or more genes Immune Score expression levels of one or more genes identified an individual as likely to benefit from treatment with a PD-L1 axis binding antagonist, and benefit was compared to treatment without a PD-L1 axis binding antagonist. including prolongation of overall survival (OS) of the individual in cases.

[0033] In another aspect, the invention features a method of selecting a therapy for an individual with cancer, the method comprising determining in a sample from the individual, CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, the immune score expression level of the one or more genes above the reference immune score expression level of the one or more genes comprising determining the gene expression level of one or more of TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 identifies an individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist, wherein the benefit comprises prolongation of the individual's OS when compared to treatment without the PD-L1 axis binding antagonist .

[0034] In some embodiments, the immune score expression level of one or more genes in the sample exceeds the reference immune score expression level, and the method further comprises administering to the individual an effective amount of a PD-L1 axis binding antagonist. include.

[0035] In another aspect, the invention features a method of treating an individual with cancer, comprising: (a) CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, Determining the gene expression level of one or more of IGJ, IGLL5, RBPJ, and MZB1, wherein the immune score expression level of the one or more genes in the sample is equal to the reference immune score of the one or more genes expression level was determined to be above, thereby identifying the individual as likely to benefit from treatment with a PD-L1 axis binding antagonist, and benefiting from treatment without a PD-L1 axis binding antagonist. determining the level of expression, including prolonging the OS of the individual in which case; and (b) administering to the individual an effective amount of a PD-L1 axis binding antagonist.

[0036] In another aspect, the invention provides reference immune score expression of one or more of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 in a sample from an individual. A method of treating cancer in an individual determined to have an Immune Score expression level of one or more genes above a level is provided, the method comprising administering to the individual an effective amount of a PD-L1 axis binding antagonist. wherein the immune score expression level of one or more genes exceeds the reference immune score expression level of the one or more genes, the individual may benefit from a treatment comprising a PD-L1 axis binding antagonist and benefits include prolongation of individual OS when compared to treatment without a PD-L1 axis binding antagonist.

[0037] In another aspect, the invention features a PD-L1 axis binding antagonist for use in a method of treating an individual with cancer comprising: (a) CD79A, CD19 in a sample from the individual; , BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1, wherein the immunoscore expression level of the one or more genes in the sample was determined to be above the reference immune score expression level for one or more genes, thereby identifying the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist, wherein benefit is associated with PD - determining expression levels, including prolongation of the individual's OS when treated without the L1 axis binding antagonist; and (b) administering an effective amount of a PD-L1 axis binding antagonist to the individual.

[0038] In another aspect, the invention provides reference immune score expression of one or more of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 in a sample from an individual. characterized by a PD-L1 axis binding antagonist for use in treating cancer in an individual determined to have an immune score expression level of one or more genes above the reference immune score of one or more genes An immune score expression level of the same one or more genes above the expression level identifies the individual as likely to benefit from a treatment comprising a PD-L1 axis binding antagonist, and benefiting from treatment with a PD-L1 axis binding antagonist. including prolongation of an individual's OS when compared to no treatment.

[0039] In some embodiments, the immune score expression level of one of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 is determined.

[0040] In some embodiments, the CD79A immune score expression level is determined.

[0041] In some embodiments, the Immunoscore reference expression level is the Immunoscore expression level of one or more genes in a reference population.

[0042] In some embodiments, the reference population is a population of individuals with cancer.

[0043] In some embodiments, the population of individuals is a first subset of individuals treated with a PD-L1 axis binding antagonist and a second subset of individuals treated with a therapy that does not include a PD-L1 axis binding antagonist. including.

[0044] In some embodiments, the Immune Score reference expression level is determined by comparing each of the first subset and the second subset of individuals with the individual's responsiveness to treatment with a PD-L1 axis binding antagonist and the reference Immune Score expression level The individual's response to treatment with a PD-L1 axis binding antagonist was significantly segregated based on a significant difference between the individual's responsiveness to treatment with a therapy that did not include a PD-L1 axis binding antagonist over Sexuality is significantly improved compared to the individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist.

[0045] In some embodiments, PD-L1 axis binding antagonist-free therapies include anti-tumor agents, chemotherapeutic agents, growth inhibitory agents, anti-angiogenic agents, radiotherapy, cytotoxic agents, or combinations thereof. .

[0046] In some embodiments, the PD-L1 axis binding antagonist-free therapy comprises a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is docetaxel.

[0047] In some embodiments, responsiveness to treatment comprises prolonging OS, prolonging PFS, or increasing BCOR.

[0048] In some embodiments, responsiveness to treatment comprises prolongation of OS.

[0049] In some embodiments, the Immunoscore reference expression level is the median expression level of each of the one or more genes in the reference population.

[0050] In some embodiments, the median expression level is the median mean Z-score of the expression levels of each of the two or more genes in the reference population.

[0051] In some embodiments, the gene comprises two or more of CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1.

[0052] In some embodiments, the two or more genes include TNFRSF17 and IGJ.

[0053] In some embodiments, the two genes consist of TNFRSF17 and IGJ.

[0054] In some embodiments, the gene comprises three or more of CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1.

[0055] In some embodiments, the genes comprise four or more of CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1.

[0056] In some embodiments, the genes comprise five or more of CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1.

[0057] In some embodiments, the genes comprise six or more of CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1.

[0058] In some embodiments, the genes comprise seven or more of CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1.

[0059] In some embodiments, the gene comprises CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1.

[0060] In another aspect, the invention features a method of identifying an individual with cancer who may benefit from treatment comprising a PD-L1 axis binding antagonist, the method comprising determining, in a sample from the individual, the gene MZB1 , DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5. , an immune score expression level of one or more genes above a reference immune score expression level of one or more genes identifies an individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0061] In another aspect, the invention features a method of selecting a therapy for an individual with cancer, the method comprising determining in a sample from the individual the genes MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2 , IGHGP, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5, and a reference immune score of one or more genes An immune score expression level of the same one or more genes above the expression level identifies the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0062] In some embodiments of each of the two preceding aspects, the Immune Score expression level of one or more genes in the sample exceeds the reference Immune Score expression level, and the method administers to the individual an effective amount of PD-L1 Further comprising administering an axial binding antagonist.

[0063] In a further aspect, the invention features a method of treating an individual with cancer, the method comprising: (a) of genes MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 in a sample from an individual Determining one or more expression levels, wherein the Immune Score expression level of one or more genes in the sample is determined to be above the reference Immune Score expression level of the one or more genes. to decide; and (b) administering to the individual an effective amount of a PD-L1 axis binding antagonist; including.

[0064] In another aspect, the present invention provides the following in a sample derived from an individual: A method of treating cancer in an individual determined to have an Immune Score expression level of one or more genes greater than a reference Immune Score expression level of one or more of IGLL5, the method comprising: administering to the individual an effective amount of a PD-L1 axis binding antagonist.

[0065] In some embodiments, the Immunoscore reference expression level is the Immunoscore expression level of one or more genes in a reference population.

[0066] In some embodiments, the reference population is a population of individuals with cancer.

[0067] In some embodiments, the population of individuals comprises a first subset of individuals treated with a PD-L1 axis binding antagonist and a second subset of individuals treated with a therapy that does not include a PD-L1 axis binding antagonist. Contains a subset.

[0068] In some embodiments, the reference immune score expression level determines each of the first subset and the second subset of individuals based on the individual's responsiveness to treatment with a PD-L1 axis binding antagonist and the reference immune score expression level The individual's response to treatment with a PD-L1 axis binding antagonist was significantly segregated based on a significant difference between the individual's responsiveness to treatment with a therapy that did not include a PD-L1 axis binding antagonist over Sexuality is significantly improved compared to the individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist.

[0069] In some embodiments, treatments that do not include PD-L1 axis binding antagonists include anti-tumor agents, chemotherapeutic agents, anti-proliferative agents, anti-angiogenic agents, radiotherapy, cytotoxic agents, or combinations thereof. include.

[0070] In some embodiments, the PD-L1 axis binding antagonist-free therapy comprises a chemotherapeutic agent.

[0071] In some embodiments, the chemotherapeutic agent is docetaxel.

[0072] In some embodiments, responsiveness to treatment comprises prolonging OS, prolonging PFS, or increasing BCOR.

[0073] In some embodiments, responsiveness to treatment comprises prolongation of OS.

[0074] In some embodiments, the reference immune score expression level is the median expression level of each of the one or more genes in the reference population.

[0075] In some embodiments, the gene is two of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 including one or more.

[0076] In some embodiments, the gene is 3 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 including one or more.

[0077] In some embodiments, the gene is 4 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 including one or more.

[0078] In some embodiments, the gene is 5 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 including one or more.

[0079] In some embodiments, the gene is 6 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 including one or more.

[0080] In some embodiments, the gene is 7 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 including one or more.

[0081] In some embodiments, the gene is 8 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 including one or more.

[0082] In some embodiments, the gene is 9 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 including one or more.

[0083] In some embodiments, the gene is 10 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 Including more than one.

[0084] In some embodiments, the gene is 11 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 Including more than one.

[0085] In some embodiments, the gene is 12 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 Including more than one.

[0086] In some embodiments, the gene is 13 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 Including more than one.

[0087] In some embodiments, the genes include MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5.

[0088] In another aspect, the invention features a method of identifying an individual with cancer who may benefit from treatment comprising a PD-L1 axis binding antagonist, the method comprising determining, in a sample from the individual, the gene MZB1 , DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5. , the Immune Score expression level of one or more genes above the reference Immune Score expression level of one or more genes identifies the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist, wherein benefit is , including prolongation of OS in individuals compared to treatment without a PD-L1 axis binding antagonist.

[0089] In another aspect, the invention features a method of selecting a therapy for an individual with cancer, the method comprising determining in a sample from the individual the genes MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2 , IGHGP, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5, and a reference immune score of one or more genes An immune score expression level of the same one or more genes above the expression level identifies the individual as likely to benefit from a treatment comprising a PD-L1 axis binding antagonist, and benefiting from treatment with a PD-L1 axis binding antagonist. including prolongation of an individual's OS when compared to no treatment.

[0090] In some embodiments of each of the two preceding aspects, the Immune Score expression level of one or more genes in the sample exceeds the reference Immune Score expression level, and the method administers to the individual an effective amount of PD-L1 Further comprising administering an axial binding antagonist.

[0091] In another aspect, the invention features a method of treating an individual with cancer, the method comprising: (a) of genes MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 in a sample from an individual determining one or more expression levels, wherein the immune score expression level of the one or more genes in the sample is determined to be above the reference immune score expression level of the one or more genes, thereby , identifying an individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist, wherein the benefit comprises prolonging the individual's OS as compared to treatment without the PD-L1 axis binding antagonist; determining expression levels; and (b) administering to the individual an effective amount of a PD-L1 axis binding antagonist; including.

[0092] In another aspect, the present invention provides the following in a sample derived from an individual: A method of treating cancer in an individual determined to have an Immune Score expression level of one or more genes greater than a reference Immune Score expression level of one or more of IGLL5, the method comprising: administering to the individual an effective amount of a PD-L1 axis binding antagonist, wherein an immune score expression level of one or more genes above a reference immune score expression level of the one or more genes treats the individual as having PD - Identified as those who may benefit from treatment comprising an L1 axis binding antagonist, where benefit includes prolongation of an individual's OS as compared to treatment without a PD-L1 axis binding antagonist.

[0093] In some embodiments, the Immunoscore reference expression level is the Immunoscore expression level of one or more genes in a reference population.

[0094] In some embodiments, the reference population is a population of individuals with cancer.

[0095] In some embodiments, the population of individuals comprises a first subset of individuals treated with a PD-L1 axis binding antagonist and a second subset of individuals treated with a therapy that does not include a PD-L1 axis binding antagonist. Contains a subset.

[0096] In some embodiments, the Immune Score reference expression level is determined by comparing each of the first subset and the second subset of individuals with the individual's responsiveness to treatment with a PD-L1 axis binding antagonist and the reference Immune Score expression level The individual's response to treatment with a PD-L1 axis binding antagonist was significantly segregated based on a significant difference between the individual's responsiveness to treatment with a therapy that did not include a PD-L1 axis binding antagonist over Sexuality is significantly improved compared to the individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist.

[0097] In some embodiments, treatments that do not include PD-L1 axis binding antagonists include anti-tumor agents, chemotherapeutic agents, anti-proliferative agents, anti-angiogenic agents, radiotherapy, cytotoxic agents, or combinations thereof. include.

[0098] In some embodiments, the PD-L1 axis binding antagonist-free therapy comprises a chemotherapeutic agent.

[0099] In some embodiments, the chemotherapeutic agent is docetaxel.

[0100] In some embodiments, responsiveness to treatment comprises prolonging OS, prolonging PFS, or increasing BCOR.

[0101] In some embodiments, responsiveness to treatment comprises prolongation of OS.

[0102] In some embodiments, the immunoscore reference expression level is the median expression level of each of the one or more genes in the reference population.

[0103] In some embodiments, the median expression level is the median mean Z-score of the expression level of each of the one or more genes in the reference population.

[0104] In some embodiments, the gene is two of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 including one or more.

[0105] In some embodiments, the gene is 3 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 including one or more.

[0106] In some embodiments, the gene is 4 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 including one or more.

[0107] In some embodiments, the gene is 5 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 including one or more.

[0108] In some embodiments, the genes are 6 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 including one or more.

[0109] In some embodiments, the gene is 7 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 including one or more.

[0110] In some embodiments, the gene is 8 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 including one or more.

[0111] In some embodiments, the gene is 9 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 including one or more.

[0112] In some embodiments, the gene is 10 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 Including more than one.

[0113] In some embodiments, the gene is 11 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 Including more than one.

[0114] In some embodiments, the gene is 12 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 Including more than one.

[0115] In some embodiments, the gene is 13 of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 Including more than one.

[0116] In some embodiments, the genes include MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5.

[0117] In another aspect, the invention features a method of identifying an individual with cancer who may benefit from treatment comprising a PD-L1 axis binding antagonist, the method comprising tertiary lymph node cancer in a tumor sample from the individual. including determining the presence of TLS-like structures (TLS), wherein the presence of TLS in the tumor sample identifies the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0118] In another aspect, the invention features a method of selecting a therapy for an individual with cancer, the method comprising determining the presence of TLS in a tumor sample from the individual, comprising: The presence of TLS in identifies an individual as likely to benefit from treatment involving a PD-L1 axis binding antagonist.

[0119] In some embodiments, the sample from the individual is determined to have the presence of TLS. The method further comprises administering to the individual an effective amount of a PD-L1 axis binding antagonist.

[0120] In another aspect, the invention features a method of treating an individual with cancer comprising (a) determining the presence of TLS in a tumor sample from the individual; and (b) an effective amount of administering to the individual a PD-L1 axis binding antagonist of.

[0121] In another aspect, the invention features a method of treating cancer in an individual determined to have the presence of TLS in a tumor sample from the individual, the method comprising treating the individual with an effective amount of PD- including administering an L1 axis binding antagonist.

[0122] In another aspect, the invention features a PD-L1 axis binding antagonist for use in a method of treating an individual with cancer, comprising: (a) the presence of TLS in a tumor sample from the individual; and (b) administering to the individual an effective amount of a PD-L1 axis binding antagonist.

[0123] In another aspect, the invention features a PD-L1 axis binding antagonist for use in treating cancer in an individual determined to have the presence of TLS in a tumor sample derived from the individual.

[0124] In some embodiments, the presence of TLS is determined by histological staining, immunohistochemistry (IHC), immunofluorescence, or gene expression analysis.

[0125] In some aspects, the histological staining comprises hematoxylin and eosin (H&E) staining.

[0126] In some embodiments, IHC or immunofluorescence comprises detecting CD62L, L-selectin, CD40, or CD8.

[0127] In some embodiments, CD62L or L-selectin is detected using a MECA-79 antibody.

[0128] In some embodiments, gene expression analysis comprises determining the expression level of the TLS gene signature in the sample.

[0129] In some embodiments, the TLS gene signature comprises one or more of the genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13.

[0130] In some embodiments, the genes comprise two or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13.

[0131] In another aspect, the invention features a method of identifying an individual with cancer who may benefit from treatment comprising a PD-L1 axis binding antagonist, the method comprising determining, in a sample from the individual, the gene CCL2 , CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13, wherein the reference immune score expression level of the two or more genes Immune Score expression levels of the same two or more genes above identify an individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0132] In another aspect, the invention features a method of selecting a therapy for an individual with cancer, the method comprising determining in a sample from the individual the genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18 , CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13, wherein the immunity of the two or more genes above the reference immune score expression level of the two or more genes A score expression level identifies an individual as likely to benefit from treatment that includes a PD-L1 axis binding antagonist.

[0133] In some embodiments, the immune score expression levels of two or more genes in the sample are above the reference immune score expression levels, and the method further comprises administering to the individual an effective amount of a PD-L1 axis binding antagonist. include.

[0134] In another aspect, the invention features a method of treating an individual with cancer, comprising: (a) the genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19 in a sample from the individual; , CCL21, CXCL9, CXCL10, CXCL11, and CXCL13, wherein the immunoscore expression levels of the two or more genes in the sample correspond to the reference levels of the two or more genes determining the expression level determined to be above the immune score expression level; and (b) administering to the individual an effective amount of a PD-L1 axis binding antagonist.

[0135] In another aspect, the invention provides a reference immunity of two or more of the genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13 in a sample from an individual. A method of treating cancer in an individual determined to have an Immune Score expression level of the same two or more genes above the Score expression level is provided, the method comprising treating the individual with an effective amount of PD-L1 axis binding. including administering an antagonist.

[0136] In another aspect, the invention features a PD-L1 axis binding antagonist for use in a method of treating an individual with cancer, comprising: (a) the gene CCL2; determining the expression levels of two or more of CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13, wherein the immune score of the two or more genes in the sample determining the expression level, wherein the expression level is determined to be above the reference immune score expression level for the two or more genes; and (b) administering to the individual an effective amount of a PD-L1 axis binding antagonist. including.

[0137] In another aspect, the invention provides a reference immunity of two or more of the genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13 in a sample from an individual. A PD-L1 axis binding antagonist is characterized for use in treating cancer in an individual determined to have an Immune Score expression level of the same two or more genes above the Score expression level.

[0138] In some embodiments, the reference immune score expression level is the immune score expression level of two or more genes in a reference population.

[0139] In some embodiments, the reference population is a population of individuals with cancer.

[0140] In some embodiments, the population of individuals is a first subset of individuals treated with a PD-L1 axis binding antagonist and a second subset of individuals treated with a therapy that does not include a PD-L1 axis binding antagonist. including.

[0141] In some embodiments, the reference Immune Score expression level determines each of the first and second subsets of individuals to be responsive to treatment with a PD-L1 axis binding antagonist and PD above the reference expression level. - Based on a significant difference between an individual's responsiveness to treatment with a therapy that does not include an L1 axis binding antagonist, and a significantly segregating individual's responsiveness to treatment with a PD-L1 axis binding antagonist, There is a significant improvement in the individual's responsiveness to treatment with therapy that does not include a PD-L1 axis binding antagonist.

[0142] In some embodiments, PD-L1 axis binding antagonist-free therapies include anti-tumor agents, chemotherapeutic agents, anti-proliferative agents, anti-angiogenic agents, radiotherapy, cytotoxic agents, or combinations thereof. .

[0143] In some embodiments, the PD-L1 axis binding antagonist-free therapy comprises a chemotherapeutic agent.

[0144] In some embodiments, the chemotherapeutic agent is docetaxel.

[0145] In some embodiments, responsiveness to treatment comprises prolonging OS, prolonging PFS, or increasing BCOR.

[0146] In some embodiments, responsiveness to treatment comprises prolongation of OS.

[0147] In some embodiments, the reference immune score expression level is the median expression level of each of the two or more genes in the reference population.

[0148] In some embodiments, the median expression level is the median mean Z-score of the expression level of each of the two or more genes in the reference population.

[0149] In some embodiments, the genes comprise three or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13.

[0150] In some embodiments, the genes comprise four or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13.

[0151] In some embodiments, the genes comprise five or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13.

[0152] In some embodiments, the genes comprise six or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13.

[0153] In some embodiments, the genes comprise seven or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13.

[0154] In some embodiments, the genes comprise eight or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13.

[0155] In some embodiments, the genes comprise nine or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13.

[0156] In some embodiments, the genes include 10 or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13.

[0157] In some embodiments, the genes comprise 11 or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13.

[0158] In some embodiments, the genes include CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13.

[0159] In some aspects, the expression level is a nucleic acid expression level.

[0160] In some embodiments, the nucleic acid expression level is the mRNA expression level.

[0161] In some embodiments, mRNA expression levels are determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, FISH, or combinations thereof.

[0162] In some embodiments, mRNA expression levels are determined using RNA-seq.

[0163] In some aspects, the expression level is a protein expression level.

[0164] In some embodiments, protein expression levels are determined by IHC, immunofluorescence, mass spectroscopy, flow cytometry, and Western blot, or combinations thereof.

[0165] In some embodiments, expression levels are detected in tumor cells, tumor-infiltrating immune cells, stromal cells, normal adjacent tissue (NAT) cells, or combinations thereof.

[0166] In another aspect, the invention features a method of identifying an individual with cancer who may benefit from treatment comprising a PD-L1 axis binding antagonist, the method comprising the steps of: wherein a number of B cells in the tumor sample that exceeds the reference number of B cells identifies the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0167] In another aspect, the invention features a method of selecting a therapy for an individual with cancer, the method comprising determining the number of B cells in a tumor sample from the individual; A number of B cells in the tumor sample that exceeds the reference number of cells identifies the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0168] In some embodiments, the number of B cells in the sample exceeds the reference number and the method further comprises administering to the individual an effective amount of a PD-L1 axis binding antagonist.

[0169] In another aspect, the invention features a method of treating an individual with cancer, comprising: (a) determining the number of B cells in a tumor sample from the individual; administering to the individual an amount of a PD-L1 axis binding antagonist.

[0170] In another aspect, the invention features a method of treating cancer in an individual determined to have a number of B cells greater than a reference number of B cells in a tumor sample from the individual, the method comprising: administering an amount of a PD-L1 axis binding antagonist effective against.

[0171] In another aspect, the invention features a PD-L1 axis binding antagonist for use in a method of treating an individual with cancer, the method comprising: (a) reducing B cells in a tumor sample from the individual; and (b) administering to the individual an effective amount of a PD-L1 axis binding antagonist.

[0172] In another aspect, the invention provides a PD-L1 axis binding antagonist for use in treating cancer in an individual determined to have a number of B cells above a reference number of B cells in a tumor sample from the individual. characterized by

[0173] In some embodiments, B cells comprise CD79+ B cells, IgG+ B cells, and / or plasma cells.

[0174] In another aspect, the invention features a method of identifying an individual with cancer who may benefit from treatment comprising a PD-L1 axis binding antagonist, the method comprising determining in a tumor sample derived from the individual comprising determining whether to have clonally expanded B cells, wherein the clonally expanded B cells in the sample identify the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist. do.

[0175] In another aspect, the invention features a method of selecting a therapy for an individual with cancer, comprising determining whether the individual has clonally expanded B cells in a tumor sample derived from the individual. including determining whether clonally expanded B cells in the sample identify the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0176] In some embodiments, the tumor sample comprises clonally expanded B cells and the method further comprises administering to the individual an effective amount of a PD-L1 axis binding antagonist.

[0177] In another aspect, the invention features a method of treating an individual with cancer, the method comprising: (a) determining that the individual has clonally expanded B cells in a tumor sample from the individual; and (b) administering to the individual an effective amount of a PD-L1 axis binding antagonist.

[0178] In another aspect, the invention features a method of treating cancer in an individual determined to have clonally expanded B cells in a tumor sample from the individual, the method comprising: administering an amount of a PD-L1 axis binding antagonist.

[0179] In another aspect, the invention features a PD-L1 axis binding antagonist for use in a method of treating an individual with cancer, comprising: (a) the individual is cloned into a tumor sample derived from the individual; and (b) administering to the individual an effective amount of a PD-L1 axis binding antagonist.

[0180] In another aspect, the invention features a PD-L1 axis binding antagonist for use in treating cancer in an individual determined to have clonally expanded B cells in a tumor sample derived from the individual. .

[0181] In some embodiments, the clonally expanded B cell is a clonally expanded plasma cell.

[0182] In some embodiments, clonally expanded B cells are detected by measuring the diversity of the B cell receptor (BCR) gene repertoire in a tumor sample.

[0183] In some embodiments, an SDI of the BCR gene repertoire in a tumor sample from an individual below a reference Shannon Diversity Index (SDI) identifies the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist. do.

[0184] In some aspects, the sample is a tissue sample, cell sample, whole blood sample, plasma sample, serum sample, or a combination thereof.

[0185] In some aspects, the tissue sample is a tumor tissue sample.

[0186] In some aspects, the tumor sample is a tumor tissue sample.

[0187] In some embodiments, the tumor tissue sample comprises tumor cells, tumor-infiltrating immune cells, stromal cells, NAT cells, or combinations thereof.

[0188] In some aspects, the tumor tissue sample is a formalin-fixed and paraffin-embedded (FFPE) sample, an archival sample, a fresh sample, or a frozen sample.

[0189] In some embodiments, the tumor tissue sample is an FFPE sample.

[0190] In some aspects, the cancer is lung cancer, kidney cancer, bladder cancer, breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, esophageal cancer, mesothelioma, melanoma, head and neck Cancer, thyroid cancer, sarcoma, prostate cancer, glioblastoma, cervical cancer, thymic carcinoma, leukemia, lymphoma, myeloma, mycosis fungoides, Merkel cell carcinoma, or hematological tumor.

[0191] In some aspects, the cancer is lung cancer, kidney cancer, bladder cancer, or breast cancer.

[0192] In some aspects, the lung cancer is non-small cell lung cancer (NSCLC).

[0193] In some embodiments, the NSCLC is non-squamous NSCLC.

[0194] In some embodiments, the NSCLC is squamous NSCLC.

[0195] In some embodiments, the benefit includes an increase in an individual's OS, an increase in an individual's PFS, and / or an improvement in an individual's BCOR as compared to treatment without a PD-L1 axis binding antagonist.

[0196] In some embodiments, the benefit comprises prolongation of an individual's OS as compared to treatment without the PD-L1 axis binding antagonist.

[0197] In some embodiments, the PD-L1 axis binding antagonist is selected from the group consisting of PD-L1 binding antagonists, PD-1 binding antagonists, and PD-L2 binding antagonists.

[0198] In some embodiments, the PD-L1 axis binding antagonist is a PD-L1 binding antagonist.

[0199] In some embodiments, the PD-L1 binding antagonist inhibits binding of PD-L1 to one or more of its ligand binding partners.

[0200] In some embodiments, the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1.

[0201] In some embodiments, the PD-L1 binding antagonist inhibits binding of PD-L1 to B7-1.

[0202] In some embodiments, the PD-L1 binding antagonist inhibits binding of PD-L1 to both PD-1 and B7-1.

[0203] In some embodiments, the PD-L1 binding antagonist is an antibody or antigen binding fragment thereof.

[0204] In some embodiments, the antibody is selected from the group consisting of atezolizumab, MDX-1105, MEDI4736 (durvalumab), and MSB0010718C (avelumab).

[0205] In some embodiments, the antibody comprises a heavy chain comprising the HVR-H1 sequence of SEQ ID NO:1, the HVR-H2 sequence of SEQ ID NO:2, and the HVR-H3 sequence of SEQ ID NO:3, and the HVR-L1 sequence of SEQ ID NO:4. , a light chain comprising the HVR-L2 sequence of SEQ ID NO:5, and the HVR-L3 sequence of SEQ ID NO:6.

[0206] In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8.

[0207] In some embodiments, the PD-L1 axis binding antagonist is a PD-1 binding antagonist.

[0208] In some embodiments, the PD-1 binding antagonist inhibits binding of PD-1 to one or more of its ligand binding partners.

[0209] In some embodiments, the PD-1 binding antagonist inhibits binding of PD-1 to PD-L1.

[0210] In some embodiments, the PD-1 binding antagonist inhibits binding of PD-1 to PD-L2.

[0211] In some embodiments, the PD-1 binding antagonist inhibits binding of PD-1 to both PD-L1 and PD-L2.

[0212] In some embodiments, the PD-1 binding antagonist is an antibody or antigen binding fragment thereof.

[0213] In some embodiments, the antibody is selected from the group consisting of: MDX-1106 (nivolumab), MK-3475 (pembrolizumab), MEDI-0680 (AMP-514), PDR001, REGN2810, and BGB-108.

[0214] In some embodiments, the PD-1 binding antagonist is an Fc fusion protein.

[0215] In some embodiments, the Fc fusion protein is AMP-224.

[0216] In some embodiments, the individual has not previously received treatment for cancer.

[0217] In some embodiments, the individual has not previously been administered a PD-L1 axis binding antagonist.

[0218] In some embodiments, the cancer is NSCLC and the individual does not have EGFR or ALK genomic tumor aberrations.

[0219] In some embodiments, the individual has previously received treatment for cancer.

[0220] In some embodiments, the individual has previously undergone treatment for cancer by administering a platinum-containing chemotherapeutic agent to the individual, and the individual has not responded to the chemotherapeutic agent.

[0221] In some embodiments, the PD-L1 axis binding antagonist is administered as monotherapy.

[0222] In some embodiments, the method further comprises administering an effective amount of one or more additional therapeutic agents.

[0223] In some embodiments, the one or more additional therapeutic agents are anti-tumor agents, chemotherapeutic agents, anti-proliferative agents, anti-angiogenic agents, radiation therapy, cytotoxic agents, immunomodulatory agents, or combinations thereof. include.

[0224] In some embodiments, the individual is human.

[0225] In another aspect, the invention provides a PD-L1 axis binding antagonist and an individual identified as likely to benefit from treatment comprising a PD-L1 binding antagonist by any one of the methods disclosed herein. and instructions for administering a PD-L1 axis binding antagonist.

[0226] In another aspect, the invention provides an individual selected for treatment comprising a PD-L1 axis binding antagonist and a PD-L1 binding antagonist by any one of the methods disclosed herein to treat PD - a kit comprising instructions for administering the L1 axis binding antagonist.

[0227] In another aspect, the invention features a kit for identifying an individual with cancer who may benefit from treatment comprising a PD-L1 axis binding antagonist, the kit comprising, in a sample from the individual: A reference immune score for the two or more genes, comprising reagents for determining expression levels of two or more of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 Immune Score expression levels of the same two or more genes above expression levels identify an individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0228] In another aspect, the invention features a kit for identifying an individual with cancer who may benefit from treatment comprising a PD-L1 axis binding antagonist, the kit comprising, in a sample from the individual: A reference immune score for one or more genes, comprising reagents for determining the expression level of one or more of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 An immune score expression level of the same one or more genes above the expression level identifies the individual as likely to benefit from a treatment comprising a PD-L1 axis binding antagonist, and benefiting from treatment with a PD-L1 axis binding antagonist. including prolongation of an individual's OS when compared to no treatment.

[0229] In another aspect, the invention features a kit for identifying an individual with cancer who may benefit from treatment comprising a PD-L1 axis binding antagonist, the method comprising, in a sample from the individual: to determine the expression level of one or more of the genes MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 wherein an immune score expression level of one or more genes above a reference immune score expression level of one or more genes identifies the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist However, benefits include prolongation of individual OS when compared to treatment without a PD-L1 axis binding antagonist.

[0230] In another aspect, the invention features a PD-L1 axis binding antagonist for use in a method of treating an individual with cancer, the method comprising: (a) of genes MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 in a sample from an individual Determining one or more expression levels, wherein the Immune Score expression level of one or more genes in the sample is determined to be above the reference Immune Score expression level of the one or more genes. deciding; and (b) administering to the individual an effective amount of a PD-L1 axis binding antagonist; including.

[0231] In another aspect, the present invention provides the following in a sample derived from an individual: , and a PD-L1 axis binding antagonist for treating cancer in an individual determined to have an immune score expression level of two or more genes above a reference immune score expression level of one or more of IGLL5 Characterized by

[0232] In another aspect, the invention features a PD-L1 axis binding antagonist for use in a method of treating an individual with cancer, the method comprising: (a) of genes MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 in a sample from an individual determining one or more expression levels, wherein the immune score expression level of the one or more genes in the sample is determined to be above the reference immune score expression level of the one or more genes, thereby , identifying an individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist, wherein the benefit comprises prolonging the individual's OS as compared to treatment without the PD-L1 axis binding antagonist; determining expression levels; and (b) administering to the individual an effective amount of a PD-L1 axis binding antagonist; including.

[0233] In another aspect, the present invention provides the following in a sample derived from an individual: , and PD-L1 axis binding for use in treating cancer in an individual determined to have an Immune Score expression level of one or more genes above a reference Immune Score expression level of one or more of IGLL5 An antagonist characterized by an Immune Score expression level of one or more genes above a reference Immune Score expression level of the one or more genes identifies an individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist. Benefits identified include prolongation of an individual's OS when compared to treatment without a PD-L1 axis binding antagonist.

[0234] In another aspect, the invention features a kit for identifying an individual with cancer who may benefit from treatment comprising a PD-L1 axis binding antagonist, the kit comprising in a tumor sample derived from the individual: A kit comprising reagents for determining the presence of tertiary lymphoid structures (TLS), wherein the presence of TLS in a tumor sample identifies an individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist. do.

[0235] In another aspect, the invention features a kit for identifying an individual with cancer who may benefit from treatment comprising a PD-L1 axis binding antagonist, the kit comprising, in a sample from the individual: reference to two or more genes, comprising reagents for determining the expression levels of two or more of the genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13 An Immune Score expression level of the same two or more genes above the Immune Score expression level identifies the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0236] In another aspect, the invention features a kit for identifying an individual with cancer who may benefit from treatment comprising a PD-L1 axis binding antagonist, the kit comprising in a tumor sample derived from the individual: comprising a reagent for determining the number of B cells, wherein the number of B cells in the tumor sample above the reference number of B cells identifies the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist do.

[0237] In another aspect, the invention features a kit for identifying an individual with cancer who may benefit from treatment comprising a PD-L1 axis binding antagonist, wherein the kit comprises a tumor sample derived from the individual comprising a reagent for determining whether the subject has clonally expanded B cells in the sample, wherein the clonally expanded B cells in the individual benefit from a treatment comprising a PD-L1 axis binding antagonist. Identify as a rich person. [Brief description of the drawing]

[0238] [Fig. 1A] B-cell gene signature and CD79A associated with improved survival with atezolizumab in the POPLAR Phase 2 trial. FIG. 1A is a differential gene expression analysis showing enrichment of B-cell gene signatures when comparing patients with OS≦6 months (n=24) versus OS≧12 months (n=43). Yellow circles indicate B-cell gene transcripts and red circles indicate Teff gene transcripts. [Fig. 1B] B-cell gene signature and CD79A associated with improved survival with atezolizumab in the POPLAR Phase 2 trial. Figure 1B is a Kaplan-Meier (KM) curve comparing survival probabilities of patients enriched for B-cell gene signatures (> median docetaxel = 11.07, < median docetaxel = 9.23, < median atezolizumab). =8.44 months) (n=194). [Fig. 1C] B-cell gene signature and CD79A associated with improved survival with atezolizumab in the POPLAR Phase 2 trial. Figure 1C is a Kaplan-Meier (KM) curve comparing survival probabilities of patients enriched for the CD79A gene (> median docetaxel = 12.45, < median docetaxel = 9.23, < median atezolizumab = 8.44). months) (n=194). [Figure 2A] Patients with elevated B-cell gene signatures associated with atezolizumab have been shown to induce tumor responses in multiple phase 3 trials. Figure 2A compares survival probabilities of patients enriched for B-cell gene signatures (both high (>median) and low (<median), as shown) in the OAK trial (n=727). KM curves (>median docetaxel=12.39, <median docetaxel=8.8, >median atezolizumab=18.04, <median atezolizumab=7.79 months) (n=591). [Fig.2B] Patients with elevated B-cell gene signatures associated with atezolizumab have been shown to induce tumor responses in multiple phase 3 trials. FIG. 2B is a KM curve comparing survival probabilities of patients enriched for B-cell gene signatures (both high (>median) and low (<median), as shown) in the BIRCH trial ( >median atezolizumab=17.74, <median atezolizumab=14.09 months) (n=591). [Figure 2C] Patients with elevated B-cell gene signatures associated with atezolizumab have been shown to induce tumor responses in multiple phase 3 trials. Figure 2C shows B cells across docetaxel and atezolizumab treatment groups in a patient population classified by RECIST V1.1 classification as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD). BCOR comparison for gene signature enrichment. The p-value was 0.34 in the docetaxel group and 0.00094 in the atezolizumab group (Kruskal-Wallis test). [Fig.2D] Patients with elevated B-cell gene signatures associated with atezolizumab have been shown to induce tumor responses in multiple phase 3 trials. Figure 2D is the progression-free survival (PFS) curve for the OAK trial (n=727) (>median docetaxel=4.17, <median docetaxel=2.83, >median atezolizumab=2.99, <median atezolizumab) value = 1.64 months). [Fig.3A] We show that patients responsive to atezolizumab have infiltration of B cells and TLS into their tumors, which is associated with improved survival. Figure 3A is an image representing immunofluorescence of a pre-treatment lung adenocarcinoma sample showing a high B-cell gene signature and grouped into atezolizumab responders: CD79A (green), CD8 (red) and Ki67 (blue). is. Scale bar: 100mm. [Fig.3B] We show that patients responsive to atezolizumab have infiltration of B cells and TLS into their tumors, which is associated with improved survival. FIG. 3B depicts H&E staining of lung adenocarcinoma from an atezolizumab-responsive patient showing the presence of TLS indicated by markings. Scale bar: 500mm. [Figure 3C-E] We show that patients responsive to atezolizumab have infiltration of B cells and TLS into their tumors, which is associated with improved survival. Figure 3C shows the association of CD79a gene expression comparing patient tissues with and without TLS (***: p<0.001, paired t-test). Figure 3D shows the association of CD3D gene expression comparing patient tissues with and without TLS (**: p<0.01 paired t-test). FIG. 3E shows the association of overall survival (OS (months)) with the presence or absence of TLS in both docetaxel and atezolizumab treatment groups in the POPLAR trial (*: p<0.05, paired t-test) (n=194). [Fig. 4A] Immunostaining for TLS is shown. IHC display of lung adenocarcinoma tissue from a patient who exhibited a high B-cell gene signature and was classified as an atezolizumab responder, showing hematoxylin & eosin (H&E) staining indicating the presence of TLS by open circles. . Scale bar is 20 μm. [Fig. 4B] Immunostaining for TLS is shown. IHC display of lung adenocarcinoma tissue from a patient who exhibited a high B-cell gene signature and was classified as an atezolizumab responder, showing panCK and CD8 (red) staining. Scale bar is 20 μm. [Fig. 4C] Immunostaining for TLS is shown. IHC display of lung adenocarcinoma tissue from a patient who exhibited a high B-cell gene signature and was classified as a tezolizumab responder, showing PNAd (peripheral lymph node addressin). Scale bar is 20 μm. [Fig. 4D] Immunostaining for TLS is shown. IHC display of lung adenocarcinoma tissue from a patient who exhibited a high B-cell gene signature and was classified as an atezolizumab responder, showing CD40 staining. Scale bar is 20 μm. [Fig. 5A] KM curves comparing survival probabilities of patients enriched for TLS gene signatures in the POPLAR trial (>median docetaxel=10.63, <median docetaxel=9.9, >median atezolizumab=15.47, <atezolizumab median=8.54 months) (n=194). [Fig.5B] KM curves comparing survival probabilities of patients enriched for TLS gene signatures in OAK are shown (>median docetaxel=10.28, <median docetaxel=10.28, >median atezolizumab=14.32, <median atezolizumab=14.32) Median = 11.76 months) (n = 727). [Fig. 5C] KM curves comparing survival probabilities of patients enriched for germinal center gene signatures in the POPLAR trial (> median docetaxel = 8.87, < median docetaxel = 10.05, < median atezolizumab = 9.72 months) (n =194). [Fig.5D] KM curves comparing survival probabilities of patients enriched for germinal center gene signatures in the OAK trial (>median docetaxel=11.43, <median docetaxel=8.9, >median atezolizumab=16.26, <median atezolizumab=16.26) median=9.95 months) (n=727). [Fig.6A] We show that the B cell repertoire is enriched in patients who benefit from atezolizumab. KM curves comparing survival probabilities of patients enriched for the plasma B-cell two-gene signature (>median docetaxel=11.07, <median docetaxel=9.53, >median atezolizumab=16.43, <median atezolizumab) value = 7.82 months) (n = 727). [Fig.6B-E] We show that the B cell repertoire is enriched in patients who benefit from atezolizumab. For (FIG. 6B) control patients (n=3), (FIG. 6C) PR (red) and SD (blue) patients before and after atezolizumab treatment (n=8), and (FIG. 6D) PD patients (n=3). , BCR sequencing was performed from the limited patient samples shown showing clonality diversity using the Shannon index, and FIG. 6E is their summary showing changes in the Shannon index. [Fig.7] Shows gene enrichment in the POPLAR trial and provides a list of atezolizumab responder-enriched genes with their HRs and p-values. [Fig. 8A] Figure 3 shows the association between B cells and PD-L1 status. Quantification of the association between B-cell gene signatures and immune cell PD-L1 levels as determined by the SP142 PD-L1 assay (Wilcoxon paired analysis) (IC0=0%, IC1=1-5%, IC2=5-49%, IC3=>50%). [Fig. 8B] Figure 3 shows the association between B cells and PD-L1 status. Quantification of the association of B-cell gene signatures with immune and tumor cell PD-L1 as determined by the SP142 PD-L1 assay (Wilcoxon paired analysis). [Figure 9A-D] TLS occurrence rates and their relationships are shown. Figure 9A shows the distribution of TLS (with germinal centers) and lymphatic aggregates (without germinal centers) based on histology. Figure 9B shows the distribution of TLS in biopsy and resection specimens. Figure 9C shows the association between the presence of TLS identified by IHC and the gene signature based on RNA sequencing of B cells. (Wilcoxon paired analysis). [Figure 9E-F] TLS occurrence rates and their relationships are shown. FIG. 9E shows the association between the presence of TLS identified by IHC and the RNA-sequencing-based gene signature of TLS (Wilcoxon pair analysis). FIG. 9F shows the association of overall survival (OS (months)) with the presence or absence of TLS in both docetaxel and atezolizumab treatment groups in the OAK trial (***: p<0.001, paired t-test). [Fig. 10] AD show the association of B cell and TLS gene signatures with other biomarkers. FIG. 10A quantifies the association between B-cell gene signature and tumor mutational burden (TMB), and FIG. 10B, between B-cell gene signature and STK11 mutation status. FIG. 10C shows the association between TLS gene signature and TMB, and FIG. 10D shows association between TLS gene signature and STK11 mutation status (Wilcoxon pair analysis). [Fig. 11A] It shows an association between improved survival and B-cell immunophenotype. KM curves comparing survival probabilities of patients enriched for naive B-cell gene signatures (>median docetaxel=10.71, <median docetaxel=9.9, >median atezolizumab=13.47, <median atezolizumab). =11.79 months) (n=727). [Fig. 11B] It shows an association between improved survival and B-cell immunophenotype. KM curves comparing survival probabilities of patients enriched for memory B cell signatures (>median docetaxel=12.39, <median docetaxel=8.8, >median atezolizumab=17.64, <median atezolizumab= 8.9 months) (n=727). [Fig. 11C] It shows an association between improved survival and B-cell immunophenotype. KM curves comparing survival probabilities of patients enriched for plasma B cells (>median docetaxel=11.53, <median docetaxel=9.72, >median atezolizumab=15.49, <median atezolizumab=9.72). months) (n=727). [Figure 12A-D] FIG. 4 shows enrichment of IgG subtype plasma cells in atezolizumab responders. Figure 12A shows % IgG; Figure 12B shows the ratio of IgG to IgM; Figure 12C shows % IgM; Figure 12D shows the relative amount of IgG compared to the total IgG and IgM content. showing. Figure summarizing BCR sequencing of different Ig domains compiled from a limited sample of patients classified as PR (brown), SD (blue) and PD (red) patients by RECIST v1.1 before and after atezolizumab treatment. (n=17). [Fig. 12E] FIG. 4 shows enrichment of IgG subtype plasma cells in atezolizumab responders. Figure 12E shows % IgA. Figure summarizing BCR sequencing of different Ig domains from a limited sample of patients classified by RECIST v1.1 into PR (brown), SD (blue) and PD (red) patients before and after atezolizumab treatment. Compiled (n=17). [Fig. 13A] It shows an association between improved survival and B-cell immunophenotype. KM curves comparing survival probabilities of patients enriched for T cell effector gene signatures along with CD79A in the OAK trial (>median docetaxel=12.97, <median docetaxel=9.12, >median atezolizumab=15.9, <median atezolizumab = 9.48 months). [Fig. 13B] It shows an association between improved survival and B-cell immunophenotype. KM curves comparing survival probabilities of patients enriched for T cell effector gene signatures along with CD79A in the POPLAR trial (> median docetaxel = 9.63, < median docetaxel = 9.35, < median atezolizumab = 8.54 months). ). [Fig. 13C] It shows an association between improved survival and B-cell immunophenotype. KM curves comparing survival probabilities of patients enriched for T-cell effector gene signatures alone in the OAK trial (>median docetaxel=11.1, <median docetaxel=9.82, >median atezolizumab=15.34, < median atezolizumab = 10.12 months). [Fig. 13D] It shows an association between improved survival and B-cell immunophenotype. KM curves comparing survival probabilities of patients enriched for T-cell effector gene signatures alone in the POPLAR trial (>median docetaxel=9.72, <median docetaxel=9.23, >median atezolizumab=15.47, < median atezolizumab = 9.72 months). [Fig. 14A] We show that the association between B-cell signatures and improved OS is consistent across major subgroups. A high B-cell signature is associated with improved OS with atezolizumab across the main subgroups: squamous versus non-squamous. [Fig. 14B] We show that the association between B-cell signatures and improved OS is consistent across major subgroups. A high B-cell signature is associated with improved OS with atezolizumab across major subgroups: biopsy versus resection specimens. [Fig. 14C] We show that the association between B-cell signatures and improved OS is consistent across major subgroups. A high B-cell signature is associated with improved OS with atezolizumab across the main subgroups: lung versus lymph node metastases. [Fig. 15A] Shows that intratumoral B cells are associated with increased OS in NSCLC patients treated with atezolizumab. Figure 15A shows differentially expressed genes (FDR Volcano plot showing P<0.05, absolute logFC>=0.5). [Fig. 15B] Shows that intratumoral B cells are associated with increased OS in NSCLC patients treated with atezolizumab. Figure 15B is the same view as Figure 15A in a patient treated with docetaxel. [Fig. 15C-D] Shows that intratumoral B cells are associated with increased OS in NSCLC patients treated with atezolizumab. Figures 15C and 15D show Kaplan-Meier (KM) curves comparing survival probabilities of patients enriched for CD79A and CD19. Gene expression was dichotomized into high (upper tertile T3) or low / intermediate (tertiles T1 and T2). [Fig. 15E-F]Shows that intratumoral B cells are associated with increased OS in NSCLC patients treated with atezolizumab. Figures 15E and 15F show Kaplan-Meier (KM) curves comparing survival probabilities of patients enriched for the IFNG and IFN inducible chemokine CXCL10. Gene expression was dichotomized into high (upper tertile T3) or low / intermediate (tertiles T1 and T2). [Fig. 15G] Shows that intratumoral B cells are associated with increased OS in NSCLC patients treated with atezolizumab. FIG. 15G is an immunofluorescence image depicting pretreatment lung adenocarcinoma tumors from two atezolizumab responsive (left panel) and two atezolizumab non-responsive patients. (Scale bar: immunofluorescence μm). [Fig. 16A] Identification of three B-cell subsets in NSCLC tumors. Left: dimensional reduction of UMAP for 20,362 cells (dots). The same UMAP is shown on the top right. Bottom right: fraction of cells in each cluster from metastatic lymph nodes (mLN), non-metastatic lymph nodes (nLN), normal adjacent lung tissue (nLung), tumor biopsies (Tbio) and tumor resection specimens (T res). Bottom middle: Relative mean expression of markers indicated in clusters in Figure 16A. [Fig. 16B] Identification of three B-cell subsets in NSCLC tumors. Left: Fraction of cells from each patient (row) of the cluster in Figure 16A. Right: absolute number of cells for each patient in the clusters in Figure 16A. [Fig. 16C] Identification of three B-cell subsets in NSCLC tumors. FIG. 16B is a violin diagram showing expression of marker genes in the cluster of FIG. 16A. [Fig. 16D] Identification of three B-cell subsets in NSCLC tumors. UMAP of six fresh NSCLC tumor-derived B cell subsets analyzed by CyTOF, including follicular B cells (HLA-DR+, CD38-), germinal center (GC) B cells (HLA-DR+, CD38+ Ki67+) and the presence of plasma cells (HLA-DR-, CD38++). [Fig. 17A] B cell subset signatures in bulk RNAseq profiles are shown. Hierarchical clustering of three B-cell signatures identified from OAK scRNA-seq data. [Fig. 17B] B cell subset signatures in bulk RNAseq profiles are shown. FIG. 4 is a scatter plot showing the correlation between plasma cell, germinal center B cell and follicular B cell signatures. Pearson R values ​​are reported. [Fig. 18A-C] We show that the plasma cell signature independently predicts response to atezolizumab. A-C are Kaplan-Meier curves for OS for each of the three signatures dichotomized into T3 (high tertile) versus T1-T2 (low / middle tertile). Log-rank test p-values ​​are reported. [Fig. 18D] We show that the plasma cell signature independently predicts response to atezolizumab. Heat map showing results from a Cox proportional hazards model testing hazard ratios within and between treatment groups. Dots represent statistically significant HRs (p<0.05). [Fig. 18E-F] We show that the plasma cell signature independently predicts response to atezolizumab. E, Forest plot showing the importance of three B-cell signatures and a previously reported 8-gene T effector signature (tGE8) in the univariate interaction model, showing the interaction between signature scores and treatment groups. being considered. F is a forest plot showing the importance of the four signatures shown in E in multivariate analysis of atezolizumab (left panel) and docetaxel (right panel) treated groups. Signatures are dichotomous in T3 versus T1-T2 in all models. [Fig. 19A] Patients with TLS / LA+ tumors show improved OS with atezolizumab. H&E staining showing tumors with tertiary lymphoid structures (TLS, left panel), only lymphoid aggregates (middle panel) or none (right panel) in each sample from POPLAR. [Fig. 19B-C] Patients with TLS / LA+ tumors show improved OS with atezolizumab. B is a bar graph representing the percentage of tumors with TLS, lymphatic aggregates only (LA), or none in each treatment arm of POPLAR. C is a Kaplan-Meier curve representing OS in tumors with TLS or LA versus neither, by treatment arm. [Fig. 20A] TLS / LA+ tumors are enriched in plasma cells. Hierarchical cluster of signatures of three B-cell subsets. Samples are ordered by TLS / LA status. [Fig. 20B] TLS / LA+ tumors are enriched in plasma cells. Volcano plot representing differentially expressed genes between tumors with TLS and / or LA versus tumors with neither. Genes from three B-cell signatures are highlighted. [Fig. 20C] TLS / LA+ tumors are enriched in plasma cells. FIG. 10 is a violin diagram showing signature z-scores of plasma cells, germinal center B cells and follicular B cells grouped by TLS / LA status. Mann-Whitney p-values ​​are reported. [Figure 21A] Additional information is provided regarding the data shown in Figures 15A-15G. Genes differentially expressed after treatment with atezolizumab between patients from POPLAR with OS<6 months (n=58) and patients from OS>12 months (n=87) (FDR P<0.05, Volcano plot showing absolute logFC>=0.5). [Fig. 21B] Additional information is provided regarding the data shown in Figures 15A-15G. FIG. 21B is the same view as FIG. 21A in a patient treated with docetaxel. [Figure 21C-D] Additional information is provided regarding the data shown in Figures 15A-15G. C and D show Kaplan-Meier (KM) curves comparing survival probabilities of patients enriched for CD79A and CD19. Gene expression was dichotomized into high (upper tertile T3) or low / intermediate (tertiles T1 and T2). [Fig.21E-F] Additional information is provided regarding the data shown in Figures 15A-15G. E and F show Kaplan-Meier (KM) curves comparing survival probabilities of patients enriched for the IFNG and IFN inducible chemokine CXCL10. Gene expression was dichotomized into high (upper tertile T3) or low / intermediate (tertiles T1 and T2). [Fig. 22A] Additional information is provided regarding the data shown in Figures 16A-16D. Expression of putative signature genes of follicular B cells, plasma cells, and GC B cells within the non-B cell scRNA-seq compartment. Highlighted are candidate markers for bulk deconvolution, showing the reason for signature gene removal due to high bulk background. [Fig. 22B] Additional information is provided regarding the data shown in Figures 16A-16D. UMAP projection of scRNA-seq expression in B cells of CyTOF marker genes representing follicular B cells, plasma cells and GC B cells reproducing CyTOF results. Follicular B cells (HLA-DR+, CD38-), germinal center (GC) B cells (HLA-DR+, CD38+ Ki67+) and plasma cells (HLADR-, CD38++). [Fig.23] Pearson correlation of signature genes of B cell subsets of all samples in OAK, described in Example 1 below. [Fig. 24A] Additional information is provided regarding Figures 18A-18F. Best overall response was stratified as objective response or long-term stable disease (SD with PFS ≥ 6 months) versus progressive disease or non-long-term stable disease (SD with PFS < 6 months) within each treatment arm. Signature scores of dichotomous plasma cells by quantile. p-values ​​are Fisher exact. [Fig.24B-C] Additional information is provided regarding Figures 18A-18F. Kaplan-Meier curves for OS for each of the three signatures, dichotomized into T3 (high tertile) versus T1-T2 (low / middle tertile). Log-rank test P-values ​​are reported. [Fig.24D-E] Additional information is provided regarding Figures 18A-18F. D is the Kaplan-Meier curves for OS for each of the three signatures, dichotomized into T3 (high tertile) versus T1-T2 (low / middle tertile). Log-rank test P-values ​​are reported. E, Kaplan-Meier curves of OS for plasma cell signatures, bifurcated into T3 vs. T1-2 in the TCGA 365 LUAD / LUSC data. Hazard ratios for overall survival with high trait signatures and associated p-values ​​are shown. [Mode for carrying out the invention]

[0239] The present disclosure provides cancer (e.g., lung cancer (e.g., non-small cell lung cancer (NSCLC)), bladder cancer (e.g., urothelial carcinoma (UC)), kidney cancer (e.g., renal cell carcinoma (RCC)). , and breast cancer (eg, triple-negative breast cancer (TNBC)).

[0240] This disclosure provides, at least in part, the presence and / or expression levels of one or more of the biomarkers disclosed herein, e.g., any gene set forth in any one of Tables 1-17 , the presence and / or level of expression of a B cell signature (e.g., a plasma B cell signature), the presence of tertiary lymphoid structures (TLS), the presence and / or level of expression of a TLS signature, the presence and / or number of B cells, and / or the presence and / or number of clonally expanded B cells can be used to identify PD-L1 axis binding antagonists (e.g., PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD- Based on the discovery that individuals who are likely to benefit from treatment with an L1 antibody (eg, atezolizumab) or a PD-1 binding antagonist (eg, an anti-PD-1 antibody) can be identified and selected.

[0241] For example, as described in Example 1 below, the present disclosure demonstrates that elevated expression levels of other B-cell signature genes, including CD79A and plasma B-cell signature genes, are associated with treatment with the anti-PD-L1 antibody atezolizumab. We demonstrate that it is associated with improved overall survival (OS) in NSCLC patients who undergo. Similarly, the presence of tertiary lymphoid structures (TLS), as well as elevated expression levels of TLS signature genes, were associated with improved OS in NSCLC patients treated with the anti-PD-L1 antibody atezolizumab. Thus, using the biomarkers disclosed herein, e.g. identifying individuals likely to benefit from treatment with e.g. and to provide individualized treatment regimens to patients who are likely to benefit.

[0242] I. Definition As used herein, the term "about" refers to the normal error range for the respective value as readily understood by those skilled in the art. Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.

[0243] As used herein, "administering" refers to a dosage of a compound (e.g., a PD-L1 axis binding antagonist (e.g., a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody, e.g., atezolizumab), or a PD-1 binding antagonist (e.g., an anti-PD-1 antibody)) or composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition comprising a PD-L1 axis binding antagonist) to a subject. Compounds and / or compositions utilized in the methods described herein can be administered, for example, intravenously (eg, by intravenous infusion), subcutaneously, intramuscularly, intradermally, transdermally, intraarterially, intraperitoneally. intra, intralesional, intracranial, intraarticular, intraprostatic, intrapleural, intratracheal, intranasal, intravitreal, intravaginal, intrarectal, topical, intratumoral, intraperitoneal, subconjunctival, intravesicular, transmucosal , intrapericardial, intraumbilical, intraocular, orally, topically, or intralocally, or by inhalation, injection, infusion, continuous infusion, local perfusion directly to target cells, catheters, or irrigation, or creams; or in a lipid composition.The method of administration may vary depending on a variety of factors, such as the compound or composition being administered and the severity of the condition, disease, or disorder being treated.

[0244] "Affinity" refers to the total strength of non-covalent interactions between a single binding site of a molecule (eg antibody) and its binding partner (eg antigen). Unless otherwise indicated, "binding affinity" as used herein refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (eg, antibody and antigen). The affinity of molecule X for its partner Y is generally defined by the dissociation constant (K D ). Affinity can be measured by common methods known in the art, including those described herein. Certain exemplary embodiments for measuring binding affinity are described below.

[0245] An "affinity matured" antibody has one or more alterations in one or more of the hypervariable regions (HVRs) relative to the parent antibody without alterations, and such alterations increase the affinity of the antibody for antigen. refers to an antibody in which is improved.

[0246] As used herein, "amplification" generally refers to the process of producing multiple copies of a desired sequence. "Multiple copies" means at least two copies. A "copy" does not necessarily mean perfect sequence complementarity or identity to the template sequence. For example, copies can be made by nucleotide analogs such as deoxyinosine, deliberate sequence modifications (e.g., sequence modifications introduced through primers containing sequences that are hybridizable to the template but not complementary), and / or during amplification. May contain any sequence errors that occur.

[0247] The term "antibody" herein is used in the broadest sense and encompasses various antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (antibodies), so long as they exhibit the desired antigen-binding activity. bispecific antibodies), and antibody fragments.

[0248] An "antibody fragment" refers to a molecule other than an intact antibody that contains a portion of the intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab') 2 , diabodies, linear antibodies, single chain antibody molecules (eg scFv), and multispecific antibodies formed from antibody fragments.

[0249] An "antibody that binds to the same epitope" as a reference antibody refers to an antibody that blocks the binding of the reference antibody to its antigen by 50% or more in a competition assay, and vice versa. Blocks bonds by 50% or more. An exemplary competition assay is provided herein.

[0250] The terms "anti-PD-L1 antibody" and "antibody that binds to PD-L1" refer to PD-L1 antibodies with sufficient affinity such that the antibodies are useful as diagnostic and / or therapeutic agents in targeting PD-L1. Refers to an antibody that can bind to L1. In one embodiment, the degree of binding of the anti-PD-L1 antibody to an unrelated non-PD-L1 protein is less than about 10% of the binding of the antibody to PD-L1, e.g., as measured by radioimmunoassay (RIA). be. In certain embodiments, the anti-PD-L1 antibodies bind to PD-L1 epitopes that are conserved among PD-L1 from different species. In certain embodiments, the anti-PD-L1 antibody is atezolizumab. PD-L1 (programmed death ligand 1) is also referred to in the art as "programmed cell death 1 ligand 1," "PDCD1LG1," "CD274," "B7-H," and "PDL1." An exemplary human PD-L1 is shown in UniProtKB / Swiss-Prot Accession No. Q9NZQ7.1.

[0251] The term "anti-cancer therapy" refers to cancer (e.g., lung cancer (e.g., non-small cell lung cancer (NSCLC), including non-squamous NSCLC and squamous NSCLC), bladder cancer (e.g., urothelial carcinoma (UC)), Refers to therapies useful for treating kidney cancer (eg renal cell carcinoma (RCC)) or breast cancer (eg triple negative breast cancer (TNBC)). Examples of anti-cancer therapeutic agents include, but are not limited to, PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists ( For example, anti-PD-1 antibodies)), chemotherapeutic agents, growth inhibitory agents, cytotoxic agents, agents used in radiotherapy, antiangiogenic agents, apoptotic agents, antitubulin agents, and to treat cancer. anti-CD20 antibodies, platelet-derived growth factor inhibitors (e.g., GLEEVEC TM (imatinib mesylate)), COX-2 inhibitors (e.g. celecoxib), interferons, cytokines, antagonists (e.g. neutralizing antibodies): PDGFR-β, BlγS, APRIL, one or more BCMA receptors , TRAIL / Apo2, other bioactive and organic chemical agents, etc. Combinations of these are also included in the present invention.

[0252] "Article of manufacture" or "kit", as used interchangeably herein, includes at least one reagent, e.g. (including NSCLC), bladder cancer (e.g. UC), kidney cancer (e.g. RCC), or breast cancer (e.g. TNBC)), or specific biomarker probes described herein. Refers to any article of manufacture (eg, package or container) or kit that contains a probe (eg, nucleic acid probe or antibody) for specific detection. In certain embodiments, an article of manufacture or kit is promoted, distributed, or sold as a unit for practicing the methods described herein.

[0253] The phrase "based on" as used herein means that information about one or more biomarkers is used to inform treatment decisions, information provided in package inserts, marketing / promotional guidance, etc. means to be

[0254] As used herein, the term "B cells" refers to lymphocytes that mature in the bone marrow, including but not limited to naive B cells, memory B cells, or plasma B cells (also called plasma cells or effector B cells). including. B cells are also known in the art as "B lymphocytes." B cells, unlike other lymphocytes such as T cells or natural killer cells, can express the B cell receptor (BCR) on their plasma membrane.

[0255] A "B-cell receptor" or "BCR" is a transmembrane receptor complex located on the plasma membrane of B-cells. The BCR contains a signal composed of a membrane-bound immunoglobulin (mIg) portion (e.g., mIgA, mIgG, mIgE, mIgM, or mIgD) and a CD79A / CD79B heterodimer (also known as Ig-α / Ig-β) Includes transmission part. Each member of the CD79A / CD79B heterodimer spans the plasma membrane and contains a cytoplasmic tail containing an immunoreceptor tyrosine-based activation motif (ITAM).

[0256] A "blocking" or "antagonist" antibody is an antibody that inhibits or reduces the biological activity of the antigen to which it binds. Preferred blocking or antagonist antibodies substantially or completely inhibit the biological activity of the antigen.

[0257] "Binding domain" means the portion of a compound or molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Binding domains include, but are not limited to, antibodies (e.g., monoclonal antibodies, polyclonal antibodies, recombinant antibodies, humanized antibodies, and chimeric antibodies), antibody fragments or portions thereof (e.g., Fab fragments, Fab' 2 , scFv antibodies, SMIPs, domain antibodies, diabodies, minibodies, scFv-Fc, affibodies, nanobodies, and VH and / or VL domains of antibodies), receptors, ligands, aptamers, and binding partners identified Other molecules are included.

[0258] The term "biomarker" as used herein refers to a sample (e.g., any gene shown in any one of Tables 1-17, e.g., CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, MZB1, CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, CXCL13, DERL3, JSRP1, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, and IGLC7), eg, predictive, diagnostic, and / or prognostic indicators. A biomarker is a disease or disorder (e.g., cancer, e.g., lung cancer (e.g., non-squamous NSCLC and squamous NSCLC) characterized by specific molecular, pathological, histological, and / or clinical features. NSCLC), bladder cancer (eg UC), kidney cancer (eg RCC), or breast cancer (eg TNBC)). In some embodiments, biomarkers are genes. Biomarkers include, but are not limited to, polynucleotides (e.g., DNA and / or RNA), polynucleotide copy number alterations (e.g., DNA copy number), polypeptides, polypeptides, and polynucleotide modifications (e.g., post-translational modifications), carbohydrates, glycolipid-based molecular markers, cells (eg, B cells), and / or histological structures (eg, tertiary lymphoid structures).

[0259] The terms "biomarker signature," "signature," "biomarker expression signature," or "expression signature" are used interchangeably herein, and their expression (e.g., in any one of Tables 1-17). any of the indicated genes, e.g. immune score expression level of one or more of CXCL10, CXCL11, CXCL13, DERL3, JSRP1, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, and IGLC7) is an indicator, e.g. , refers to one or a combination of biomarkers that are predictive, diagnostic, and / or prognostic. A biomarker signature is a disease or disorder (e.g., cancer, e.g., lung cancer (e.g., non-squamous NSCLC and squamous NSCLC) characterized by specific molecular, pathological, histological, and / or clinical features. (including NSCLC), bladder cancer (eg, UC), renal cancer (eg, RCC), or breast cancer (eg, TNBC)). In some embodiments, a biomarker signature is a "gene signature." The term "gene signature" is used interchangeably with "gene expression signature" and describes one or a combination of polynucleotides whose expression is indicative, e.g., predictive, diagnostic, and / or prognostic. Point. The gene signature is, for example, a B-cell gene signature (e.g., one or more of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and / or MZB1), naive B-cell genes. signature (e.g., one or more of the genes ABCB4, BCL7A, BEND5, BRAF, IL4R, LINC00921, MEP1A, MICAL3, NIPSNAP3B, PSG2, SELL, TCL1A, UGT1A8, and / or ZNF286A), memory B-cell gene signature (e.g., , one or more of the genes AIM2, ALOX5, CLCA3P, FAM65B, IFNA10, IL7, NPIPB15, SP140, TNFRSF13B, TRAF4, and / or ZBTB32), plasma cell gene signature (e.g., genes DERL3, JSRP1, TNFRSF17, SLAMF7, One or more of IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7 and / or IGLL5 and / or genes ABCB9, AMPD1, ANGPT4, ATXN8OS, C11, CCr10 , HIST1H2AE, HIST1H2BG, IGHE, KCNA3, KCNG2, LOC100130100, MAN1A1, MANEA, MAST1, MROH7, MZB1, PAX7, PDK1, RASGRP3, REN, SPAG4, ST6GALNAC4, TGM5, UGT2B17, ZBP1, and / or ZNF16 above), a TLS signature (e.g., one or more of the genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and / or CXCL13), or a T effector signature (e.g., one or more of the genes CD8A, EOMES, GZMA, TBX21, IFNG, GZMB, CXCL9 and / or CXCL10). In some embodiments, a biomarker signature is a "protein signature." The term "protein signature" is used interchangeably with "protein expression signature", one or a combination of polypeptides whose expression is indicative, e.g., predictive, diagnostic, and / or prognostic. point to

[0260] Unless otherwise indicated, the term "CD79A" as used herein refers to the cluster of differentiated CD79A genes, including primates (e.g., humans) and rodents (e.g., mice and rats). Any native CD79A from any vertebrate source, including mammals, is included. CD79A is also known in the art as Ig-alpha, B cell antigen receptor complex-associated protein alpha chain, and MB-1 membrane glycoprotein. The term encompasses "full-length," unprocessed CD79A, and any form of CD79A that results from processing within the cell. The term also includes naturally occurring variants of CD79A, such as splice or allelic variants. An exemplary human CD79A nucleic acid sequence is listed in SEQ ID NO: 13 (NCBI Reference Sequence: NM_001783.4). The amino acid sequence of an exemplary protein encoded by human CD79A is SEQ ID NO: 14 (UNIPROT TM Accession No. P11912-1).

[0261] Unless otherwise indicated, the term "SLAMF7" as used herein may be derived from any vertebrate source, including mammals such as primates (e.g. humans) and rodents (e.g. mice and rats). Refers to any native SLAMF7 (signaling lymphocyte activation molecule (SLAM) family member 7). The term encompasses "full-length" unprocessed SLAMF7 as well as any form of SLAMF7 resulting from processing within the cell. The term also includes naturally occurring variants of SLAMF7, such as splice or allelic variants. An exemplary human SLAMF7 nucleic acid sequence is listed in SEQ ID NO: 15 (NCBI Reference Sequence: NM_021181.5). The amino acid sequence of an exemplary protein encoded by human SLAMF7 is SEQ ID NO: 16 (UNIPROT TM Accession No.Q9NQ25-1).

[0262] As used herein, the term "BTK" is derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. Refers to any naturally occurring BTK (tyrosine kinase). The term encompasses "full-length," unprocessed BTK, as well as any form of BTK resulting from processing within a cell. The term also includes naturally occurring variants of BTK, such as splice or allelic variants. An exemplary human BTK nucleic acid sequence is listed in SEQ ID NO: 17 (NCBI Reference Sequence: NM_000061.2). The amino acid sequence of an exemplary protein encoded by human BTK is SEQ ID NO: 18 (UNIPROT TM Accession No. Q06187-1).

[0263] Unless otherwise indicated, the term "TNFRSF17" as used herein may be derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). Refers to any native TNFRSF17 (tumor necrosis factor receptor superfamily member 17). TNFRSF17 is also known in the art as B-cell maturation antigen (BCMA). The term encompasses "full length" unprocessed TNFRSF17 as well as any form of TNFRSF17 resulting from processing within the cell. The term also includes naturally occurring variants of TNFRSF17, such as splice or allelic variants. An exemplary human TNFRSF17 nucleic acid sequence is listed in SEQ ID NO: 19 (NCBI Reference Sequence: NM_001192.3). The amino acid sequence of an exemplary protein encoded by human TNFRSF17 is SEQ ID NO: 20 (UNIPROT TM Accession No. Q02223-1).

[0264] As used herein, the term "IGJ" is from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. Refers to any native IGJ (immunoglobulin J chain). The term encompasses "full-length," unprocessed IGJ, as well as any form of IGJ resulting from intracellular processing. The term also includes naturally occurring variants of IGJ, such as splice or allelic variants. An exemplary human IGJ nucleic acid sequence is listed in SEQ ID NO: 21 (NCBI Reference Sequence: NM_144646.4). The amino acid sequence of an exemplary protein encoded by human IGJ is SEQ ID NO: 22 (UNIPROT TM Accession No. P01591-1).

[0265] As used herein, the term "IGLL5" is from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. It refers to any native IGLL5 (immunoglobulin lambda-like polypeptide 5). IGLL5 is also known in the art as IGL, IGLV, and VL_MAR. The term encompasses "full-length" unprocessed IGLL5 as well as any form of IGLL5 that results from intracellular processing. The term also includes naturally occurring variants of IGLL5, such as splice or allelic variants. An exemplary human IGLL5 nucleic acid sequence is listed in SEQ ID NO: 23 (NCBI Reference Sequence: NM_001178126.2). The amino acid sequence of an exemplary protein encoded by human IGLL5 is SEQ ID NO: 24 (UNIPROT TM Accession No.B9A064-1).

[0266] As used herein, the term "RBPJ" is from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. Refers to any native RBPJ (recombinant signal binding protein of the immunoglobulin kappa J region). RBPJ is also known in the art as CBF1 and hairless recombinant binding protein suppressor. The term encompasses "full-length," unprocessed RBPJ, as well as any form of RBPJ resulting from intracellular processing. The term also includes naturally occurring variants of RBPJ, such as splice or allelic variants. An exemplary human RBPJ nucleic acid sequence is listed in SEQ ID NO: 25 (NCBI Reference Sequence: NM_005349.3). The amino acid sequence of an exemplary protein encoded by human RBPJ is SEQ ID NO: 26 (UNIPROT TM Accession No. Q06330-1).

[0267] Unless otherwise indicated, the term "MZB1" as used herein may be derived from any vertebrate source, including mammals such as primates (e.g. humans) and rodents (e.g. mice and rats). Refers to any native MZB1 (marginal zone B and B1 cell-specific protein). MZB1 is also known in the art as MEDA-7, PACAP, and pERp1. The term encompasses "full length" unprocessed MZB1 as well as any form of MZB1 resulting from processing within the cell. The term also includes naturally occurring variants of MZB1, such as splice or allelic variants. An exemplary human MZB1 nucleic acid sequence is listed in SEQ ID NO: 27 (NCBI Reference Sequence: NM_016459.4). The amino acid sequence of an exemplary protein encoded by human MZB1 is SEQ ID NO: 28 (UNIPROT TM Accession No.Q8WU39-1).

[0268] As used herein, the term "CCL2" is from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. It refers to any natural CCL2 (chemokine (C-C motif) ligand 2). CCL2 is also known in the art as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. The term encompasses "full-length" unprocessed CCL2 as well as any form of CCL2 resulting from processing within the cell. The term also includes naturally occurring variants of CCL2, such as splice or allelic variants. An exemplary human CCL2 nucleic acid sequence is listed in SEQ ID NO: 29 (NCBI Reference Sequence: NM_002982.4). The amino acid sequence of an exemplary protein encoded by human CCL2 is SEQ ID NO: 30 (UNIPROT TM Accession No.P13500-1).

[0269] As used herein, the term "CCL3" is from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. Refers to any naturally occurring CCL3 (chemokine (C-C motif ligand 3). CCL3 is also known in the art as macrophage inflammatory protein 1-alpha (MIP-1-alpha). It includes "full-length" unprocessed CCL3, and any form of CCL3 resulting from processing within a cell.The term also includes naturally occurring variants of CCL3, such as splice or allelic variants. The nucleic acid sequence of an exemplary human CCL3 is listed in SEQ ID NO: 31 (NCBI Reference Sequence: NM_002983.3) The amino acid sequence of an exemplary protein encoded by human CCL3 is SEQ ID NO: 32 (UNIPROT TM Accession No.P10147-1).

[0270] As used herein, the term "CCL4" is derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. Refers to any naturally occurring CCL4 (chemokine (C-C motif ligand 4). CCL4 is also known in the art as macrophage inflammatory protein 1-beta (MIP-1-beta). It includes "full-length" unprocessed CCL4, and any form of CCL4 resulting from processing within a cell.The term also includes naturally occurring variants of CCL4, such as splice or allelic variants. An exemplary human CCL4 nucleic acid sequence is listed in SEQ ID NO: 33 (NCBI Reference Sequence: NM_002984.4) The amino acid sequence of an exemplary protein encoded by human CCL4 is SEQ ID NO: 34 (UNIPROT TM Accession No. P13236-1).

[0271] As used herein, the term "CCL5" is from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. Refers to any naturally occurring CCL5 (chemokine (C-C motif ligand 5). CCL5 is known in the art as RANTES (expressed and secreted in normal T cells under activation control), SCYA5, SIS-delta, Also known as SISd, TCP228, and eoCP, this term encompasses "full-length" unprocessed CCL5 and any form of CCL5 resulting from processing within the cell. An exemplary human CCL5 nucleic acid sequence is listed in SEQ ID NO: 35 (European Nucleotide Archive Accession No. AF043341.1). The amino acid sequence of an exemplary protein encoded is SEQ ID NO: 36 (UNIPROT TM Accession No.P13501-1).

[0272] As used herein, the term "CCL8" is derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. Refers to any naturally occurring CCL8 (chemokine (C-C motif ligand 8). CCL8 is also known in the art as monocyte chemoattractant protein 2 (MCP2). Encompasses unprocessed CCL8, and any form of CCL8 resulting from processing within a cell.The term also includes naturally occurring variants of CCL8, such as splice or allelic variants.Exemplary humans The nucleic acid sequence of CCL8 is listed in SEQ ID NO: 37 (NCBI Reference Sequence: NM_005623.3) The amino acid sequence of an exemplary protein encoded by human CCL8 is SEQ ID NO: 38 (UNIPROT TM Accession No.P80075-1).

[0273] As used herein, the term "CCL18" is derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. Refers to any naturally occurring CCL18 (chemokine (C-C motif ligand 18). CCL18 is known in the art as PARC (pulmonary and activation-regulated), dendritic cell (DC)-chemokine 1 (DC-CK1), selective Also known as activated macrophage activation-associated CC chemokine-1 (AMAC-1), and macrophage inflammatory protein-4 (MIP-4), the term refers to "full-length" unprocessed CCL18 and Encompasses any form of CCL18 that results from processing within a cell.The term also includes naturally occurring variants of CCL18, such as splice or allelic variants.Exemplary human CCL18 nucleic acid sequences include: The amino acid sequence of an exemplary protein encoded by human CCL18 is listed in SEQ ID NO: 40 (UNIPROT TM Accession No.P55774-1).

[0274] As used herein, the term "CCL19" is derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. Refers to any naturally occurring CCL19 (chemokine (C-C motif ligand 19). CCL19 is also known in the art as EBI1 ligand chemokine (ELC) and macrophage inflammatory protein-3-beta (MIP-3-beta). The term encompasses "full-length" unprocessed CCL19 and any form of CCL19 resulting from processing within the cell.The term includes naturally occurring variants of CCL19, such as splice variants. or allelic variants.An exemplary human CCL19 nucleic acid sequence is listed in SEQ ID NO: 41 (NCBI Reference Sequence: NM_006274.3).The amino acid sequence of an exemplary protein encoded by human CCL19 is: SEQ ID NO: 42 (UNIPROT TM Accession No.Q99731-1).

[0275] As used herein, the term "CCL21" is derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. Refers to any naturally occurring CCL21 (chemokine (C-C motif ligand 21). CCL21 is also known in the art as 6Ckine, exodus-2, and secondary lymphoid tissue chemokine (SLC). Encompasses "full-length" unprocessed CCL21 and any form of CCL21 resulting from processing within a cell.The term also includes naturally occurring variants of CCL21, such as splice or allelic variants. The nucleic acid sequence of an exemplary human CCL21 is listed in SEQ ID NO: 43 (NCBI Reference Sequence: NM_002989.4) The amino acid sequence of an exemplary protein encoded by human CCL21 is SEQ ID NO: 44 (UNIPROT TM Accession No.O00585-1).

[0276] As used herein, the term "CXCL9" is derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. Refers to any naturally occurring CXCL9 (chemokine (C-X-C motif ligand 9). CXCL9 is also known in the art as a monokine induced by gamma interferon (MIG). This term refers to "full-length" Encompasses unprocessed CXCL9, and any form of CXCL9 resulting from processing within a cell.This term also includes naturally occurring variants of CXCL9, such as splice or allelic variants.Exemplary humans The nucleic acid sequence of CXCL9 is listed in SEQ ID NO: 45 (NCBI Reference Sequence: NM_002416.3) The amino acid sequence of an exemplary protein encoded by human CXCL9 is SEQ ID NO: 46 (UNIPROT TM Accession No.Q07325-1).

[0277] As used herein, the term "CXCL10" is derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. Refers to any naturally occurring CXCL10 (C-X-C motif chemokine ligand 10). CXCL10 is also known in the art as interferon gamma-inducible protein 10 (IP-10) or small inducible cytokine B10. The term encompasses "full length" unprocessed CXCL10 as well as any form of CXCL10 resulting from processing within the cell. The term also includes naturally occurring variants of CXCL10, such as splice or allelic variants. An exemplary human CXCL10 nucleic acid sequence is listed in SEQ ID NO: 47 (NCBI Reference Sequence: NM_001565.4). The amino acid sequence of an exemplary protein encoded by human CXCL10 is SEQ ID NO: 48 (UNIPROT TM Accession No. P02778-1).

[0278] As used herein, the term "CXCL11" is derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. Refers to any naturally occurring CXCL11 (C-X-C motif chemokine ligand 11). CXCL11 is also known in the art as interferon-inducible T cell alpha chemoattractant (I-TAC) and interferon gamma-inducible protein 9 (IP-9). The term encompasses "full length" unprocessed CXCL11 as well as any form of CXCL11 resulting from processing within the cell. The term also includes naturally occurring variants of CXCL11, such as splice or allelic variants. An exemplary human CXCL11 nucleic acid sequence is listed in SEQ ID NO: 49 (NCBI Reference Sequence: NM_005409.5). The amino acid sequence of an exemplary protein encoded by human CXCL11 is SEQ ID NO: 50 (UNIPROT TM Accession No.O14625-1).

[0279] As used herein, the term "CXCL13" is derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. It refers to any naturally occurring CXCL13 (C-X-C motif chemokine ligand 13). CXCL13 is also known in the art as B lymphocyte chemoattractant (BLC) and B cell attractant chemokine 1 (BCA-1). The term encompasses "full-length" unprocessed CXCL13, as well as any form of CXCL13 that results from processing within the cell. The term also includes naturally occurring variants of CXCL13, such as splice or allelic variants. An exemplary human CXCL13 nucleic acid sequence is listed in SEQ ID NO: 51 (NCBI Reference Sequence: NM_006419.2). The amino acid sequence of an exemplary protein encoded by human CXCL13 is SEQ ID NO: 52 (UNIPROT TM Accession No.O43927-1).

[0280] Unless otherwise indicated, the term "CD8A" as used herein refers to the cluster of differentiation 8a genes, including primates (e.g. humans) and rodents (e.g. mice and rats). Any native CD8A from any vertebrate source, including mammals, is included. The term encompasses "full-length," unprocessed CD8A, and any form of CD8A that results from processing within the cell. The term also includes naturally occurring variants of CD8A, such as splice or allelic variants. An exemplary human CD8A nucleic acid sequence is SEQ ID NO: 53 (GENBANK TM Accession No.M12828.1). The amino acid sequence of an exemplary protein encoded by human CD8A is SEQ ID NO: 54 (UNIPROT TM Accession No. P01732-1).

[0281] Unless otherwise indicated, the term "EOMES" as used herein refers to the eomesodermin gene, which includes mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). Any naturally occurring EOMES from any vertebrate source is included, including. EOMES is also known in the art as T-box brain protein 2 (Tbr2). The term encompasses "full-length," unprocessed EOMES as well as any form of EOMES resulting from processing within a cell. The term also includes naturally occurring variants of EOMES, such as splice variants or allelic variants. An exemplary human EOMES nucleic acid sequence is listed in SEQ ID NO: 55 (NCBI Reference Sequence: NM_005442.4). The amino acid sequence of an exemplary protein encoded by human EOMES is SEQ ID NO: 56 (UNIPROT TM Accession No.O95936-1).

[0282] Unless otherwise indicated, the term "GZMA" as used herein refers to the granzyme A gene, which includes mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). Any natural GZMA from any vertebrate source is included, including The term encompasses "full-length," unprocessed GZMA, as well as any form of GZMA resulting from processing within the cell. The term also includes naturally occurring variants of GZMA, such as splice variants or allelic variants. An exemplary human GZMA nucleic acid sequence is SEQ ID NO: 57 (GENBANK TM Accession No.BC015739). The amino acid sequence of an exemplary protein encoded by human GZMA is SEQ ID NO: 58 (UNIPROT TM Accession No.P12544-1).

[0283] Unless otherwise indicated, the term "TBX21" as used herein refers to the T-box transcription factor TBX21 gene, which includes primates (e.g., humans) and rodents (e.g., mice and rats). Any native TBX21 from any vertebrate source is included, including mammals such as. TBX21 is also known in the art as T-PET, T-bet, TBLYM, and T-box21. The term encompasses "full-length" unprocessed TBX21 as well as any form of TBX21 resulting from processing within the cell. The term also includes naturally occurring variants of TBX21, such as splice or allelic variants. An exemplary human TBX21 nucleic acid sequence is listed in SEQ ID NO: 59 (NCBI Reference Sequence: NM_013351.2). The amino acid sequence of an exemplary protein encoded by human TBX21 is SEQ ID NO: 60 (UNIPROT TM Accession No.Q9UL17-1).

[0284] Unless otherwise indicated, the term "IFNG" as used herein refers to the interferon gamma gene, which includes mammals such as primates (e.g. humans) and rodents (e.g. mice and rats). Any natural IFNG from any vertebrate source is included, including IFNG is also known in the art as type II interferons. The term encompasses "full-length," unprocessed IFNG as well as any form of IFNG resulting from processing within the cell. The term also includes naturally occurring variants of IFNG, such as splice variants or allelic variants. An exemplary human IFNG nucleic acid sequence is listed in SEQ ID NO: 61 (NCBI Reference Sequence: NM_000619.3). The amino acid sequence of an exemplary protein encoded by human IFNG is SEQ ID NO: 62 (UNIPROT TM Accession No. P01579-1).

[0285] Unless otherwise indicated, the term "GZMB" as used herein refers to the granzyme B gene, which includes mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). Any naturally occurring GZMB from any vertebrate source is included, including. The term encompasses "full-length," unprocessed GZMB, as well as any form of GZMB resulting from processing within the cell. The term also includes naturally occurring variants of GZMB, such as splice variants or allelic variants. An exemplary human GZMB nucleic acid sequence is SEQ ID NO: 63 (GENBANK TM Accession No. J03072). The amino acid sequence of an exemplary protein encoded by human GZMB is SEQ ID NO: 64 (UNIPROT TM Accession No.P10144-1).

[0286] Unless otherwise indicated, the term "DERL3" as used herein refers to the derlin-3 gene, which includes mammals such as primates (e.g. humans) and rodents (e.g. mice and rats). Any native DERL3 from any vertebrate source, including animals, is included. The term encompasses "full-length" unprocessed DERL3 as well as any form of DERL3 resulting from processing within the cell. The term also includes naturally occurring variants of DERL3, such as splice or allelic variants. An exemplary human DERL3 nucleic acid sequence is listed in SEQ ID NO: 65 (European Nucleotide Archive Accession No. AK125830.1). The amino acid sequence of an exemplary protein encoded by human DERL3 is SEQ ID NO: 66 (UNIPROT TM Accession No.Q96Q80-1).

[0287] Unless otherwise indicated, the term "JSRP1" as used herein refers to the junctional sarcoplasmic reticulum protein 1 gene, which includes primates (e.g., humans) and rodents (e.g., mice and rats). Any native JSRP1 from any vertebrate source is included, including mammals such as. The term encompasses "full-length" unprocessed JSRP1 as well as any form of JSRP1 resulting from processing within the cell. The term also includes naturally occurring variants of JSRP1, such as splice or allelic variants. An exemplary human JSRP1 nucleic acid sequence is listed in SEQ ID NO: 67 (European Nucleotide Archive Accession No.BC021201.2). The amino acid sequence of an exemplary protein encoded by human JSRP1 is SEQ ID NO: 68 (UNIPROT TM Accession No.Q96MG2-1).

[0288] Unless otherwise indicated, the term "IGHG2" as used herein refers to the immunoglobulin heavy constant gamma 2 gene, which includes primates (e.g. humans) and rodents (e.g. mice and rats). Any naturally occurring IGHG2 from any vertebrate source, including mammals such as. The term encompasses "full-length" unprocessed IGHG2 as well as any form of IGHG2 that results from processing within the cell. The term also includes naturally occurring variants of IGHG2, such as splice or allelic variants. An exemplary human IGHG2 nucleic acid sequence is listed in SEQ ID NO: 69 (European Nucleotide Archive Accession No. AL928742.). The amino acid sequence of an exemplary protein encoded by human IGHG2 is SEQ ID NO: 70 (UNIPROT TM Accession No. P01859-1).

[0289] Unless otherwise indicated, the term "IGHGP" as used herein refers to the immunoglobulin heavy constant gamma P gene, which includes primates (e.g., humans) and rodents (e.g., mice and rats). Any naturally occurring IGHGP from any vertebrate source is included, including mammals such as. The term encompasses "full-length", unprocessed IGHGP as well as any form of IGHGP resulting from processing within the cell. The term also includes naturally occurring variants of IGHGP, such as splice variants or allelic variants. An exemplary human IGHGP nucleic acid sequence is listed in SEQ ID NO: 71 (NCBI Reference Sequence No. NG_001019.6).

[0290] Unless otherwise indicated, the term "IGLV3-1" as used herein refers to the immunoglobulin lambda variable 3-1 gene, which includes primates (e.g., humans) and rodents (e.g., mice). Any naturally occurring IGLV3-1 from any vertebrate source is included, including mammals, such as mammals (e.g., rats and rats). The term encompasses "full-length" unprocessed IGLV3-1 and any form of IGLV3-1 that results from processing within the cell. The term also includes naturally occurring variants of IGLV3-1, such as splice or allelic variants. An exemplary human IGLV3-1 nucleic acid sequence is listed in SEQ ID NO: 72 (European Nucleotide Archive Accession No. AC245028.2). The amino acid sequence of an exemplary protein encoded by human IGLV3-1 is SEQ ID NO: 73 (UNIPROT TM Accession No. P01715-1).

[0291] Unless otherwise indicated, the term "IGLV6-57" as used herein refers to the immunoglobulin lambda variable 6-57 gene, which includes primates (e.g., humans) and rodents (e.g., mice). Any naturally occurring IGLV6-57 from any vertebrate source is included, including mammals, such as mammals (e.g., rats and rats). The term encompasses "full-length" unprocessed IGLV6-57 as well as any form of IGLV6-57 that results from processing within the cell. The term also includes naturally occurring variants of IGLV6-57, such as splice or allelic variants. An exemplary human IGLV6-57 nucleic acid sequence is listed in SEQ ID NO: 74 (European Nucleotide Archive Accession No. AC245060.1). The amino acid sequence of an exemplary protein encoded by human IGLV6-57 is SEQ ID NO: 75 (UNIPROT TM Accession No.P01721-1).

[0292] Unless otherwise indicated, the term "IGHA2" as used herein refers to the immunoglobulin heavy constant alpha 2 gene, which includes primates (e.g. humans) and rodents (e.g. mice and rats). Any native IGHA2 from any vertebrate source is included, including mammals such as. The term encompasses "full-length" unprocessed IGHA2 as well as any form of IGHA2 that results from processing within the cell. The term also includes naturally occurring variants of IGHA2, such as splice or allelic variants. An exemplary human IGHA2 nucleic acid sequence is listed in SEQ ID NO: 76 (European Nucleotide Archive Accession No. AL928742.). The amino acid sequence of an exemplary protein encoded by human IGHA2 is SEQ ID NO: 77 (UNIPROT TM Accession No. P01877-1).

[0293] Unless otherwise indicated, the term "IGKV4-1" as used herein refers to the immunoglobulin kappa variable 4-1 gene, which includes primates (e.g., humans) and rodents (e.g., mice). Any naturally-occurring IGKV4-1 from any vertebrate source, including mammals (such as mammals, such as rats and rats) is included. The term encompasses "full-length" unprocessed IGKV4-1, as well as any form of IGKV4-1 that results from intracellular processing. The term also includes naturally occurring variants of IGKV4-1, such as splice or allelic variants. An exemplary human IGKV4-1 nucleic acid sequence is listed in SEQ ID NO: 78 (European Nucleotide Archive Accession No. X02990.1). The amino acid sequence of an exemplary protein encoded by human IGKV4-1 is SEQ ID NO: 79 (UNIPROT TM Accession No.P06312-1).

[0294] Unless otherwise indicated, the term "IGKV1-12" as used herein refers to the immunoglobulin kappa variable 1-12 gene, which includes primates (e.g., humans) and rodents (e.g., mice). Any naturally-occurring IGKV1-12 from any vertebrate source, including mammals, including mammals (such as rats and rats). The term encompasses "full-length" unprocessed IGKV1-12, as well as any form of IGKV1-12 resulting from intracellular processing. The term also includes naturally occurring variants of IGKV1-12, such as splice or allelic variants. An exemplary human IGKV1-12 nucleic acid sequence is listed in SEQ ID NO: 80 (European Nucleotide Archive Accession No. AC245015.2). The amino acid sequence of an exemplary protein encoded by human IGKV1-12 is SEQ ID NO: 81 (UNIPROT TM Accession No.A0A0C4DH73-1).

[0295] Unless otherwise indicated, the term "IGLC7" as used herein refers to the immunoglobulin lambda constant 7 gene, which includes primates (e.g., humans) and rodents (e.g., mice and rats). Any native IGLC7 from any vertebrate source, including mammals, is included. The term encompasses "full-length" unprocessed IGLC7 as well as any form of IGLC7 resulting from processing within the cell. The term also includes naturally occurring variants of IGLC7, such as splice or allelic variants. An exemplary human IGLC7 nucleic acid sequence is listed in SEQ ID NO: 82 (European Nucleotide Archive Accession No. AC245028.2). The amino acid sequence of an exemplary protein encoded by human IGLC7 is SEQ ID NO: 83 (UNIPROT TM Accession No.A0M8Q6-1).

[0296] The term "clonally expanded B cells" refers to B cells with common antigen specificity, eg, as assessed by sequence homology to the mIg portion of the BCR. For example, clonally expanded B cells have at least 85% sequence identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%) across the heavy and / or light chains of the mIg portion. %, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 100% sequence identity) (e.g., the mIg portion thereof). 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, across the heavy and / or light chain CDR1, CDR2, and / or CDR3 regions of 95%, 96%, 97%, 98%, 99%, 99.9% or 100% sequence identity).

[0297] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, cancer, lymphoma, blastoma, sarcoma, and leukemia, or lymphoid malignancies. More specific examples of such cancers include, but are not limited to, lung cancer, including small cell lung cancer, NSCLC (e.g., nonsquamous NSCLC and squamous NSCLC), adenocarcinoma of the lung, and squamous cell carcinoma of the lung. bladder cancer (e.g., urothelial carcinoma (UC), muscle-invasive bladder cancer (MIBC), and BCG-refractory non-muscle-invasive bladder cancer (NMIBC)); renal cancer or renal cancer (e.g., , renal cell carcinoma (RCC)); cancers of the urinary tract; breast cancer (e.g., HER2+ and triple-negative breast cancer (TNBC); (HER2-) negative); prostate cancer, e.g., castration-resistant prostate cancer (CRPC); cancer of the peritoneum; hepatocellular carcinoma; cancer or stomach cancer; pancreatic cancer; glioblastoma; cervical cancer; ovarian cancer; liver cancer; liver cancer; Endometrial cancer or uterine cancer; salivary gland cancer; prostate cancer; vulvar cancer; thyroid cancer; liver cancer; anal cancer; and melanoma, including nodular melanoma; multiple myeloma and B-cell lymphomas (low-grade / follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL, intermediate-grade / follicular NHL; Intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small uncleaved cell NHL; bulky NHL; mantle cell lymphoma; AIDS-related lymphoma; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); hairy cell leukemia; chronic myeloblastic leukemia (CML) post-transplant lymphoproliferative disease (PTLD); and myelodysplastic syndrome (MDS), and abnormal vascular proliferation associated with phacomatosis, edema (such as that associated with brain tumors), Meigs syndrome, cancer of the brain, head Includes cervical cancer and related metastases. The terms "cell proliferative disorder" and "proliferative disorder" refer to disorders associated with some degree of abnormal cell proliferation. In one embodiment, the cell proliferative disorder is cancer (e.g., lung cancer (e.g., NSCLC, including non-squamous NSCLC and squamous NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (eg, TNBC). In another embodiment, the cell proliferative disorder is a tumor.

[0298] A "chemotherapeutic agent" is a cancer (e.g., lung cancer, (e.g., NSCLC, including non-squamous NSCLC and squamous NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer ( For example, chemicals useful in the treatment of TNBC)). Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carbocone, methledopa; and uredopa; methylamelamine, including ethyleneimine and altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamin; acetogenins (especially bratacin and bratacinone); delta-9-tetrahydrocannabinol (Dronabinol, MARINOL®); Beta-Lapachone; Lapachol; Colchicine; Betulinic Acid; , scopolectin, and 9-aminocaptothecin); bryostatin; callistatin; cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogues, KW-2189 and CB1-TM1); eruterobin; pancratistatin; Genmustards, such as chlorambucil, chlornafadine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novenmbichin, phenesterine, prednimastine, trofosphamide, uracil mustard; Nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimstine, and ranimnustine; et al., Angew. Chem Intl. Ed. Engl., 33:183-186 (1994)); CDP323, an oral alpha-4 integrin inhibitor; Related chromoproteins (enginein antibiotics chromophore), alacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, cardinophylline, chromomycin , dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (ADRIAMYCIN®, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, doxorubicin HCl liposome injection (DOXIL ®), liposomal doxorubicin TLC D-99 (MYOCET®), pegylated liposomal doxorubicin (including CAELYX®), and deoxydoxorubicin), epirubicin, ethorubicin, idarubicin, marcellomycin, mitomycin C Mitomycin, mycophenolic acid, nogaramycin, olibomycin, peplomycin, porphyromycin, puromycin, quelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin; antimetabolites such as such as methotrexate, gemcitabine (GEMZAR®), tegafur (UFTORAL®), capecitabine (XELODA®), epothilones, and 5-fluorouracil (5-FU); combretastin; folic acid analogs; denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamipurine, thioguanine; cusuridine; androgens, such as carsterone, dromostanolone propionate, epithiostanol, mepithiostane, testolactone; anti-adrenal agents, such as aminoglutethimide, mitotane, trilostane; folic acid replacement fluids such as furolinic acid; Aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecoltin; diaziquone; lonidainine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; Saccharide complexes (JHS Natural Products, Eugene, OR); Lazoxane; Rizoxin; Sizofuran; Spirogermanium; urethane; vindesine (ELDISINE®, FILDESIN®); dacarbazine; mannomustine; mitobronitol; mitractol; ); thiotepa; taxoids such as paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.J.), albumin-engineered nanoparticle formulations of paclitaxel (Abraxane TM ), and docetaxel (TAXOTERE®, Rhome-Poulene Rorer, Antony, France); clambucil; 6-thioguanine; mercaptopurine; methotrexate; platinum-based agents; tubes containing vinblastine (VELBAN®), vincristine (ONCOVIN®), vindesine (ELDISINE®, FILDESIN®), and vinorelbine (NAVELBINE®) vinca that prevents phosphorus polymerization from forming microtubules; etoposide (VP-16); ifosfamide; mitoxantrone; leucovorin; methylornithine (DMFO); retinoids such as retinoic acid, including bexarotene (TARGRETIN®); bisphosphonates such as clodonate (e.g. BONEFOS® or OSTAC®), etidronate (DIDROCAL®) ), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate ( ACTONEL®); troxacitabine (1,3-dioxolane nucleoside cytosine analogue); antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways involved in abnormal cell proliferation, e.g., PKC-alpha, Raf , H-Ras, and epidermal growth factor receptor (EGF-R) (e.g., erlotinib (TARCEVA TM )); and VEGF-A, which reduces cell proliferation; vaccines such as THERATOPE® vaccines and gene therapy vaccines, e.g. BAY439006 (sorafenib; Bayer); SU-11248 (sunitinib, SUTENT®, Pfizer); perifosine, COX-2 inhibitors (e.g. celecoxib or etoricoxib), bioprecipitation inhibitors (e.g. PS341); bortezomib (VELCADE®); CCI-779; tipifarnib (R11577); Bcl-2 inhibitors such as sodium (GENASENSE®); pixantrone; EGFR inhibitors; tyrosine kinase inhibitors; serine-threonine kinase inhibitors such as rapamycin (sirolimus, RAPAMUNE®); , SARASAR TM ), and pharmaceutically acceptable salts, acids or derivatives of any of the above; and combinations of two or more of the above, such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone combination therapy); and FOLFOX (oxaliplatin in combination with 5-FU and leucovorin (ELOXATIN TM ) and a therapeutic regimen with a pharmaceutically acceptable salt, acid or derivative of any of the above); and combinations of two or more of the above.

[0299] Chemotherapeutic agents, as defined herein, include cancer (e.g., lung cancer (e.g., NSCLC, including non-squamous NSCLC and squamous NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), Also includes "anti-hormonal agents" or "endocrine therapeutics" that act to control, reduce, block, or inhibit the effects of hormones that may promote the growth of breast cancer (eg, TNBC). They may themselves be hormones and include, but are not limited to, antiestrogens and selective estrogen receptor modulators (SERMs) such as tamoxifen (including NOLVADEX® tamoxifen), raloxifene, drolo xifene, 4-hydroxy tamoxifen, trioxyphen, keoxifene, LY117018, onapristone, and FARESTON® toremifene; aromatase inhibitors, such as 4(5)-imidazole, which inhibit the enzyme aromatase that regulates adrenal estrogen production , aminoglutethimide, MEGASE® megestrol acetate, AROMASIN® exemestane, formestani, fadrozole, RIVISOR® vorozole, FEMARA® letrozole, and ARIMIDEX® anastrozole; and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; and troxacitabine (a 1,3-dioxolane nucleoside cytosine analogue); antisense oligonucleotides, particularly signaling pathways involved in the proliferation of adherent cells. ribozymes such as VEGF expression inhibitors (e.g. ANGIOZYME® ribozyme) and HER2 expression inhibitors; gene therapy vaccines such as ALLOVECTIN ( Vaccines such as LEUVECTIN® vaccine, LEUVECTIN® vaccine and VAXID® vaccine; PROLEUKIN® rIL-2; LURTOTECAN® Topoisomerase 1 inhibitor; ABARELIX® rmRH; Esperamicin (see US Pat. No. 4,675,187), and pharmaceutically acceptable salts, acids and derivatives of any of the above; and combinations of two or more of the above.

[0300] The term "chimeric" antibody refers to antibodies in which a portion of the heavy and / or light chain is derived from a particular source or species and the remainder of the heavy and / or light chain is derived from a different source or species. point to

[0301] The "class" of an antibody refers to the type of constant domain or region possessed by its heavy chains. There are five major classes of antibodies: IgA, IgD, IgE, IgG and IgM, some of which have further subclasses (isotypes), such as IgG 1 , IgG 2 , IgG 3 , IgG 4 , IGA 1 , and IgA 2 can be divided into The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0302] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents the function of cells and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 chemotherapeutic agents or drugs (e.g. methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); proliferation inhibitors; enzymes and fragments thereof, such as nucleolytic enzymes; antibiotics; Included are various anti-tumor or anti-cancer agents disclosed.

[0303] As used herein, the term "simultaneously" is used to refer to administration of two or more therapeutic agents, at least partially overlapping in time of administration. Co-administration thus includes a dosing regimen in which administration of one or more agents continues after administration of one or more other agents has ceased.

[0304] As used herein, "delaying progression" of a disorder or disease refers to a disease or disorder (e.g., cancer, e.g., lung cancer (e.g., NSCLC, including non-squamous NSCLC and squamous NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., TNBC)). . This delay can be of varying duration depending on the disease history and / or subject being treated. As will be apparent to those skilled in the art, a sufficient or significant delay can in effect encompass prophylaxis, in that the subject does not develop the disease.

[0305] The terms "determining", "determining", "detecting", "detecting" and grammatical variations thereof refer to any means of determining or detecting, including direct and indirect determination or detection including.

[0306] A "disorder" or "disease" refers to a mammal with the disorder in question (e.g., cancer, e.g., lung cancer (e.g., NSCLC, including non-squamous NSCLC and squamous NSCLC), bladder cancer (e.g., UC), renal cancer). Any condition that would benefit from treatment, including, but not limited to, chronic and acute disorders or diseases, including conditions that predispose to (e.g., RCC), or breast cancer (e.g., TNBC).

[0307] As used herein, the term "diagnosis" refers to a molecular or pathological condition, disease or condition (e.g. cancer, e.g. lung cancer (e.g. NSCLC, including non-squamous NSCLC and squamous NSCLC), bladder cancer (e.g. , UC), renal cancer (eg RCC), or breast cancer (eg TNBC)). For example, "diagnosis" can refer to identification of a particular type of cancer. "Diagnosis" may be defined as a specific subtype (e.g., one biomarker or combination of biomarkers (e.g., a specific gene or protein encoded by those genes), e.g., by histopathological criteria, or by molecular characteristics. )) can also be referred to as a subtype) cancer classification characterized by the expression of )).

[0308] "Effector functions" refer to those biological activities attributable to the Fc region of an antibody that vary with the antibody's isotype. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity (CDC), Fc receptor binding, antibody dependent cell-mediated cytotoxicity (ADCC), phagocytosis, cell surface receptors (e.g. PD- L1) downregulation, and B cell activation.

[0309] An "effective amount" of a compound, e.g., a PD-L1 axis binding antagonist (e.g., a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody, e.g., atezolizumab) or a PD-1 binding antagonist (e.g., an anti-PD-1 antibody) )), or a composition thereof (e.g., a pharmaceutical composition) has a desired therapeutic or prophylactic outcome, e.g., a specific disease or disorder (e.g., cancer, e.g. NSCLC, including NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., TNBC)) overall survival (OS), progression-free survival (PFS), or overall response ( For example, at least the minimum amount necessary to achieve a measurable improvement in best overall response (BCOR). Effective amounts herein may vary depending on factors such as the individual's medical condition, age, sex, weight, and the ability of the antibody to elicit the desired response in the subject. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the beneficial effects of the treatment. Beneficial or desired results for prophylactic use include biochemical, histological and / or behavioral manifestations of the disease, its complications, and intermediate pathological manifestations during the development of the disease. Outcomes such as elimination or reduction of risk, reduction in severity, or delay in onset of disease, including type. An effective amount may be administered in one or more administrations. For the purposes of this disclosure, an effective amount of drug, compound, or pharmaceutical composition is that amount sufficient to achieve prophylactic or therapeutic treatment, directly or indirectly. As understood in the clinical context, an effective amount of drug, compound or pharmaceutical composition may optionally be achieved in combination with another drug, compound or pharmaceutical composition. Thus, an "effective amount" can be considered in the context of administration of one or more therapeutic agents, which alone, in conjunction with one or more other agents, can achieve or achieve a desired result. If given, it can be considered to be given in an effective amount. For example, an effective amount of a PD-L1 axis binding antagonist (e.g., a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody, e.g., atezolizumab) or a PD-1 binding antagonist (e.g., anti-PD- 1 antibody)) reduces the number of cancer cells; reduces the size of primary tumors; inhibits (i.e. slows to some extent, preferably stops) cancer cell invasion into peripheral organs; inhibits tumor metastasis inhibit (ie, slow, preferably stop) to some extent; inhibit tumor growth to some extent; and / or alleviate one or more of the symptoms associated with the disorder to some extent. To the extent the agent may prevent the growth of existing cancer cells and / or kill existing cancer cells, it may be cytostatic and / or cytotoxic. For cancer therapies, in vivo efficacy should be measured, for example, by assessing survival time, time to progression (TTP), response rate (RR), duration of response, and / or quality of life. can be done.

[0310] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain, including at least part of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, the human IgG heavy chain Fc region extends from Cys226 or from Pro230 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified, the numbering of amino acid residues within the Fc region or constant region is according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. according to the EU numbering system, also known as the EU index, as described in

[0311] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FRs of variable domains generally consist of four FR domains: FR1, FR2, FR3 and FR4. Therefore, HVR and FR sequences generally appear in VH (or VL) in the following sequence: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0312] The terms "full-length antibody," "intact antibody," and "whole antibody," as used herein, have a structure substantially similar to that of a native antibody or have an Fc region as defined herein. used interchangeably to refer to an antibody having a heavy chain containing

[0313] A "human antibody" is an antibody that has an amino acid sequence corresponding to an antibody produced by a human or human cells, or an antibody of non-human origin utilizing human antibody repertoires or other human antibody coding sequences. This definition of human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues. Human antibodies can be generated using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Cole et al., Monoclonal antibodies and Cancer Therapy, Alan R. Liss, p.77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991). are also available for the preparation of human monoclonal antibodies. See also van Dijk et al., Curr. Opin. Pharmacol., 5:368-74 (2001). Human antibodies are administered to transgenic animals, such as immunized xeno mice, that have been modified to produce such antibodies in response to antigen challenge, but whose endogenous loci have been disabled. (for example, XENOMOUSE TM See US Pat. Nos. 6,075,181 and 6,150,584 for technology). See also, for example, Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) on human antibodies generated by human B-cell hybridoma technology.

[0314] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody comprises substantially all of at least one, typically two variable domains, wherein all or substantially all of the HVRs (e.g., CDRs) correspond to non-human antibodies. and all or substantially all of the FRs correspond to human antibodies. A humanized antibody may comprise at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of an antibody, eg, a non-human antibody, refers to an antibody that has undergone humanization.

[0315] The term "hypervariable region" or "HVR" as used herein is hypervariable in sequence ("complementarity determining region" or "CDR") and / or structurally distinct loops ( Refers to each of the regions of an antibody variable domain that form a “hypervariable loop”) and / or contain antigen-contacting residues (“antigen-contacting”). Generally, an antibody contains 6 HVRs, 3 in VH (H1, H2, H3) and 3 in VL (L1, L2, L3). As used herein, exemplary HVRs are: (a) occurs at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) hypervariable loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); (b) occurs at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) CDR (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) occurs at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) antigen contact (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)); and (d) HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49 Any combination of (a), (b), and / or (c), including -65(H2), 93-102(H3), and 94-102(H3) including.

[0316] Unless otherwise indicated, HVR residues and other residues (eg, FR residues) within the variable domain are numbered herein according to Kabat et al. (supra).

[0317] An "isolated" antibody is one that has been separated from a component of its natural environment. In some embodiments, antibodies are determined, for example, by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC). purified to greater than 95% or greater than 99% purity. For a review of methods for assessing antibody purity see, eg, Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0318] An "isolated" nucleic acid refers to a nucleic acid molecule that is separated from a component of its natural environment. An isolated nucleic acid includes the nucleic acid molecule contained within cells that normally contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location different from its natural chromosomal location.

[0319] As used herein, the term "label" refers to a detectable compound or composition. A label is typically conjugated or fused, directly or indirectly, to a reagent such as a polynucleotide probe or antibody to facilitate detection of the reagent to which it is conjugated or fused. A label may itself be detectable (eg, a radioisotopic or fluorescent label) or, in the case of an enzymatic label, catalyze a chemical modification of a substrate compound or composition resulting in a detectable product.

[0320] The terms "level of expression" or "expression level" are generally used interchangeably and usually refer to the amount of a biomarker in a biological sample. "Expression" generally refers to the process by which information (eg, genetic coding information and / or epigenetic information) is converted into structures that exist and function in cells. Thus, "expression" as used herein can refer to transcription into a polynucleotide, translation into a polypeptide, or further polynucleotide and / or polypeptide modification (e.g., post-translational modification of a polypeptide). be. Transcribed polynucleotides, translated polypeptides, or fragments of polynucleotide and / or polypeptide modifications (e.g., post-translational modifications of polypeptides) may also be transcripts produced by alternative splicing or degraded fragments. expressed irrespective of whether derived from an original transcript or from post-translational processing of the polypeptide, eg, by proteolysis. "Expressed genes" include those that are transcribed as mRNA into a polynucleotide and then translated into a polypeptide, and those that are transcribed into RNA but not translated into a polypeptide (eg, translocated and ribosomal RNA). Expression levels can be measured by methods known to those of skill in the art and also disclosed herein, including, for example, RT-qPCR and RNA-seq. The evaluated expression levels can be used to determine response to therapy.

[0321] The term "immune score expression level" refers to the expression level of a single gene of interest (e.g., normalized expression level) or multiple genes of interest (e.g., at least two, at least three 1, at least 4, at least 5, or more genes). Immunoscore expression levels for multiple genes of interest are aggregates known to those skilled in the art and also disclosed herein, including, for example, calculating the median or mean expression levels of all genes of interest. can be determined by the method. Prior to aggregation, the expression level of each gene of interest is normalized to the expression level of, for example, one or more housekeeping genes using statistical methods known to those skilled in the art and also disclosed herein. or normalized to the total library size, or normalized to the median or mean expression level of all genes measured. In some cases, prior to aggregation of multiple genes of interest, the normalized expression level of each gene of interest is normalized by calculating the Z-score of the normalized expression level of each gene of interest. can do. In some cases, each gene of interest can have an assigned weight score, and the Immune Score expression level of multiple genes of interest is calculated by incorporating the weight scores and weighted for all genes of interest. An average expression level can be determined. For example, the Immune Score expression level is a single gene selected from any one of Tables 1-17, e.g. MZB1, CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, CXCL13, DERL3, JSRP1, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1- 12, and a number that reflects the normalized expression level of IGLC7. Alternatively, the Immunoscore expression level can be determined, for example, by the genes shown in any one of Tables 1-17, such as CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, MZB1 , CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, CXCL13, DERL3, JSRP1, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12 , and IGLC7, or combinations thereof, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 , at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or more aggregated and normalized expression levels (e.g. , median normalized expression level, or mean normalized expression level). In some cases, the Immune Score expression level is, for example, a gene shown in any one of Tables 1-17, e.g. , MZB1, CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, CXCL13, DERL3, JSRP1, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1 at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 of -12, and IGLC7, or combinations thereof; Aggregated Z-score expression levels for at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or more (eg, mean Z-score normalized expression level, or median Z-score normalized expression level).

[0322] As used herein, the term "reference immune score expression level" refers to another immune score expression level (e.g., Tables 1-17) for making diagnostic, prognostic, prognostic, and / or therapeutic decisions. for example, CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, MZB1, CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21 , CXCL10, CXCL11, CXCL13, DERL3, JSRP1, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, and IGLC7) Score refers to expression level. For example, the reference immune score expression level may be a reference sample, a reference population, and / or a pre-assigned value (e.g., a PD-L1 axis binding antagonist (e.g., PD-L1 binding antagonist (e.g., anti-PD - PD-L1 axis binding antagonists in the same reference population as a first subset of individuals treated with therapy with an L1 antibody (e.g., atezolizumab) or a PD-1 binding antagonist (e.g., anti-PD-1 antibody)) and a second subset of individuals treated with a non-PD-L1 axis binding antagonist therapy that does not include / or prior to significantly (e.g., statistically significant) segregation based on a significant difference between an individual's responsiveness to treatment with a non-PD-L1 axis binding antagonist therapy below a cutoff value. a cut-off value determined at 20000000000000000000000000000000000000000000000000000000000000000000000001(2000) to treatment with a non-PD-L1 axis-binding antagonist therapy, wherein the individual's responsiveness to treatment with a PD-L1-axis-binding antagonist therapy is above the cut-off value. PD that is significantly (e.g., statistically significant) improved compared to responsiveness and / or the individual's responsiveness to treatment with a non-PD-L1 axis binding antagonist therapy is below the cutoff value - a significantly (e.g., statistically significant) improvement in the expression level (e.g., in Tables 1-17, cut-off value) compared to the individual's responsiveness to treatment with an L1 axis binding antagonist therapy; one or more genes represented by any one of e.g. , CCL19, CCL21, CXCL9, CXCL10, CXCL11, CXCL13, DERL3, JSRP1, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, and IGLC7) from can be derived. One of ordinary skill in the art will appreciate that numerical values ​​of the Reference Immunoscore expression level are useful for indications (e.g., cancer (e.g., breast cancer, lung cancer (NSCLC, including non-squamous NSCLC and squamous NSCLC), kidney cancer, or bladder cancer), depending on the methodology used to detect expression levels (e.g. RNA-seq or RT-qPCR), the statistical method used to generate the immune score, and / or the particular combination of genes tested. You will understand that things can change.

[0323] "Elevated expression", "elevated expression level" or "elevated level" of a gene or combination of genes in a subject (e.g., the genes shown in any one of Tables 1-17, e.g., CD79A , CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, MZB1, CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, CXCL13, DERL3, JSRP1, IGHG2 , IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, and IGLC7), control, e.g., a disease or disorder (e.g., cancer, e.g., lung cancer (e.g., one or more subjects not suffering from bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., TNBC)), or an internal standard (eg, housekeeping genes), or refers to increased expression or elevated levels relative to a reference level, eg, a reference immune score expression level.

[0324] "Reduced expression," "reduced expression level," or "reduced level" of a gene or combination of genes in a subject (e.g., the genes shown in any one of Tables 1-17, e.g., CD79A , CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, MZB1, CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, CXCL13, DERL3, JSRP1, IGHG2 , IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, and IGLC7) of a control, e.g., a disease or disorder (e.g., cancer, e.g., lung cancer (e.g., one or more subjects not suffering from bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., TNBC)), or an internal standard (eg, housekeeping genes), or refers to decreased expression or reduced levels compared to a reference level, eg, reference immune score expression level. In some embodiments, reduced expression is little or no expression.

[0325] As used herein, a "standard gene" is a gene or group of genes used for comparison purposes, such as housekeeping genes (e.g., 1, 2, 3, 4, 5, 6, or more genes). A "housekeeping gene", as used herein, encodes a protein whose activity is essential for the maintenance of cellular function and is typically a gene or group of genes that are similarly present in all cell types (e.g. 1, 2, 3, 4, 5, 6 or more genes).

[0326] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies that make up the population contain, for example, naturally occurring mutations or monoclonal antibodies. Identical and / or binds the same epitope, except for possible variant antibodies, such as variants that are usually present in minor amounts, that arise during the production of the preparation. Each monoclonal antibody in a monoclonal antibody preparation is directed against a single determinant on the antigen, in contrast to polyclonal antibody preparations, which typically contain different antibodies directed against different determinants (epitopes). . Thus, the modifier "monoclonal" indicates the characteristics of antibodies obtained from a substantially homogeneous population of antibodies and is not constructed to require production of the antibody by any particular method. For example, monoclonal antibodies for use in accordance with the present invention include, but are not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci. Such and other exemplary methods for making monoclonal antibodies, which can be made by a variety of techniques without limitation, are described herein.

[0327] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (eg, a cytotoxic moiety) or a radiolabel. A naked antibody can be present in a pharmaceutical composition.

[0328] "Native antibody" refers to naturally occurring immunoglobulin molecules with varying structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, comprising two identical light chains and two identical heavy chains disulfide-linked. From N-terminus to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2 and CH3). Similarly, from N-terminus to C-terminus, each light chain has a variable region (VL), also called a variable light domain or light chain variable domain, followed by one constant light (CL) domain. The light chains of antibodies can be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains.

[0329] The term "oligonucleotide" includes, but is not limited to, relatively short polynucleotides (e.g., single-stranded deoxyribonucleotides, single- or double-stranded ribonucleotides, RNA:DNA hybrids and double-stranded DNA). less than about 250 nucleotides in length). Oligonucleotides, such as single-stranded DNA probe oligonucleotides, are often synthesized by chemical methods, for example, using commercially available automated oligonucleotide synthesizers. However, oligonucleotides can be made by a variety of other methods, including in vitro recombinant DNA-mediated techniques, and by expression of DNA in cells and organisms.

[0330] The term "package insert" is used to refer to instructions customarily included in the commercial packaging of therapeutic products, including indications, dosage, administration, concomitant therapies, contraindications and / or cautions regarding the use of such therapeutic products. Contains information about the matter.

[0331] The term "pharmaceutical formulation" refers to a preparation that is in a form such that the biological activity of the active ingredients contained in the preparation is effective and that does not contain additional ingredients that are unacceptably toxic to the subject to whom the formulation is administered. point to things

[0332] "Pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0333] Unless otherwise indicated, the term "protein" as used herein refers to any protein from any vertebrate source, including mammals such as primates (e.g. humans) and rodents (e.g. mice and rats). Refers to natural proteins. The term includes not only the "full-length," unprocessed protein, but all forms of the protein that result from processing within the cell. The term also includes naturally occurring variants of proteins, eg, splice or allelic variants.

[0334] A "percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is determined after aligning the sequences and introducing gaps as necessary to achieve maximum percent sequence identity, after which any conservative substitutions It is defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in a reference polypeptide, if not considered part of the identity. Alignments for purposes of determining percent amino acid sequence identity may be performed in a variety of ways within the skill in the art, e.g. can be accomplished using computer software available in the United States. Those skilled in the art can determine appropriate parameters for alignment of sequences, including any algorithms needed to achieve maximal alignment over the entire length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values ​​are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc. and the source code, together with user documentation, has been submitted to the United States Copyright Office (Washington D.C., 20559) under United States Copyright Registration No. TXU510087. registered as. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, Calif.) or can be compiled from source code. ALIGN-2 programs should be compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters were set by the ALIGN-2 program and remain unchanged.

[0335] In situations where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (alternatively , a given amino acid sequence A having or containing a certain % amino acid sequence identity to, with, or to a given amino acid sequence B) can be described as: 100 x Fractional X / Y (Where X is the number of amino acid residues scored as identical by the sequence alignment program ALIGN-2 as being identical in that program's alignment of A and B, and Y is the total number of amino acid residues in B. is calculated by It will be understood that the % amino acid sequence identity of A to B differs from the % amino acid sequence identity of B to A if the length of amino acid sequence A differs from the length of amino acid sequence B. Unless otherwise specified, all % amino acid sequence identity values ​​used herein are obtained using the ALIGN-2 computer program as described in the immediately preceding paragraph.

[0336] The term "pharmaceutical formulation" refers to a preparation that is in a form such that the biological activity of the active ingredients contained in the preparation is effective and that does not contain additional ingredients that are unacceptably toxic to the subject to whom the formulation is administered. point to things

[0337] "Pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0338] The terms "programmed death ligand 1" and "PD-L1" are used herein to refer to native sequence PD-L1 polypeptides, polypeptide variants, and fragments of native sequence polypeptides and polypeptide variants, which are herein (as defined further in this document). The PD-L1 polypeptides described herein can be isolated from a variety of sources, such as from human tissue types, or from another source, or prepared by recombinant or synthetic methods. Possible.

[0339] A "PD-L1 polypeptide variant" or variant thereof has at least about 80% amino acid sequence identity to any of the native sequence PD-L1 polypeptide sequences disclosed herein. means a PD-L1 polypeptide as defined in , typically an active PD-L1 polypeptide. Such PD-L1 polypeptide variants include, for example, PD-L1 polypeptides with one or more amino acid residues added or deleted at the N-terminus or C-terminus of the native amino acid sequence. . Typically, PD-L1 polypeptide variants will have at least about 80% amino acid sequence identity, alternatively at least about 81%, 82%, 83%, or at least about 81%, 82%, 83%, to the native sequence PD-L1 polypeptide sequences disclosed herein. 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acids have sequence identity. Typically, PD-L1 variant polypeptides are at least about 10 amino acids in length, or at least about 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289 amino acids long, or longer than that. Optionally, the PD-L1 variant polypeptide has no more than one conservative amino acid substitution compared to the native PD-L1 polypeptide sequence, or 2, 3, Has no more than 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitutions. A "native sequence PD-L1 polypeptide" includes a polypeptide having the same amino acid sequence as the corresponding PD-L1 polypeptide derived from nature.

[0340] The term "PD-L1 axis binding antagonist" refers to a PD-L1 axis binding partner and one of its binding partners so as to eliminate T cell dysfunction resulting from signaling on the PD-1 signaling axis. Refers to a molecule that inhibits interaction with the above, resulting in restoration or enhancement of T cell function. As used herein, PD-L1 axis binding antagonists include PD-L1 binding antagonists and PD-1 binding antagonists, as well as molecules that interfere with the interaction between PD-L1 and PD-1 (e.g., PD-L2-Fc fusions).

[0341] The term "PD-L1 binding antagonist" reduces, blocks, inhibits, abrogates signaling resulting from the interaction of PD-L1 with one or more of its binding partners such as PD-1 or B7-1. , or refers to interfering molecules. In some embodiments, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partner. In certain embodiments, the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and / or B7-1. In some embodiments, the PD-L1 binding antagonists are anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and PD-L1, such as PD-1 or B7-1. Other molecules that reduce, block, inhibit, abrogate, or interfere with signaling due to interaction with one or more of the binding partners are included. In one embodiment, the PD-L1 binding antagonist reduces negative co-stimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes that mediated signaling through PD-L1; Alleviate the dysfunctional state of dysfunctional T cells (eg, enhance effector responses to antigen recognition). In some embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antibody. In certain embodiments, the anti-PD-L1 antibody is atezolizumab (CAS Registry Number: 1422185-06-5), also known as MPDL3280A and described herein. In another specific embodiment, the anti-PD-L1 antibody is YW243.55.S70 described herein. In another specific embodiment, the anti-PD-L1 antibody is MDX-1105 as described herein. In another specific embodiment, the anti-PD-L1 antibody is MEDI4736 (durvalumab) as described herein. In yet another specific embodiment, the anti-PD-L1 antibody is MSB0010718C (avelumab) as described herein.

[0342] As used herein, a "PD-1 binding antagonist" reduces signaling resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and / or PD-L2. , blocking, inhibiting, abrogating, or interfering molecules. In some embodiments, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its binding partner. In certain embodiments, the PD-1 binding antagonist inhibits binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies and antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, small molecule antagonists, polynucleotide antagonists, and PD-1, PD-L1 and / or Including other molecules that reduce, block, inhibit, abrogate, or interfere with signaling resulting from interaction with PD-L2. In one embodiment, the PD-1 binding antagonist reduces negative signals mediated by or through cell surface proteins expressed on T lymphocytes and other cells mediated through PD-1 or PD-L1. and alleviate the dysfunctional state of dysfunctional T cells. In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. In certain embodiments, the PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific embodiment, the PD-1 binding antagonist is MK-3475 (pembrolizumab). In another specific embodiment, the PD-1 binding antagonist is MEDI-0680 (AMP-514). In another specific embodiment, the PD-1 binding antagonist is PDR001. In another specific embodiment, the PD-1 binding antagonist is REGN2810. In another specific embodiment, the PD-1 binding antagonist is BGB-108. In another specific embodiment, the PD-1 binding antagonist is AMP-224.

[0343] "Polynucleotide," or "nucleic acid," as used interchangeably herein, refer to polymers of nucleotides of any length, and include DNA and RNA. Nucleotides may be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or analogs thereof, or any substrate that can be incorporated into a polymer by a DNA or RNA polymerase or by a synthetic reaction. . A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. Modifications to the nucleotide structure, if present, may be imparted before or after assembly of the polymer. A sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after synthesis, such as by conjugation with a label. Other types of modifications include, e.g., "caps," substitutions with one or more analogues of natural nucleotides, internucleotide modifications, e.g., those with uncharged linkages (e.g., methylphosphonates, phosphotriesters, phosphoramidates, carbamates, etc.) and those with charged bonds (e.g., phosphorothioates, phosphorodithioates, etc.), pendant moieties such as proteins (e.g., nucleases, toxins, antibodies, signal peptides, ply-L-lysine, etc.). etc., those with intercalators (e.g., acridine, psoralen, etc.), those containing chelating agents (e.g., metals, radioactive metals, boron, metal oxides, etc.), those containing alkylating agents, modifications Included are those with linkages (eg, alpha anomeric nucleic acids, etc.), as well as unmodified forms of one or more polynucleotides. In addition, any of the hydroxyl groups normally present in the sugar may be replaced, e.g., by a phosphonate group, a phosphate group, protected by standard protecting groups, or activated to access additional nucleotides. Additional linkages may be provided or conjugated to a solid or semi-solid support. The 5' and 3' terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of 1-20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups. Polynucleotides can also include analogous forms of ribose or deoxyribose sugars commonly known in the art, including, for example, 2'-O-methyl-, 2'-O- allyl-, 2'-fluoro- or 2'-azido-ribose, carbocyclic sugar analogs, α-anomeric sugars, epimeric sugars such as arabinose, xylose, or lyxose, pyranose sugars, furanose sugars, sedoheptulose, acyclic Formula analogs, and abasic nucleoside analogs such as methyl riboside are included. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, phosphates P(O)S (“thioates”), P(S)S (“dithioates”), (O)NR2 (“amidates”), P(O )R, P(O)OR', CO or CH2 ("formacetal"), wherein each R or R' is independently H or an ether (-O- ) substituted or unsubstituted alkyl (1-20 C) optionally containing a bond, aryl, alkenyl, cycloalkyl, cycloalkenyl, or araldyl. Not all bonds in a polynucleotide need be identical. The foregoing description applies to all polynucleotides referred to herein, including RNA and DNA.

[0344] As used herein, the technique of "polymerase chain reaction" or "PCR" generally refers to the process by which minute specific pieces of nucleic acid, RNA, and / or DNA are Refers to procedures that are amplified as described in the specification. In general, sequence information from the ends of the region of interest or beyond must be available so that oligonucleotide primers can be designed, the sequences of these primers on opposite sides of the template to be amplified. Identical or similar to chain. The 5' terminal nucleotides of the two primers can coincide with the ends of the material to be amplified. PCR can be used to amplify specific RNA sequences, specific DNA sequences from total genomic DNA and cDNA transcribed from total cellular RNA, bacteriophage or plasmid sequences, and the like. For reviews, see Mullis et al., Cold Spring Harbor Symp. Quant. Biol., 51:263 (1987); Erlich, ed., PCR Technology, (Stockton Press, NY, 1989). As used herein, PCR is considered an example of a nucleic acid polymerase reaction method for amplifying a nucleic acid test sample that involves using known nucleic acids (DNA or RNA) as primers, but only and utilizes a nucleic acid polymerase to amplify or produce a specific piece of nucleic acid, or to amplify or produce a specific piece of nucleic acid that is complementary to a specific nucleic acid.

[0345] As used herein, the term "reverse transcriptase polymerase chain reaction" or "RT-PCR" refers to the replication and amplification of RNA sequences. In this method, reverse transcription is coupled to PCR, eg, as described in US Pat. No. 5,322,770, which is hereby incorporated by reference in its entirety. In RT-PCR, an RNA template is converted into cDNA by the reverse transcriptase activity of the enzyme, which is then amplified using the same or the polymerizing activity of a different enzyme. Both thermostable and thermolabile reverse transcriptases and polymerases can be used. "Reverse transcriptase" (RT) can also include retroviruses, reverse transcriptases from other viruses, as well as DNA polymerases that exhibit reverse transcriptase activity.

[0346] As used herein, the term "reverse transcriptase quantitative polymerase chain reaction" or "RT-qPCR" means that the nucleic acid to be amplified is RNA that is first reverse transcribed into cDNA, and at each step of the PCR reaction It is a form of PCR in which the amount of PCR product is measured.

[0347] "Quantitative real-time polymerase chain reaction" or "qRT-PCR" refers to a form of PCR in which the amount of PCR product is measured at each step of the PCR reaction. This technique has been used in various publications, including Cronin et al., Am. J. Pathol. 164(1):35-42 (2004); and Ma et al., Cancer Cell 5:607-616 (2004). It is described in.

[0348] The term "multiplex PCR" refers to the use of multiple primer sets on nucleic acid obtained from a single source (e.g., individual) for the purpose of amplifying two or more DNA sequences in a single reaction. Refers to a single PCR reaction performed.

[0349] The term "RNA-seq," also called "whole transcriptome shotgun sequencing (WTSS)," refers to high-throughput sequencing for sequencing and / or quantifying cDNA to obtain information about the RNA content of a sample. Refers to the use of sing technology. Publications describing RNA-seq include: Wang et al., Nature Reviews Genetics 10(1):57-63 (2009); Ryan et al. BioTechniques 45(1):81-94 (2008); and Maher et al., Nature 458(7234):97-101 (2009).

[0350] The term "polynucleotide", when used in the singular or plural, generally refers to any polyribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. Refers to a nucleotide or polydeoxyribonucleotide. Thus, for example, polynucleotides as defined herein include, but are not limited to, single- and double-stranded DNA, DNA containing single- and double-stranded regions, single- and double-stranded RNA, and Hybrid molecules comprising DNA and RNA, which may be RNA comprising single- and double-stranded regions, single-stranded, or more typically double-stranded, or which may comprise single- and double-stranded regions. include. In addition, the term "polynucleotide" as used herein refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA. The strands within such regions may be from the same molecule or from different molecules. Such regions may include one or all of such molecules, but more typically include only some regions of such molecules. One of the molecules in the triple helical region is often an oligonucleotide. The term "polynucleotide" specifically includes cDNA. The term includes DNAs (including cDNAs) and RNAs that contain one or more modified bases. Thus, DNAs or RNAs with backbones modified for stability or for other reasons are "polynucleotides" as that term is intended herein. Moreover, DNAs or RNAs containing unusual bases, such as inosine, or modified bases, such as tritiated bases, are included within the term "polynucleotides" as defined herein. In general, the term "polynucleotide" includes all chemically, enzymatically, and / or metabolically modified forms of unmodified polynucleotides, as well as viruses and cells characterized by simple and complex cells. DNA and RNA chemical forms.

[0351] "Response to treatment," "responsiveness to treatment," or "benefit of treatment" refers to (1) some degree of inhibition of disease progression (e.g., cancer progression), including slowing and complete arrest; (3) inhibition (i.e., reduction, slowing, or complete arrest) of cancer cell invasion into adjacent peripheral organs and / or tissues; (4) inhibition of metastasis (i.e., reduction, slowing); (5) some relief of one or more symptoms associated with the disease or disorder (e.g., cancer); (6) overall survival (OS HR<1) and progression-free survival (PFS); HR<1), and / or (9) treatment (e.g., PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, Any end that demonstrates benefit to an individual, including, but not limited to, a reduction in mortality at a given time point following treatment comprising e.g., atezolizumab) or a PD-1 binding antagonist (e.g., anti-PD-1 antibody) can be assessed using points As used herein, a patient who is "non-responding" to a particular form of therapy is a patient who does not exhibit any or all of the above benefits after administration of the desired therapy. is.

[0352] As used herein, "progression-free survival" or "PFS" refers to the disease being treated (e.g., cancer, e.g., lung cancer (e.g., NSCLC, including non-squamous NSCLC and squamous NSCLC), bladder Refers to the length of time during and after treatment that the cancer (eg, UC), kidney cancer (eg, RCC), or breast cancer (eg, TNBC)) does not progress or worsen. Progression-free survival can include the amount of time an individual experiences a complete or partial response, as well as the amount of time an individual experiences stable disease.

[0353] As used herein, “overall survival” or “OS” refers to the survival of an individual for a specified period of time (e.g., 6 months, 1 year, 2 years, 3 years, 4 years, 5, 10, 15, or 20 years or longer) during and after treatment.

[0354] As used herein, "complete response" or "CR" refers to the disappearance of all signs of cancer in response to treatment. This does not necessarily mean that the cancer has been cured.

[0355] As used herein, "partial response" or "PR" refers to a reduction in the size of one or more tumors or lesions, or the extent of cancer in the body, in response to treatment.

[0356] As used herein, "hazard ratio" or "HR" is a statistical definition of event incidence. For purposes of the present invention, a hazard ratio is the probability of an event (e.g., PFS or OS) in an experimental (e.g., treatment) group versus the probability of an event (e.g., PFS or OS) in a control / treatment group at any particular time point. It is defined as being divided by . A HR value of 1 indicates that the relative risk of the endpoint (e.g., death) is equal in both the 'treated' and 'control' groups; and a value less than 1 indicates greater risk in the control group compared to the treatment group. The "hazard ratio" (ie, PFS HR) in a progression-free survival analysis is the sum of the differences between the two progression-free survival curves and represents the reduction in risk of death for treatment compared to control over follow-up. The "hazard ratio" (ie, OS HR) in overall survival analysis is the sum of the differences between the two overall survival curves and represents the reduction in risk of death for treatment compared to control over the follow-up period.

[0357] "Prolonged survival" or "prolonged survival" refers to individuals who do not express a biomarker at a specified level compared to untreated individuals (i.e., compared to individuals not treated with a drug). and / or compared to individuals treated with an approved anti-tumor therapeutic agent, means that overall survival or progression-free survival is increased in treated individuals. "Objective response rate" refers to a measurable response, including complete response (CR) or partial response (PR).

[0358] "Reduce or inhibit" means a total reduction of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or greater means the ability to bring about Reduce or inhibit the disorder being treated (e.g., cancer, e.g., lung cancer (e.g., NSCLC, including non-squamous NSCLC and squamous NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (eg TNBC)), the presence or size of metastases, or the size of the primary tumor.

[0359] As used herein, a “reference sample,” “reference cell,” “reference tissue,” “control sample,” “control cell,” or “control tissue” refers to a sample, cell , refers to an organization, standard, or level. In one embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue are obtained from the same subject or individual. In another embodiment, the reference sample is obtained from one or more individuals who are not the subject or individual. In any of the foregoing embodiments, one or more individuals from whom the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained has cancer. In certain embodiments, one or more individuals from whom the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained has cancer and is treated with an anti-cancer therapy (e.g., PD-L1 have been previously treated with one or more doses of an axially-linked antagonist. In other embodiments, one or more individuals from whom the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained has cancer and is not receiving treatment. In any of the foregoing embodiments, the subject / individual and one or more individuals who are not subjects or individuals have the same cancer. In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is a healthy and / or non-diseased portion (e.g., tissue or cell) of the same subject or individual's body. obtained from For example, healthy and / or non-diseased cells or tissue adjacent to diseased cells or tissue (eg, cells or tissue adjacent to a tumor). In another embodiment, the reference sample is obtained from untreated tissue and / or cells of the body of the same subject or individual. In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is a healthy and / or non-diseased portion (e.g., tissue or cells). In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from untreated tissue and / or cells of the body of an individual that is not the subject or individual.

[0360] The term "sample," as used herein, refers to cells and / or other molecules that are characterized and / or identified, for example, based on physical, biochemical, chemical, and / or physiological properties. Refers to a composition obtained or derived from a subject and / or individual of interest that contains an entity. For example, "disease sample" and variations thereof refer to any sample obtained from a subject of interest that is expected or known to contain the cellular and / or molecular entity to be characterized. Samples include, but are not limited to, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous humor, lymph, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, Blood-derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, sweat, mucus, tumor lysates, and tissue culture media, tissue extracts such as homogenized tissue, tumor tissue, cell extracts, and their Includes combinations.

[0361] As used herein, the terms "individual", "patient" or "subject" are used interchangeably and any single animal, more preferably a mammal (e.g., cat, dogs, horses, rabbits, zoo animals, cattle, pigs, sheep, and non-human animals such as non-human primates). In certain embodiments, the individual, patient, or subject is human.

[0362] As used herein, "treatment" (and grammatical variations thereof such as "treat" or "treating") refers to the natural history of the subject being treated Refers to clinical intervention in an attempt to change the , and can be performed for prevention or during the course of clinicopathology. Desired effects of treatment include, but are not limited to, diseases (e.g., cancer, e.g., lung cancer (e.g., NSCLC, including non-squamous NSCLC and squamous NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., , RCC), or breast cancer (e.g., TNBC)), relieve symptoms, reduce any direct or indirect pathological consequences of the disease, prevent metastasis, slow down the rate of disease progression. Includes reduction, amelioration or alleviation of condition, and remission or improved prognosis. In some embodiments, the treatments described herein delay the onset of disease or disease (e.g., cancer, e.g., lung cancer (e.g., NSCLC, including non-squamous NSCLC and squamous NSCLC), It is used to slow the progression of bladder cancer (eg UC), kidney cancer (eg RCC), or breast cancer (eg TNBC). In some cases, treatment can increase overall survival (OS) (e.g., about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, About 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more). In some cases, treatment reduces OS by, e.g., about 5% to about 500%, e.g., about 10% to about 450%, e.g., about 20% to about 400%, e.g., about 25% to about 350%. For example, about 30% to about 400%, for example, about 35% to about 350%, for example, about 40% to about 300%, for example, about 45% to about 250%, for example, about 50% to about 200% For example, about 55% to about 150%, for example, about 60% to about 100%, for example, about 65% to about 100%, for example, about 70% to about 100%, for example, about 75% to about 100% For example, about 80% to about 100%, for example, about 85% to about 100%, for example, about 90% to about 100%, for example, about 95% to about 100%, for example, about 98% to about 100% can be increased. In some cases, treatment can increase progression-free survival (PFS) (e.g., about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% About 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, or about 99% or greater). In some cases, treatment reduces PFS by, for example, about 5% to about 500%, such as about 10% to about 450%, such as about 20% to about 400%, such as about 25% to about 350%. For example, about 30% to about 400%, for example, about 35% to about 350%, for example, about 40% to about 300%, for example, about 45% to about 250%, for example, about 50% to about 200% For example, about 55% to about 150%, for example, about 60% to about 100%, for example, about 65% to about 100%, for example, about 70% to about 100%, for example, about 75% to about 100% For example, about 80% to about 100%, for example, about 85% to about 100%, for example, about 90% to about 100%, for example, about 95% to about 100%, for example, about 98% to about 100% can be increased.

[0363] A "tissue sample" or "cell sample" refers to a similar collection of cells obtained from tissue of a subject or individual. Sources of tissue or cell samples include solid tissue from fresh, frozen and / or preserved organs, tissue samples, biopsies, and / or aspirates; blood or any blood component such as plasma; brain; Bodily fluids such as spinal fluid, amniotic fluid, ascites, or interstitial fluid; can be cells at any stage in the subject's pregnancy or development. A tissue sample may be a primary or cultured cell or cell line. Optionally, the tissue or cell sample is a disease (e.g. cancer, e.g. lung cancer (e.g. NSCLC, including non-squamous NSCLC and squamous NSCLC), bladder cancer (e.g. UC), renal cancer (e.g. RCC), or breast cancer (eg TNBC)) tissues / organs. Tissue samples may contain compounds that are not naturally mixed with native tissue, such as preservatives, anticoagulants, buffers, fixatives, nutrients, or antibiotics.

[0364] For the purposes of this specification, a "section" of a tissue sample means a single portion or piece of tissue sample, eg, a slice of tissue or cells cut from the tissue sample. It is understood that multiple sections of the tissue sample are taken and analyzed. However, it is understood that the same section of tissue sample can be analyzed at both the morphological and molecular level, or can be analyzed for both polypeptides and polynucleotides.

[0365] The terms "tertiary lymphoid structures" and "TLS" are used interchangeably herein to refer to ectopic lymphoid structures that can develop in non-lymphoid tissues, e.g., at sites of chronic inflammation, including tumors. used. These terms can refer, for example, to structures of various tissues, from clusters of lymphocytes to isolated structures resembling secondary lymphoid organs. For example, the term encompasses TLS-like structures. In some cases, TLS is associated with distinct T and B cell compartments, fibroblastic reticular cell (FRC) networks, peripheral nodal addressin (PNAd + ) evidence of class switching and reactive germinal centers (GCs) within high endothelial venules (HEV), follicular dendritic cells (FDC), B-cell zones, and / or expression of activation-induced cytidine deaminase (AID); May contain enzymes expressed in GC B cells involved in somatic hypermutation and initiation of immunoglobulin gene class switching. For a review of TLS in cancer, see Colbeck et al.Front.Immunol.8:1830, 2017.

[0366] "Tumor," as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. The terms "cancer", "cancerous", "cell proliferative disease", "proliferative disease" and "tumor" when referred to herein are not mutually exclusive.

[0367] The terms "variable region" or "variable domain" refer to the domains of the heavy or light chains of an antibody that are involved in binding the antibody to antigen. The heavy and light chain variable domains (VH and VL, respectively) of native antibodies have generally similar structures, with each domain comprising four conserved framework regions (FR) and three hypervariable regions. (HVR) and (e.g. Kindt et al., Kuby Immunology, 6 th See ed., W.H. Freeman and Co., p.91 (2007). ) A single VH or VL domain is sufficient to confer antigen binding specificity. Additionally, antibodies that bind a particular antigen can be isolated using the VH or VL domain of the antibody that binds the antigen and screening a library for complementary VL or VH domains, respectively. See, eg, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0368] II. Diagnostic method Provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., anti-PD-1 (e.g., lung cancer (e.g., non-small cell lung cancer (NSCLC)), bladder cancer (e.g., urothelial carcinoma (UC)), renal cancer (e.g., , renal cell carcinoma (RCC)), or breast cancer (eg, triple negative breast cancer (TNBC)).

[0369] Further provided herein are cancers (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., TNBC)) Methods for selecting a therapy for an individual with cancer; Methods for determining whether an individual with cancer is likely to respond to treatment comprising a PD-L1 axis binding antagonist; A method for predicting an individual's responsiveness to a treatment comprising a PD-L1 axis binding antagonist; and an individual with cancer a PD-L1 axis binding antagonist (e.g., a PD-L1 binding -L1 antibodies (eg, atezolizumab) or PD-1 binding antagonists (eg, anti-PD-1 antibodies)) for monitoring response to therapy.

[0370] Any of the methods provided herein can comprise determining the presence and / or expression level of any biomarker disclosed herein. For example, a biomarker may be the presence and / or expression level of a biomarker shown in any one of Tables 1-17 below in a sample obtained from an individual; TLS in a sample obtained from an individual; number of B cells in a sample obtained from the individual; presence of clonally expanded B cells in the sample from the individual; and / or combinations thereof. Any sample type disclosed herein can be used, including any suitable sample, eg, a tumor sample.

[0371] Any of the methods provided herein involve selecting a therapy for an individual, e.g., a therapy comprising a PD-L1 axis binding antagonist (e.g., those described in Section IV below). It can contain more.

[0372] Any of the methods provided herein can further comprise administering to the individual a PD-L1 axis binding antagonist (eg, those described in Section IV below).

[0373] Table 1: Exemplary biomarkers TIFF2023529206000001.tif133170

[0374] For example, provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., anti-PD -1 antibody)) (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., TNBC)). )), which comprises in a sample from the individual one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) above the reference immune score expression level of one or more genes Immune Score expression levels of the same one or more genes identify the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0375] In another example, provided herein are cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., , TNBC)) is a method of selecting a therapy for an individual with TB), the method comprising the addition of one or more (e.g., 1, 2, 3) of the genes shown in Table 1 in a sample from the individual. , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); If the immune score expression level of the one or more genes above the gene's reference immune score expression level indicates that the individual is a PD-L1 axis binding antagonist (e.g., a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody, e.g., identified as potentially benefiting from treatment, including atezolizumab) or PD-1 binding antagonists (eg, anti-PD-1 antibodies).

[0376] In some cases, one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), the immune score expression level of the gene is above the reference immune score expression level, and the method administers to the individual an effective amount of a PD-L1 axis binding antagonist (e.g., a PD-L1 binding antagonist (eg, an anti-PD-L1 antibody, eg, atezolizumab) or a PD-1 binding antagonist (eg, an anti-PD-1 antibody)). Any suitable PD-L1 axis binding antagonist, such as any PD-L1 axis binding antagonist provided herein (eg, those described in Section IV below) may be administered.

[0377] Any suitable Immunoscore reference expression level may be used. In some cases, the reference immune score expression level is the immune score expression level of one or more genes in a reference population. In some cases, the reference population is a population of individuals with cancer. In some cases, the population of individuals is a first subset of individuals treated with a PD-L1 axis binding antagonist and a second subset of individuals treated with a therapy that does not include a PD-L1 axis binding antagonist. including. In some cases, the reference Immune Score expression level is the individual's responsiveness to treatment with a PD-L1 axis binding antagonist and the reference Immune Score expression level for each of the first subset and the second subset of individuals. Based on a significant difference between an individual's responsiveness to treatment with a treatment that does not include a PD-L1 axis binding antagonist that outperforms, the individual's responsiveness to treatment with a PD-L1 axis binding antagonist is significantly segregated. is significantly improved compared to an individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist. In some cases, treatments that do not include PD-L1 axis binding antagonists include anti-tumor agents, chemotherapeutic agents, anti-proliferative agents, anti-angiogenic agents, radiotherapy, cytotoxic agents, or combinations thereof. . In some cases, treatments that do not include PD-L1 axis binding antagonists include chemotherapeutic agents. In some cases, the chemotherapeutic agent is docetaxel. In some cases, responsiveness to treatment includes prolonging OS, prolonging progression-free survival (PFS), or increasing best overall response (BCOR). In some cases, responsiveness to treatment includes prolongation of OS. In some cases, the reference immune score expression level is the median expression level of each of the one or more genes in the reference population. In some cases, the median expression level is the median mean Z-score of the expression level of each of the one or more genes in the reference population.

[0378] Any suitable sample can be used. In some cases, the sample is a tissue sample, cell sample, whole blood sample, plasma sample, serum sample, or a combination thereof. In some cases, the tissue sample is a tumor tissue sample. In some examples, the tumor sample is a tumor tissue sample. In some cases, the tumor tissue sample comprises tumor cells, tumor-infiltrating immune cells, stromal cells, NAT cells, or combinations thereof. In some cases, the tumor tissue sample is a formalin-fixed paraffin-embedded (FFPE) sample, an archival sample, a fresh sample, or a frozen sample. In some cases, the tumor tissue sample is an FFPE sample.

[0379] The cancer may be any suitable cancer type. In some cases, the cancer is lung cancer, kidney cancer, bladder cancer, breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, esophageal cancer, mesothelioma, melanoma, head and neck cancer. Cancer, thyroid cancer, sarcoma, prostate cancer, glioblastoma, cervical cancer, thymic carcinoma, leukemia, lymphoma, myeloma, mycosis fungoides, Merkel cell carcinoma, or hematological tumor. In some cases, the cancer is lung cancer, kidney cancer, bladder cancer, or breast cancer. In some cases, the lung cancer is non-small cell lung cancer (NSCLC). In some cases, the NSCLC is non-squamous NSCLC. In some cases, the NSCLC is squamous NSCLC.

[0380] In some cases, the benefit includes an increase in an individual's OS, an increase in an individual's PFS, and / or an improvement in an individual's BCOR as compared to treatment without the PD-L1 axis binding antagonist. In some cases, the benefit includes prolongation of an individual's OS as compared to treatment without the PD-L1 axis binding antagonist.

[0381] A.B cell signature (i) Gene signature associated with B cells In some embodiments, the methods provided herein can comprise determining the expression level of one or more genes in a B cell signature. Any suitable B cell signature can be used. For example, a B cell signature can include one or more (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11) genes shown in Table 2.

[0382] Table 2: Exemplary B cell signature genes TIFF2023529206000002.tif75170

[0383] For example, provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., anti-PD -1 antibody)) (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., TNBC)). )), the method comprising one of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 in a sample from the individual A reference immune score expression level of one or more genes, comprising determining one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11) expression levels Immune Score expression levels of the same one or more genes above identify the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0384] In another example, provided herein are cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., , TNBC)), wherein the method comprises determining in a sample from the individual the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ , and MZB1 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11); If the immune score expression level of one or more genes above the gene's reference immune score expression level indicates that the individual is a PD-L1 axis binding antagonist (e.g., a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody, e.g., identified as potentially benefiting from treatment, including atezolizumab) or PD-1 binding antagonists (eg, anti-PD-1 antibodies).

[0385] In some cases, the method includes determining the expression level of one of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1.

[0386] In some cases, the method includes determining the expression level of CD79A.

[0387] In some cases, the method includes determining the expression level of CD19.

[0388] In some cases, the method includes determining the expression level of BANK1.

[0389] In some cases, the method includes determining the expression level of JCHAIN.

[0390] In some cases, the method includes determining the expression level of SLAMF7.

[0391] In some cases, the method includes determining the expression level of BTK.

[0392] In some cases, the method includes determining the expression level of TNFRSF17.

[0393] In some cases, the method includes determining the expression level of IGJ.

[0394] In some cases, the method includes determining the expression level of IGLL5.

[0395] In some cases, the method includes determining the expression level of RBPJ.

[0396] In some cases, the method includes determining the expression level of MZB1.

[0397] In some cases, the immune score expression level of one or more genes in the sample is above the reference immune score expression level, and the method administers to the individual an effective amount of a PD-L1 axis binding antagonist (e.g. , administering a PD-L1 binding antagonist (eg, an anti-PD-L1 antibody, eg, atezolizumab) or a PD-1 binding antagonist (eg, an anti-PD-1 antibody). Any suitable PD-L1 axis binding antagonist, such as any PD-L1 axis binding antagonist provided herein (eg, those described in Section IV below) may be administered.

[0398] Any suitable Immunoscore reference expression level may be used. In some cases, the reference immune score expression level is the immune score expression level of one or more genes in a reference population. In some cases, the reference population is a population of individuals with cancer. In some cases, the population of individuals is a first subset of individuals treated with a PD-L1 axis binding antagonist and a second subset of individuals treated with a therapy that does not include a PD-L1 axis binding antagonist. including. In some cases, the reference Immune Score expression level is the individual's responsiveness to treatment with a PD-L1 axis binding antagonist and the reference Immune Score expression level for each of the first subset and the second subset of individuals. Based on a significant difference between an individual's responsiveness to treatment with a treatment that does not include a PD-L1 axis binding antagonist that outperforms, the individual's responsiveness to treatment with a PD-L1 axis binding antagonist is significantly segregated. is significantly improved compared to an individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist. In some cases, treatments that do not include PD-L1 axis binding antagonists include anti-tumor agents, chemotherapeutic agents, anti-proliferative agents, anti-angiogenic agents, radiotherapy, cytotoxic agents, or combinations thereof. . In some cases, treatments that do not include PD-L1 axis binding antagonists include chemotherapeutic agents. In some cases, the chemotherapeutic agent is docetaxel. In some cases, responsiveness to treatment includes prolonged OS, prolonged PFS, or increased BCOR. In some cases, responsiveness to treatment includes prolongation of OS. In some cases, the reference immune score expression level is the median expression level of each of the one or more genes in the reference population. In some cases, the median expression level is the median mean Z-score of the expression level of each of the one or more genes in the reference population.

[0399] For example, provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., anti-PD -1 antibody)) (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., TNBC)). )), the method comprising one of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 in a sample from the individual a reference immune score expression level of one or more genes, including determining one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11) expression levels; identifies an individual as likely to benefit from a treatment comprising a PD-L1 axis binding antagonist, and benefiting from a treatment that does not comprise a PD-L1 axis binding antagonist. including prolongation of OS for individuals when compared to

[0400] In another example, provided herein are cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., , TNBC)), wherein the method comprises determining in a sample from the individual the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ , and MZB1 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11); If the immune score expression level of the one or more genes above the gene's reference immune score expression level indicates that the individual is a PD-L1 axis binding antagonist (e.g., a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody, e.g., atezolizumab) or a PD-1 binding antagonist (e.g., an anti-PD-1 antibody)), where the benefit, when compared to treatment without the PD-L1 axis binding antagonist, Includes prolongation of individual OS.

[0401] In some cases, the immune score expression level of one or more genes in the sample is above the reference immune score expression level, and the method administers to the individual an effective amount of a PD-L1 axis binding antagonist (e.g. , administering a PD-L1 binding antagonist (eg, an anti-PD-L1 antibody, eg, atezolizumab) or a PD-1 binding antagonist (eg, an anti-PD-1 antibody). Any suitable PD-L1 axis binding antagonist, such as any PD-L1 axis binding antagonist provided herein (eg, those described in Section IV below) may be administered.

[0402] In some cases, the gene comprises two or more of CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1.

[0403] For example, provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., anti-PD -1 antibody)) is a method of identifying an individual with cancer who may benefit from treatment comprising, in a sample derived from the individual, the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, determining the expression levels of two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11) of TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 , an Immune Score expression level of two or more genes above the reference Immune Score expression level of the same two or more genes identifies the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0404] In another example, provided herein is a method of selecting a therapy for an individual with cancer, the method comprising determining in a sample from the individual the genes CD79A, CD19, BANK1 , JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 expression levels of two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11) wherein an Immune Score expression level of two or more genes that exceeds a reference Immune Score expression level of the two or more genes will cause the individual to benefit from treatment comprising a PD-L1 axis binding antagonist. identify as a person.

[0405] In further examples, provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., anti-PD-1 antibody)). For example, a method of identifying an individual with TNBC)), which method includes the expression of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 in a sample from the individual. Reference immune score expression of two or more genes, including determining expression levels of two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11) of Immune Score expression levels of the same two or more genes above the level identify the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist, and benefit does not comprise a PD-L1 axis binding antagonist. Includes prolongation of an individual's OS as compared to treatment.

[0406] In yet another example, provided herein is cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., For example, a method of selecting a therapy for an individual with TNBC)), the method comprising determining in a sample from the individual the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, Two or more genes, including determining expression levels of two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11) of RBPJ, and MZB1 If the immune score expression levels of the same two or more genes above the reference immune score expression levels of ) or a PD-1 binding antagonist (e.g., an anti-PD-1 antibody)), wherein the benefit is greater when compared to a treatment that does not include a PD-L1 axis binding antagonist including OS extensions.

[0407] In some cases, the immune score expression levels of two or more genes in the sample are above the reference immune score expression levels, and the method administers to the individual an effective amount of a PD-L1 axis binding antagonist (e.g. , administering a PD-L1 binding antagonist (eg, an anti-PD-L1 antibody, eg, atezolizumab) or a PD-1 binding antagonist (eg, an anti-PD-1 antibody). Any suitable PD-L1 axis binding antagonist, such as any PD-L1 axis binding antagonist provided herein (eg, those described in Section IV below) may be administered.

[0408] Any combination of B cell signature genes can be determined. For example, the combination is two genes selected from CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1, such as any one of the combinations shown in Table 3. can include In another embodiment, the combination includes three genes selected from CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1, e.g. may include any one of In another embodiment, the combination includes four genes selected from CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1, e.g. may include any one of In another embodiment, the combination includes 5 genes selected from CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1, e.g. may include any one of In another embodiment, the combination includes six genes selected from CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1, e.g. may include any one of In another embodiment, the combination includes 7 genes selected from CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1, e.g. may include any one of

[0409] Table 3: Exemplary two-gene combinations of B-cell signature genes. TIFF2023529206000003.tif250170TIFF2023529206000004.tif156170

[0410] Table 4: Exemplary three-gene combinations of B-cell signature genes. TIFF2023529206000005.tif251170TIFF2023529206000006.tif255170TIFF2023529206000007.tif199170

[0411] Table 5: Exemplary four-gene combinations of B-cell signature genes. TIFF2023529206000008.tif250170TIFF2023529206000009.tif255170TIFF2023529206000010.tif68170

[0412] Table 6: Exemplary 5 gene combinations of B-cell signature genes. TIFF2023529206000011.tif250170TIFF2023529206000012.tif236170

[0413] Table 7: Exemplary 6-gene combinations of B-cell signature genes. TIFF2023529206000013.tif255170TIFF2023529206000014.tif83170

[0414] Table 8: Exemplary seven-gene combinations of B-cell signature genes. TIFF2023529206000015.tif214170

[0415] In some cases, the gene includes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1.

[0416] In some cases, the expression level is a nucleic acid expression level. For example, in some cases the nucleic acid expression level is the mRNA expression level. mRNA expression levels can be determined using any suitable technique, such as any technique disclosed herein. In some cases, mRNA expression levels are determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, FISH, or combinations thereof. In some cases, mRNA expression levels are detected using RNA-seq.

[0417] In other cases, the expression level is a protein expression level. Protein expression levels can be determined using any suitable technique, eg, any technique disclosed herein. In some cases, protein expression levels are determined by IHC, immunofluorescence, mass spectroscopy, flow cytometry, and Western blot, or combinations thereof.

[0418] Any suitable sample can be used. In some cases, the sample is a tissue sample, cell sample, whole blood sample, plasma sample, serum sample, or a combination thereof. In some cases, the tissue sample is a tumor tissue sample. In some examples, the tumor sample is a tumor tissue sample. In some cases, the tumor tissue sample comprises tumor cells, tumor-infiltrating immune cells, stromal cells, NAT cells, or combinations thereof. In some cases, the tumor tissue sample is an FFPE sample, archival sample, fresh sample, or frozen sample. In some cases, the tumor tissue sample is an FFPE sample.

[0419] The cancer may be any suitable cancer type. In some cases, the cancer is lung cancer, kidney cancer, bladder cancer, breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, esophageal cancer, mesothelioma, melanoma, head and neck cancer. Cancer, thyroid cancer, sarcoma, prostate cancer, glioblastoma, cervical cancer, thymic carcinoma, leukemia, lymphoma, myeloma, mycosis fungoides, Merkel cell carcinoma, or hematological tumor. In some cases, the cancer is lung cancer, kidney cancer, bladder cancer, or breast cancer. In some cases, the lung cancer is NSCLC. In some cases, the NSCLC is non-squamous NSCLC. In some cases, the NSCLC is squamous NSCLC.

[0420] In some cases, the benefit includes an increase in an individual's OS, an increase in an individual's PFS, and / or an improvement in an individual's BCOR as compared to treatment without the PD-L1 axis binding antagonist. In some cases, the benefit includes prolongation of an individual's OS as compared to treatment without the PD-L1 axis binding antagonist.

[0421] (ii) gene signature associated with plasma B cells In some embodiments, the B cell signature used with the compositions and methods of the invention is a plasma B cell signature. Any suitable plasma B cell signature can be used. For example, the plasma B cell signature is one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) shown in Table 9. It can contain genes.

[0422] Table 9: Exemplary Plasma B Cell Signature Genes TIFF2023529206000016.tif94170

[0423] For example, provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., anti-PD -1 antibody)) (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., TNBC)). )), the method includes the genes MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, ILGV6-57, IGHA2, IGKV4- one or more of 1, IGKV1-12, IGLC7, and IGLL5 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) determining an expression level, wherein an Immune Score expression level of one or more genes above a reference Immune Score expression level of the one or more genes indicates that the individual will benefit from treatment comprising a PD-L1 axis binding antagonist. Identify as eligible.

[0424] In another example, provided herein are cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., , TNBC)), wherein the method comprises determining the presence of the genes MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6 in a sample from the individual. one or more of -57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, or 14), wherein an immune score expression level of the one or more genes above a reference immune score expression level of the one or more genes indicates that the individual is PD-L1 axis bound. Identify as likely to benefit from treatment with an antagonist (e.g., PD-L1 binding antagonist (e.g., anti-PD-L1 antibody, e.g., atezolizumab) or PD-1 binding antagonist (e.g., anti-PD-1 antibody)) .

[0425] In some cases, the method includes one of the genes MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5. determining the expression level of one.

[0426] In some cases, the method includes determining the expression level of MZB1.

[0427] In some cases, the method includes determining the expression level of DERL3.

[0428] In some cases, the method includes determining the expression level of JSRP1.

[0429] In some cases, the method includes determining the expression level of TNFRSF17.

[0430] In some cases, the method includes determining the expression level of SLAMF7.

[0431] In some cases, the method includes determining the expression level of IGHG2.

[0432] In some cases, the method includes determining the expression level of IGHGP.

[0433] In some cases, the method includes determining the expression level of IGLV3-1.

[0434] In some cases, the method includes determining the expression level of IGLV6-57.

[0435] In some cases, the method includes determining the expression level of IGHA2.

[0436] In some cases, the method includes determining the expression level of IGKV4-1.

[0437] In some cases, the method includes determining the expression level of IGKV1-12.

[0438] In some cases, the method includes determining the expression level of IGLC7.

[0439] In some cases, the method includes determining the expression level of IGLL5.

[0440] In some cases, the immune score expression level of one or more genes in the sample is above the reference immune score expression level, and the method administers to the individual an effective amount of a PD-L1 axis binding antagonist (e.g. , administering a PD-L1 binding antagonist (eg, an anti-PD-L1 antibody, eg, atezolizumab) or a PD-1 binding antagonist (eg, an anti-PD-1 antibody). Any suitable PD-L1 axis binding antagonist, such as any PD-L1 axis binding antagonist provided herein (eg, those described in Section IV below) may be administered.

[0441] Any suitable Immunoscore reference expression level may be used. In some cases, the reference immune score expression level is the immune score expression level of one or more genes in a reference population. In some cases, the reference population is a population of individuals with cancer. In some cases, the population of individuals is a first subset of individuals treated with a PD-L1 axis binding antagonist and a second subset of individuals treated with a therapy that does not include a PD-L1 axis binding antagonist. including. In some cases, the reference Immune Score expression level is the individual's responsiveness to treatment with a PD-L1 axis binding antagonist and the reference Immune Score expression level for each of the first subset and the second subset of individuals. Based on a significant difference between an individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist that outperforms, a significant segregation of individuals to treatment with a PD-L1 axis binding antagonist, where Responsiveness is significantly improved compared to the individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist. In some cases, treatments that do not include PD-L1 axis binding antagonists include anti-tumor agents, chemotherapeutic agents, anti-proliferative agents, anti-angiogenic agents, radiotherapy, cytotoxic agents, or combinations thereof. . In some cases, treatments that do not include PD-L1 axis binding antagonists include chemotherapeutic agents. In some cases, the chemotherapeutic agent is docetaxel. In some cases, responsiveness to treatment includes prolonged OS, prolonged PFS, or increased BCOR. In some cases, responsiveness to treatment includes prolongation of OS. In some cases, the reference immune score expression level is the median expression level of each of the one or more genes in the reference population. In some cases, the median expression level is the median mean Z-score of the expression level of each of the one or more genes in the reference population.

[0442] For example, provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., anti-PD -1 antibody)) (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., TNBC)). )), the method includes the genes MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, ILGV6-57, IGHA2, IGKV4- one or more of 1, IGKV1-12, IGLC7, and IGLL5 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) determining an expression level, wherein an Immune Score expression level of one or more genes above a reference Immune Score expression level of the one or more genes indicates that the individual will benefit from treatment comprising a PD-L1 axis binding antagonist. Identified as potential recipients, benefits include prolongation of an individual's OS when compared to treatment that does not include a PD-L1 axis binding antagonist.

[0443] In another example, provided herein are cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., , TNBC)), wherein the method comprises determining the presence of the genes MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6 in a sample from the individual. one or more of -57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, or 14), wherein an immune score expression level of the one or more genes above a reference immune score expression level of the one or more genes indicates that the individual is PD-L1 axis bound. identified as likely to benefit from treatment involving an antagonist (e.g., a PD-L1 binding antagonist (e.g., anti-PD-L1 antibody, e.g., atezolizumab) or a PD-1 binding antagonist (e.g., anti-PD-1 antibody)). , benefit includes prolongation of individual OS when compared to treatment without a PD-L1 axis binding antagonist. In some cases, the immune score expression level of one or more genes in the sample is above the reference immune score expression level, and the method administers to the individual an effective amount of a PD-L1 axis binding antagonist (e.g. , administering a PD-L1 binding antagonist (eg, an anti-PD-L1 antibody, eg, atezolizumab) or a PD-1 binding antagonist (eg, an anti-PD-1 antibody). Any suitable PD-L1 axis binding antagonist, such as any PD-L1 axis binding antagonist provided herein (eg, those described in Section IV below) may be administered.

[0444] In some cases, the genes are two of MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 Including above.

[0445] For example, provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., anti-PD -1 antibody)) is a method of identifying an individual with cancer who may benefit from treatment comprising, in a sample derived from the individual, the genes MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, Two or more of IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14), wherein the immune score expression level of the two or more genes above the reference immune score expression level of the two or more genes causes the individual to Identify those who may benefit from treatment that includes a PD-L1 axis binding antagonist.

[0446] In another example, provided herein is a method of selecting a therapy for an individual with cancer, the method comprising determining in a sample from the individual the genes MZB1, DERL3, JSRP1 , TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14), wherein immune score expression of two or more genes above the reference immune score expression level of the same two or more genes The level identifies the individual as likely to benefit from treatment that includes a PD-L1 axis binding antagonist.

[0447] In further examples, provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., anti-PD-1 antibody)). For example, TNBC)) is a method of identifying an individual having TNBC)), which method includes the genes MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2 in a sample from the individual. , IGKV4-1, IGKV1-12, IGLC7, and IGLL5 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ) determining the expression level, wherein the Immune Score expression level of the two or more genes above the reference Immune Score expression level of the two or more genes indicates that the individual will benefit from treatment comprising a PD-L1 axis binding antagonist. Identified as potential recipients, the benefit includes prolongation of the individual's OS when compared to treatment that does not include a PD-L1 axis binding antagonist.

[0448] In yet another example, provided herein is cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., For example, a method of selecting a therapy for an individual with TNBC)), the method comprising determining in a sample from the individual the genes MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, Two or more of IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14), wherein an Immune Score expression level of the two or more genes above a reference Immune Score expression level of the two or more genes defines the individual as a PD-L1 axis binding antagonist. (e.g., a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody, e.g., atezolizumab) or a PD-1 binding antagonist (e.g., an anti-PD-1 antibody)). Benefits include prolongation of an individual's OS when compared to treatment that does not include a PD-L1 axis binding antagonist.

[0449] In some cases, the immune score expression levels of two or more genes in the sample are above the reference immune score expression levels, and the method administers to the individual an effective amount of a PD-L1 axis binding antagonist (e.g. , administering a PD-L1 binding antagonist (eg, an anti-PD-L1 antibody, eg, atezolizumab) or a PD-1 binding antagonist (eg, an anti-PD-1 antibody). Any suitable PD-L1 axis binding antagonist, such as any PD-L1 axis binding antagonist provided herein (eg, those described in Section IV below) may be administered.

[0450] Any combination of plasma B cell signature genes can be determined. For example, the combination includes two genes selected from MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5; For example, any one of the combinations shown in Table 10 may be included. In another embodiment, the combination is selected from MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 Any one of the three genes, eg, combinations shown in Table 11, may be included. In another embodiment, the combination is selected from MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 Any one of the four genes, eg, combinations shown in Table 12, may be included. In another embodiment, the combination is selected from MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 Any one of the 5 genes, eg, combinations shown in Table 13, may be included. In another embodiment, the combination is selected from MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 Any one of the 6 genes, eg, combinations shown in Table 14, may be included. In another embodiment, the combination is selected from MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5 Any one of the 7 genes, eg, combinations shown in Table 15, may be included.

[0451] Table 10: Exemplary two-gene combinations of plasma B-cell signature genes. TIFF2023529206000017.tif250170TIFF2023529206000018.tif214170

[0452] Table 11: Exemplary three-gene combinations of plasma B-cell signature genes. TIFF2023529206000019.tif243170

[0453] Table 12: Exemplary four-gene combinations of plasma B-cell signature genes. TIFF2023529206000020.tif249170TIFF2023529206000021.tif32170

[0454] Table 13: Exemplary 5 gene combinations of plasma B-cell signature genes. TIFF2023529206000022.tif200170

[0455] Table 14: Exemplary 6-Gene Combinations of Plasma B-Cell Signature Genes TIFF2023529206000023.tif192170

[0456] Table 15: Exemplary seven-gene combinations of plasma B-cell signature genes. TIFF2023529206000024.tif156170

[0457] In some cases, the gene includes MZB1, DERL3, JSRP1, TNFRSF17, SLAMF7, IGHG2, IGHGP, IGLV3-1, IGLV6-57, IGHA2, IGKV4-1, IGKV1-12, IGLC7, and IGLL5.

[0458] In some cases, the expression level is a nucleic acid expression level. For example, in some cases the nucleic acid expression level is the mRNA expression level. mRNA expression levels can be determined using any suitable technique, such as any technique disclosed herein. In some cases, mRNA expression levels are determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, FISH, or combinations thereof. In some cases, mRNA expression levels are detected using RNA-seq.

[0459] In other cases, the expression level is a protein expression level. Protein expression levels can be determined using any suitable technique, eg, any technique disclosed herein. In some cases, protein expression levels are determined by IHC, immunofluorescence, mass spectroscopy, flow cytometry, and Western blot, or combinations thereof.

[0460] Any suitable sample can be used. In some cases, the sample is a tissue sample, cell sample, whole blood sample, plasma sample, serum sample, or a combination thereof. In some cases, the tissue sample is a tumor tissue sample. In some examples, the tumor sample is a tumor tissue sample. In some cases, the tumor tissue sample comprises tumor cells, tumor-infiltrating immune cells, stromal cells, NAT cells, or combinations thereof. In some cases, the tumor tissue sample is an FFPE sample, archival sample, fresh sample, or frozen sample. In some cases, the tumor tissue sample is an FFPE sample.

[0461] The cancer may be any suitable cancer type. In some cases, the cancer is lung cancer, kidney cancer, bladder cancer, breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, esophageal cancer, mesothelioma, melanoma, head and neck cancer. Cancer, thyroid cancer, sarcoma, prostate cancer, glioblastoma, cervical cancer, thymic carcinoma, leukemia, lymphoma, myeloma, mycosis fungoides, Merkel cell carcinoma, or hematological tumor. In some cases, the cancer is lung cancer, kidney cancer, bladder cancer, or breast cancer. In some cases, the lung cancer is NSCLC. In some cases, the NSCLC is non-squamous NSCLC. In some cases, the NSCLC is squamous NSCLC.

[0462] In some cases, the benefit includes an increase in an individual's OS, an increase in an individual's PFS, and / or an improvement in an individual's BCOR as compared to treatment without the PD-L1 axis binding antagonist. In some cases, the benefit includes prolongation of an individual's OS as compared to treatment without the PD-L1 axis binding antagonist.

[0463] B. Tertiary lymphoid structures (TLS) In some aspects, the methods provided herein treat cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., , TNBC))), determining the presence of TLS in a sample (eg, a tumor sample).

[0464] For example, provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., anti-PD -1 antibody)) (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., TNBC)). )), the method comprising determining the presence of tertiary lymphoid structures (TLS) in a sample (e.g., a tumor sample) from the individual, wherein the presence of TLS in the sample The presence identifies the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0465] In another example, provided herein are cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., , TNBC)), the method comprising determining the presence of TLS in a sample (e.g., a tumor sample) from the individual, wherein the presence of TLS in the sample is determined. The presence indicates that the individual has a PD-L1 axis binding antagonist (e.g., a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody, e.g., atezolizumab) or a PD-1 binding antagonist (e.g., an anti-PD-1 antibody)). Identify those who may benefit from treatment, including

[0466] In some cases, the sample from the individual is determined to have the presence of TLS, and the method includes administering to the individual an effective amount of a PD-L1 axis binding antagonist (e.g., a PD-L1 binding antagonist (e.g., anti-PD -L1 antibody (eg, atezolizumab) or PD-1 binding antagonist (eg, anti-PD-1 antibody)). Any suitable PD-L1 axis binding antagonist, such as any PD-L1 axis binding antagonist provided herein (eg, those described in Section IV below) may be administered.

[0467] Any suitable technique can be used to determine the presence of TLS in a sample. For example, in some cases the presence of TLS is determined by histological staining, IHC, immunofluorescence, or gene expression analysis.

[0468] Any suitable histological staining technique can be used. For example, in some cases histological staining includes hematoxylin and eosin (H&E) staining.

[0469] Any suitable IHC or immunofluorescence technique can be used. In some cases, IHC or immunofluorescence is performed using, for example, antibodies (e.g., anti-CD62L antibodies, anti-L-selectin antibodies, anti-CD40 antibodies, and / or anti-CD8 antibodies) to detect CD62L, L-selectin, Including detecting CD40, or CD8. In some cases, CD62L or L-selectin is detected using a MECA-79 antibody.

[0470] In some cases, gene expression analysis includes determining the level of expression of the TLS gene signature in the sample. For example, gene expression analysis can include determining the expression level of any of the TLS signatures disclosed herein (eg, Section II, subsection C below). In some cases, the TLS gene signature is one or more of the genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13 (e.g., 1, 2, 3 , 4, 5, 6, 7, 8, 9, 10, 11, or 12). In some cases, the genes include two or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13.

[0471] In some cases, a sample can contain one TLS. In other cases, the sample contains multiple TLS, e.g. 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, It may contain 90, 100, or more TLS.

[0472] Any suitable sample can be used. In some cases, the sample is a tissue sample, cell sample, whole blood sample, plasma sample, serum sample, or a combination thereof. In some cases, the tissue sample is a tumor tissue sample. In some examples, the tumor sample is a tumor tissue sample. In some cases, the tumor tissue sample comprises tumor cells, tumor-infiltrating immune cells, stromal cells, NAT cells, or combinations thereof. In some cases, the tumor tissue sample is an FFPE sample, archival sample, fresh sample, or frozen sample. In some cases, the tumor tissue sample is an FFPE sample.

[0473] The cancer may be any suitable cancer type. In some cases, the cancer is lung cancer, kidney cancer, bladder cancer, breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, esophageal cancer, mesothelioma, melanoma, head and neck cancer. Cancer, thyroid cancer, sarcoma, prostate cancer, glioblastoma, cervical cancer, thymic carcinoma, leukemia, lymphoma, myeloma, mycosis fungoides, Merkel cell carcinoma, or hematological tumor. In some cases, the cancer is lung cancer, kidney cancer, bladder cancer, or breast cancer. In some cases, the lung cancer is NSCLC. In some cases, the NSCLC is non-squamous NSCLC. In some cases, the NSCLC is squamous NSCLC.

[0474] In some cases, the benefit includes an increase in an individual's OS, an increase in an individual's PFS, and / or an improvement in an individual's BCOR as compared to treatment without the PD-L1 axis binding antagonist. In some cases, the benefit includes prolongation of an individual's OS as compared to treatment without the PD-L1 axis binding antagonist.

[0475] C. TLS signature In some embodiments, the methods provided herein can include determining the expression level of one or more genes in the TLS signature. Any suitable TLS signature can be used. For example, a TLS signature can include one or more (e.g., 1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) genes shown in Table 16. .

[0476] Table 16: Exemplary TLS Signature Genes TIFF2023529206000025.tif81170

[0477] For example, provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., anti-PD -1 antibody)) (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., TNBC)). )) of the genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13 in a sample from the individual. referencing one or more genes, including determining the expression level of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of An Immune Score expression level of the same one or more genes above the Immune Score expression level identifies the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0478] In another example, provided herein are cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., , TNBC)), wherein the method comprises determining, in a sample from the individual, the genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10 , CXCL11, and CXCL13 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12); An immune score expression level of one or more genes above a reference immune score expression level of the same gene or genes indicates that the individual is a PD-L1 axis binding antagonist (e.g., a PD-L1 binding antagonist (e.g., anti-PD-L1 Identify those who may benefit from therapy, including antibodies (eg, atezolizumab) or PD-1 binding antagonists (eg, anti-PD-1 antibodies).

[0479] In some cases, the Immunoscore expression levels of one or more (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) genes in the sample are similar. above the reference immune score expression level of one or more genes, and the method comprises administering to the individual an effective amount of a PD-L1 axis binding antagonist (e.g., a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody, e.g., , atezolizumab) or a PD-1 binding antagonist (eg, an anti-PD-1 antibody)). Any suitable PD-L1 axis binding antagonist, such as any PD-L1 axis binding antagonist provided herein (eg, those described in Section IV below) may be administered.

[0480] Any suitable Immunoscore reference expression level may be used. In some cases, the reference immune score expression level is the immune score expression level of one or more genes in a reference population. In some cases, the reference population is a population of individuals with cancer. In some cases, the population of individuals is a first subset of individuals treated with a PD-L1 axis binding antagonist and a second subset of individuals treated with a therapy that does not include a PD-L1 axis binding antagonist. including. In some cases, the reference Immune Score expression level is the individual's responsiveness to treatment with a PD-L1 axis binding antagonist and the reference Immune Score expression level for each of the first subset and the second subset of individuals. Based on a significant difference between an individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist that outperforms, a significant segregation of individuals to treatment with a PD-L1 axis binding antagonist, where Responsiveness is significantly improved compared to the individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist. In some cases, treatments that do not include PD-L1 axis binding antagonists include anti-tumor agents, chemotherapeutic agents, anti-proliferative agents, anti-angiogenic agents, radiotherapy, cytotoxic agents, or combinations thereof. . In some cases, treatments that do not include PD-L1 axis binding antagonists include chemotherapeutic agents. In some cases, the chemotherapeutic agent is docetaxel. In some cases, responsiveness to treatment includes prolonged OS, prolonged PFS, or increased BCOR. In some cases, responsiveness to treatment includes prolongation of OS. In some cases, the reference immune score expression level is the median expression level of each of the one or more genes in the reference population. In some cases, the median expression level is the median mean Z-score of the expression level of each of the one or more genes in the reference population.

[0481] In some cases, the genes include two or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13.

[0482] For example, provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., anti-PD -1 antibody)) (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., TNBC)). )) of the genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13 in a sample from the individual. a reference immune score of two or more genes Immune Score expression levels of the same two or more genes above expression levels identify an individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0483] In another example, provided herein are cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., , TNBC)), wherein the method comprises determining, in a sample from the individual, the genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10 , CXCL11, and CXCL13 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12); Immune Score expression levels for the same two or more genes above the reference Immune Score expression levels for the above genes indicate that the individual is a PD-L1 axis binding antagonist (e.g., a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody, identified as potentially benefiting from treatment, including atezolizumab) or PD-1 binding antagonists (eg, anti-PD-1 antibodies).

[0484] In some cases, the Immune Score expression levels of two or more genes in the sample exceed the reference Immune Score expression levels, and the method further comprises administering to the individual an effective amount of a PD-L1 axis binding antagonist. include. Any suitable PD-L1 axis binding antagonist, such as any PD-L1 axis binding antagonist provided herein (eg, those described in Section IV below) may be administered.

[0485] In some cases, the reference immune score expression level is the immune score expression level of two or more genes in a reference population. In some cases, the reference population is a population of individuals with cancer. In some cases, the population of individuals is a first subset of individuals treated with a PD-L1 axis binding antagonist and a second subset of individuals treated with a therapy that does not include a PD-L1 axis binding antagonist. including. In some cases, the reference Immune Score expression level determines each of the first and second subsets of individuals to be responsive to treatment with a PD-L1 axis binding antagonist and to have PD above the reference expression level. - significant segregation based on a significant difference between an individual's responsiveness to treatment with a therapy that does not include an L1 axis binding antagonist, where the individual's responsiveness to treatment with a PD-L1 axis binding antagonist is significantly improved compared to an individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist. In some cases, treatments that do not include PD-L1 axis binding antagonists include anti-tumor agents, chemotherapeutic agents, anti-proliferative agents, anti-angiogenic agents, radiotherapy, cytotoxic agents, or combinations thereof. . In some cases, treatments that do not include PD-L1 axis binding antagonists include chemotherapeutic agents. In some cases, the chemotherapeutic agent is docetaxel. In some cases, responsiveness to treatment includes prolonged OS, prolonged PFS, or increased BCOR. In some cases, responsiveness to treatment includes prolongation of OS. In some cases, the reference immune score expression level is the median expression level of each of two or more genes in the reference population. In some cases, the median expression level is the median mean Z-score of the expression levels of each of the two or more genes in the reference population.

[0486] In some cases, the genes include three or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13. In some cases, the genes include four or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13. In some cases, the genes include five or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13. In some cases, the genes include six or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13. In some cases, the genes include seven or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13. In some cases, the genes include eight or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13. In some cases, the genes include nine or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13. In some cases, the genes include 10 or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13. In some cases, the genes include 11 or more of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13.

[0487] Any combination of TLS signature genes, e.g., any combination of two genes selected from CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13; CCL2, CCL3, any combination of three genes selected from CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11 and CXCL13; any combination of 4 genes selected from CXCL10, CXCL11, and CXCL13; any combination; any combination of 6 genes selected from CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13; CCL2, CCL3, CCL4, CCL5, CCL8, Any combination of 7 genes selected from CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11 and CXCL13; any combination of 8 genes selected from; any combination of 9 genes selected from CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13; Any combination of 10 genes selected from CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11 and CXCL13; CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21 , CXCL9, CXCL10, CXCL11, and CXCL13; Any combination of the 12 genes can be determined.

[0488] In some cases, the genes include CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13.

[0489] In some cases, the expression level is a nucleic acid expression level. For example, in some cases the nucleic acid expression level is the mRNA expression level. mRNA expression levels can be determined using any suitable technique, such as any technique disclosed herein. In some cases, mRNA expression levels are determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, FISH, or combinations thereof. In some cases, mRNA expression levels are detected using RNA-seq.

[0490] In other cases, the expression level is a protein expression level. Protein expression levels can be determined using any suitable technique, eg, any technique disclosed herein. In some cases, protein expression levels are determined by IHC, immunofluorescence, mass spectroscopy, flow cytometry, and Western blot, or combinations thereof.

[0491] Any suitable sample can be used. In some cases, the sample is a tissue sample, cell sample, whole blood sample, plasma sample, serum sample, or a combination thereof. In some cases, the tissue sample is a tumor tissue sample. In some examples, the tumor sample is a tumor tissue sample. In some cases, the tumor tissue sample comprises tumor cells, tumor-infiltrating immune cells, stromal cells, NAT cells, or combinations thereof. In some cases, the tumor tissue sample is an FFPE sample, archival sample, fresh sample, or frozen sample. In some cases, the tumor tissue sample is an FFPE sample.

[0492] The cancer may be any suitable cancer type. In some cases, the cancer is lung cancer, kidney cancer, bladder cancer, breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, esophageal cancer, mesothelioma, melanoma, head and neck cancer. Cancer, thyroid cancer, sarcoma, prostate cancer, glioblastoma, cervical cancer, thymic carcinoma, leukemia, lymphoma, myeloma, mycosis fungoides, Merkel cell carcinoma, or hematological tumor. In some cases, the cancer is lung cancer, kidney cancer, bladder cancer, or breast cancer. In some cases, the lung cancer is NSCLC. In some cases, the NSCLC is non-squamous NSCLC. In some cases, the NSCLC is squamous NSCLC.

[0493] In some cases, the benefit includes an increase in an individual's OS, an increase in an individual's PFS, and / or an improvement in an individual's BCOR as compared to treatment without a PD-L1 axis binding antagonist. In some cases, the benefit includes prolongation of an individual's OS as compared to treatment without the PD-L1 axis binding antagonist.

[0494] D. B cell numbers and clonally expanded B cells In some aspects, the methods provided herein comprise determining the presence and / or number of B cells in a sample from an individual. In some embodiments, the methods provided herein can comprise determining the presence and / or number of clonally expanded B cells in a sample from the individual.

[0495] For example, provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., anti-PD -1 antibody)) (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., TNBC)). )), the method comprising determining the number of B cells in a sample (e.g., a tumor sample) from the individual, wherein the number of B cells in the sample exceeds a reference number of B cells. The number of cells identifies an individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0496] In another example, provided herein are cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., , TNBC)), the method comprising determining the number of B cells in a sample (e.g., a tumor sample) from the individual; The number of B cells in the tumor sample that outnumbers the individual to a PD-L1 axis binding antagonist (e.g., PD-L1 binding antagonist (e.g., anti-PD-L1 antibody, e.g., atezolizumab) or PD-1 binding antagonist (e.g., anti-PD-L1 antibody, e.g., atezolizumab). Identified as potentially benefiting from therapy, including, for example, anti-PD-1 antibodies)).

[0497] In some cases, the number of B cells in the sample exceeds the reference number, and the method includes administering to the individual an effective amount of a PD-L1 axis binding antagonist (e.g., a PD-L1 binding antagonist (e.g., anti-PD -L1 antibody (eg, atezolizumab) or PD-1 binding antagonist (eg, anti-PD-1 antibody)). Any suitable PD-L1 axis binding antagonist, such as any PD-L1 axis binding antagonist provided herein (eg, those described in Section IV below) may be administered.

[0498] The presence and / or number of any suitable type of B cells can be determined. For example, in some cases B cells include CD79+ B cells, IgG+ B cells, and / or plasma cells.

[0499] In some embodiments, the presence and / or number of clonally expanded B cells can be determined.

[0500] For example, provided herein are PD-L1 axis binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., anti-PD-1 antibodies). individuals with cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., TNBC)) that may benefit from treatment including A method of identifying, the method comprising determining whether an individual has clonally expanded B cells in a sample (e.g., a tumor sample) from the individual; B-cells expanded to 100 cells identify the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0501] In another example, provided herein are cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., , TNBC)), wherein the method determines whether the individual has clonally expanded B cells in a sample (e.g., tumor sample) from the individual. wherein the clonally expanded B cells in the sample sensitize the individual to a PD-L1 axis-binding antagonist (e.g., an anti-PD-L1 antibody, e.g., atezolizumab) or a PD-1-binding antagonist (e.g., , anti-PD-1 antibodies))).

[0502] In some cases, the sample (e.g., a tumor sample) comprises clonally expanded B cells and the method comprises administering to the individual an effective amount of a PD-L1 axis binding antagonist (e.g., an anti-PD-L1 antibody, e.g. , atezolizumab) or a PD-1 binding antagonist (eg, an anti-PD-1 antibody)).

[0503] A clonally expanded B cell can be any type of B cell. For example, in some cases the clonally expanded B cell is a clonally expanded plasma cell.

[0504] Clonally expanded B cells can be detected by any suitable technique. For example, in some cases, clonally expanded B cells are detected by measuring the diversity of the B cell receptor (BCR) gene repertoire in tumor samples. In some cases, an SDI of the BCR gene repertoire in a tumor sample from an individual below the reference Shannon Diversity Index (SDI) identifies the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist. do.

[0505] Any suitable sample can be used. In some cases, the sample is a tissue sample, cell sample, whole blood sample, plasma sample, serum sample, or a combination thereof. In some cases, the tissue sample is a tumor tissue sample. In some examples, the tumor sample is a tumor tissue sample. In some cases, the tumor tissue sample comprises tumor cells, tumor-infiltrating immune cells, stromal cells, NAT cells, or combinations thereof. In some cases, the tumor tissue sample is an FFPE sample, archival sample, fresh sample, or frozen sample. In some cases, the tumor tissue sample is an FFPE sample.

[0506] The cancer may be any suitable cancer type. In some cases, the cancer is lung cancer, kidney cancer, bladder cancer, breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, esophageal cancer, mesothelioma, melanoma, head and neck cancer. Cancer, thyroid cancer, sarcoma, prostate cancer, glioblastoma, cervical cancer, thymic carcinoma, leukemia, lymphoma, myeloma, mycosis fungoides, Merkel cell carcinoma, or hematological tumor. In some cases, the cancer is lung cancer, kidney cancer, bladder cancer, or breast cancer. In some cases, the lung cancer is NSCLC. In some cases, the NSCLC is non-squamous NSCLC. In some cases, the NSCLC is squamous NSCLC.

[0507] In some cases, the benefit includes an increase in an individual's OS, an increase in an individual's PFS, and / or an improvement in an individual's BCOR as compared to treatment without a PD-L1 axis binding antagonist. In some cases, the benefit includes prolongation of an individual's OS as compared to treatment without the PD-L1 axis binding antagonist.

[0508] E.T effector signature Any of the methods described herein can further comprise determining the presence and / or expression level of one or more T effector signature genes. Any suitable T effector signature can be used. For example, a T effector signature can include one or more (eg, 1, 2, 3, 4, 5, 6, 7, or 8) genes shown in Table 17. In some cases CD274 is additionally detected.

[0509] Table 17: Exemplary T effector signature genes TIFF2023529206000026.tif61170

[0510] For example, provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., anti-PD -1 antibody)) (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., TNBC)). )), which method comprises in a sample from the individual the presence of (i) one or more of the genes shown in Table 1 (e.g., 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) and (ii) the genes CD8A, EOMES, GZMA, TBX21, IFNG, GZMB, one or more genes shown in Table 1, comprising determining the expression level of one or more of CXCL9 and CXCL10 (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) and one or more reference immune score expression levels of CD8A, EOMES, GZMA, TBX21, IFNG, GZMB, CXCL9, and CXCL10 (i) one or more genes shown in Table 1, and (ii) Immune Score expression level of one or more of the genes CD8A, EOMES, GZMA, TBX21, IFNG, GZMB, CXCL9, and CXCL10 identifies the individual as likely to benefit from treatment comprising a PD-L1 axis binding antagonist do.

[0511] In another example, provided herein are cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., , TNBC)), the method comprising: (i) one or more of the genes shown in Table 1 (e.g., 1, TNBC) in a sample from the individual; 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) and (ii) the genes CD8A, EOMES, GZMA , TBX21, IFNG, GZMB, CXCL9, and CXCL10 (e.g., 1, 2, 3, 4, 5, 6, 7, or 8), according to Table 1. above the reference immune score expression level of one or more of the indicated genes and one or more of the genes CD8A, EOMES, GZMA, TBX21, IFNG, GZMB, CXCL9, and CXCL10, (i) 1 shown in Table 1 Immune Score expression levels of one or more genes and (ii) one or more of the genes CD8A, EOMES, GZMA, TBX21, IFNG, GZMB, CXCL9, and CXCL10 are associated with an individual being tested for a PD-L1 axis binding antagonist (e.g. , anti-PD-L1 antibodies (eg, atezolizumab) or PD-1 binding antagonists (eg, anti-PD-1 antibodies)).

[0512] In some cases, (i) one or more genes shown in Table 1 and (ii) one of the genes CD8A, EOMES, GZMA, TBX21, IFNG, GZMB, CXCL9, and CXCL10 in the sample The immune score expression level is above the reference immune score expression level, and the method further comprises administering to the individual an effective amount of a PD-L1 axis binding antagonist. Any suitable PD-L1 axis binding antagonist, such as any PD-L1 axis binding antagonist provided herein (eg, those described in Section IV below) may be administered.

[0513] In some cases, the reference immune score expression level is the expression level of (i) one or more genes shown in Table 1 and (ii) the genes CD8A, EOMES, GZMA, TBX21, IFNG, GZMB, CXCL9 in the reference population. , and the immune score expression level of one or more of CXCL10. In some cases, the reference population is a population of individuals with cancer. In some cases, the population of individuals is a first subset of individuals treated with a PD-L1 axis binding antagonist and a second subset of individuals treated with a therapy that does not include a PD-L1 axis binding antagonist. including. In some cases, the reference Immune Score expression level determines each of the first and second subsets of individuals to be responsive to treatment with a PD-L1 axis binding antagonist and to have PD above the reference expression level. - significant segregation based on a significant difference between an individual's responsiveness to treatment with a therapy that does not include an L1 axis binding antagonist, where the individual's responsiveness to treatment with a PD-L1 axis binding antagonist is significantly improved compared to an individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist. In some cases, treatments that do not include PD-L1 axis binding antagonists include anti-tumor agents, chemotherapeutic agents, anti-proliferative agents, anti-angiogenic agents, radiotherapy, cytotoxic agents, or combinations thereof. . In some cases, treatments that do not include PD-L1 axis binding antagonists include chemotherapeutic agents. In some cases, the chemotherapeutic agent is docetaxel. In some cases, responsiveness to treatment includes prolonged OS, prolonged PFS, or increased BCOR. In some cases, responsiveness to treatment includes prolongation of OS. In some cases, the reference immune score expression level is the median expression level of each of two or more genes in the reference population. In some cases, the median expression level is determined by (i) one or more of the genes shown in Table 1 and (ii) the genes CD8A, EOMES, GZMA, TBX21, IFNG, GZMB, CXCL9 in the reference population. , and median mean Z-scores of each of the expression levels of one or more of CXCL10.

[0514] In another example, provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) cancers (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer that may benefit from treatment including anti-PD-1 antibodies) (e.g., TNBC)), which method comprises in a sample from the individual: (i) the B cell signature genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, one or more of IGLL5, RBPJ, and MZB1 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11), and (ii) the T effector signature genes CD8A, EOMES, GZMA , TBX21, IFNG, GZMB, CXCL9, and CXCL10 (e.g., 1, 2, 3, 4, 5, 6, 7, or 8); (i) one or more B-cell signature genes and (ii) one or more T effector signature genes above the reference immune score expression levels of the B-cell signature genes and one or more T effector signature genes Expression levels identify individuals as likely to benefit from treatment that includes a PD-L1 axis binding antagonist.

[0515] In yet another example, provided herein is cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., For example, TNBC)) is a method of selecting a therapy for an individual with TNBC)), which method comprises determining in a sample from the individual: (i) the B-cell signature genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, one or more of TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11), and (ii) a T effector signature Determining the expression level of one or more (eg, 1, 2, 3, 4, 5, 6, 7, or 8) of the genes CD8A, EOMES, GZMA, TBX21, IFNG, GZMB, CXCL9, and CXCL10 and above the reference immune score expression level of one or more B-cell signature genes, and one or more T effector signature genes: (i) one or more B-cell signature genes; Immune Score expression levels of T effector signature genes indicate that an individual has a PD-L1 axis binding antagonist (e.g., an anti-PD-L1 antibody, e.g., atezolizumab) or a PD-1 binding antagonist (e.g., an anti-PD-1 antibody). Identify those who may benefit from treatment, including

[0516] In some cases, the immune score expression level of (i) one or more B cell signature genes and (ii) one or more T effector signature genes in the sample exceeds the reference immune score expression level, and the method comprises: further comprising administering an amount of a PD-L1 axis binding antagonist effective against. Any suitable PD-L1 axis binding antagonist, such as any PD-L1 axis binding antagonist provided herein (eg, those described in Section IV below) may be administered.

[0517] In some cases, the reference immune score expression level is the immune score expression level of (i) one or more B cell signature genes and (ii) one or more T effector signature genes in the reference population. In some cases, the reference population is a population of individuals with cancer. In some cases, the population of individuals is a first subset of individuals treated with a PD-L1 axis binding antagonist and a second subset of individuals treated with a therapy that does not include a PD-L1 axis binding antagonist. including. In some cases, the reference Immune Score expression level determines each of the first and second subsets of individuals to be responsive to treatment with a PD-L1 axis binding antagonist and to have PD above the reference expression level. - significant segregation based on a significant difference between an individual's responsiveness to treatment with a therapy that does not include an L1 axis binding antagonist, where the individual's responsiveness to treatment with a PD-L1 axis binding antagonist is significantly improved compared to an individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist. In some cases, treatments that do not include PD-L1 axis binding antagonists include anti-tumor agents, chemotherapeutic agents, anti-proliferative agents, anti-angiogenic agents, radiotherapy, cytotoxic agents, or combinations thereof. . In some cases, treatments that do not include PD-L1 axis binding antagonists include chemotherapeutic agents. In some cases, the chemotherapeutic agent is docetaxel. In some cases, responsiveness to treatment includes prolonged OS, prolonged PFS, or increased BCOR. In some cases, responsiveness to treatment includes prolongation of OS. In some cases, the reference immune score expression level is the median expression level of each of two or more genes in the reference population. In some cases, the median expression level is the mean Z-score of the expression level of each of (i) one or more B cell signature genes and (ii) one or more T effector signature genes in a reference population. is the median of

[0518] In another example, provided herein are PD-L1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) or PD-1 binding antagonists (e.g., anti-PD-L1 antibodies, e.g., atezolizumab) cancers (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer that may benefit from treatment including anti-PD-1 antibodies) (e.g., TNBC)), the method comprising: (i) the TLS signature genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9 in a sample from the individual; , one or more of CXCL10, CXCL11, and CXCL13 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 12), and (ii) the T effector signature gene CD8A, determining the expression level of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) of EOMES, GZMA, TBX21, IFNG, GZMB, CXCL9, and CXCL10; (i) one or more TLS signature genes and (ii) one or more T effector signature genes above the reference immune score expression levels of one or more B cell signature genes and one or more T effector signature genes Immune Score expression levels identify individuals as likely to benefit from treatment comprising a PD-L1 axis binding antagonist.

[0519] In yet another example, provided herein is cancer (e.g., lung cancer (e.g., NSCLC), bladder cancer (e.g., UC), renal cancer (e.g., RCC), or breast cancer (e.g., For example, a method of selecting a therapy for an individual with TNBC)), the method comprising: (i) the TLS signature genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19 in a sample from the individual; , one or more of CCL21, CXCL9, CXCL10, CXCL11, and CXCL13 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 12), and (ii) a T effector Determining the expression level of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) of the signature genes CD8A, EOMES, GZMA, TBX21, IFNG, GZMB, CXCL9, and CXCL10 (i) one or more TLS signature genes, and (ii) one or more Immune Score expression levels of T effector signature genes indicate that the individual is a PD-L1 axis binding antagonist (e.g., a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody, e.g., atezolizumab) or a PD-1 binding antagonist (e.g., Identify those who may benefit from therapy, including anti-PD-1 antibodies)).

[0520] In some cases, the immune score expression level of (i) one or more TLS signature genes and (ii) one or more T effector signature genes in the sample exceeds the reference immune score expression level, and the method comprises: further comprising administering an effective amount of a PD-L1 axis binding antagonist. Any suitable PD-L1 axis binding antagonist, such as any PD-L1 axis binding antagonist provided herein (eg, those described in Section IV below) may be administered.

[0521] In some cases, the reference immune score expression level is the immune score expression level of (i) one or more TLS signature genes and (ii) one or more T effector signature genes in a reference population. In some cases, the reference population is a population of individuals with cancer. In some cases, the population of individuals is a first subset of individuals treated with a PD-L1 axis binding antagonist and a second subset of individuals treated with a therapy that does not include a PD-L1 axis binding antagonist. including. In some cases, the reference Immune Score expression level determines each of the first and second subsets of individuals to be responsive to treatment with a PD-L1 axis binding antagonist and to have PD above the reference expression level. - significant segregation based on a significant difference between an individual's responsiveness to treatment with a therapy that does not include an L1 axis binding antagonist, where the individual's responsiveness to treatment with a PD-L1 axis binding antagonist is significantly improved compared to an individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist. In some cases, treatments that do not include PD-L1 axis binding antagonists include anti-tumor agents, chemotherapeutic agents, anti-proliferative agents, anti-angiogenic agents, radiotherapy, cytotoxic agents, or combinations thereof. . In some cases, treatments that do not include PD-L1 axis binding antagonists include chemotherapeutic agents. In some cases, the chemotherapeutic agent is docetaxel. In some cases, responsiveness to treatment includes prolonged OS, prolonged PFS, or increased BCOR. In some cases, responsiveness to treatment includes prolongation of OS. In some cases, the reference immune score expression level is the median expression level of each of two or more genes in the reference population. In some cases, the median expression level is the mean Z-score of the expression level of each of (i) one or more TLS signature genes and (ii) one or more T effector signature genes in a reference population. Median.

[0522] In some instances of any of the foregoing methods, the presence and / or expression level of CD274 is further determined.

[0523] In any of the methods described herein, the method includes CD79A, CD274, and one or more of the T effector signature genes CD8A, EOMES, GZMA, TBX21, IFNG, GZMB, CXCL9, and CXCL10 (e.g., 1, 2, 3, 4, 5, 6, 7, or 8).

[0524] F. Determination of expression levels (i) Detection method Immunoscore expression levels of genes described herein (e.g., one or more genes shown in any one of Tables 1-17) are expressed at nucleic acid expression levels, and preferably mRNA expression levels. may be based on The presence and / or expression level / amount of the genes described herein include, but are not limited to, DNA, mRNA, cDNA, proteins, protein fragments and / or gene copy numbers known in the art. can be determined qualitatively and / or quantitatively based on any suitable criteria.

[0525] In some cases, nucleic acid expression levels of genes described herein (eg, one or more genes shown in any one of Tables 1-17) are polymerase chain reaction (PCR)-based. It can be measured by assays such as quantitative PCR, real-time PCR, quantitative real-time PCR (qRT-PCR), reverse transcriptase PCR (RT-PCR), and reverse transcriptase quantitative PCR (RT-qPCR). Platforms for performing quantitative PCR assays include Fluidigm (e.g. BIOMARK TM HD System) is included. Other amplification-based methods include, for example, transcription-mediated amplification (TMA), strand displacement amplification (SDA), nucleic acid sequence-based amplification (NASBA), and signal amplification methods such as bDNA.

[0526] In some cases, nucleic acid expression levels of genes described herein (e.g., one or more genes shown in any one of Tables 1-17) can be determined by, e.g., RNA-seq, SAGE methods. (It can also be measured by sequencing-based techniques such as serial analysis of gene expression, high-throughput sequencing techniques (e.g., massively parallel sequencing), and Sequenom MassARRAY® technology. Nucleic acid expression levels (e.g., table The expression level of one or more of the genes shown in any one of 1 to 17)) can also be measured by, for example, NanoString nCounter and comprehensive gene expression analysis (HiCEP). Additional protocols for assessing the status of genes and gene products can be found, for example, in Ausubel et al., eds., 1995, Current Protocols In Molecular Biology, Part 2 (Northern blotting), Part 4 (Southern blotting). Methods), Part 15 (Immunoblotting) and Part 18 (PCR analysis).

[0527] Other methods for detecting nucleic acid levels of the genes described herein (e.g., one or more genes shown in any one of Tables 1-17) include by microarray technology, tissue or Protocols for examining or detecting mRNA, such as target mRNA, in cell samples are included. Nucleic acid microarrays are used to reverse transcribe and label test and control mRNA samples from test and control tissue samples to generate cDNA probes. The probes are then hybridized to an array of nucleic acids fixed to a solid support. Arrays are constructed such that the sequence and position of each member of the array is known. Hybridization of a labeled probe with a particular array member indicates that the sample from which the probe was derived expresses that gene.

[0528] Primers and probes may be labeled with detectable markers such as, for example, radioisotopes, fluorescent compounds, bioluminescent compounds, chemiluminescent compounds, metal chelators, or enzymes. Such probes and primers can be used to detect the presence in a sample of expressed genes, such as one or more of the genes set forth in any one of Tables 1-17. As one skilled in the art will appreciate, many different primers and probes have been prepared based on the sequences provided herein (or their flanking sequences in the case of genomic DNA) and described herein. can be used to effectively amplify, clone, and / or determine the presence and / or expression levels of the gene(s) involved.

[0529] Other methods of detecting nucleic acid expression levels of the genes described herein (eg, one or more genes shown in any one of Tables 1-17) include electrophoresis, Northern blot and Southern blot. analysis, in situ hybridization (e.g. single or multiplex nucleic acid in situ hybridization), RNAse protection assays, and microarrays (e.g. Illumina BEADARRAY TM Technologies; including bead arrays for gene expression detection (BADGE).

[0530] In some cases, the immune score expression levels of genes described herein (e.g., one or more of the genes shown in any one of Tables 1-17) can be obtained by RNA-seq, PCR, RT - qPCR, qPCR, multiplex qPCR, multiplex RT-qPCR, NANOSTRING® nCOUNTER® gene expression assay, microarray analysis, SAGE (Serial Analysis of Gene Expression), Northern blot analysis, MassARRAY, ISH, and It can be analyzed by a number of methodologies including, but not limited to, whole genome sequencing, or combinations thereof.

[0531] In further instances, the immune score expression levels of the genes described herein (e.g., one or more of the genes shown in any one of Tables 1-17) can be analyzed using RNA-seq, RT-qPCR, qPCR. , multiplex qPCR, multiplex RT-qPCR, microarray analysis, SAGE, MassARRAY technology, FACS, Western blot, ELISA, immunoprecipitation, immunohistochemistry, immunofluorescence, radioimmunoassay, dot blotting, immunodetection methods, HPLC, It can be detected in a sample using a method selected from the group consisting of surface plasmon resonance, optical spectroscopy, mass spectroscopy, HPLC, and ISH, or combinations thereof.

[0532] (ii) RT-qPCR In some cases, the nucleic acid expression level of a gene described herein (eg, one or more genes shown in any one of Tables 1-17) is determined by reverse transcription quantitative polymerase chain reaction ( can be detected using RT-qPCR). RT-qPCR technology is a form of PCR in which the nucleic acid to be amplified is RNA that is first reverse transcribed into cDNA and the amount of PCR product is measured at each step of the PCR reaction. Since RNA cannot be used as a template for PCR, the first step in gene expression profiling by PCR is the reverse transcription of the RNA template into cDNA, followed by its amplification in a PCR reaction. For example, the reverse transcriptase can include avilo myeloblastosis virus reverse transcriptase (AMY-RT) or Moloney murine leukemia virus reverse transcriptase (MMLV-RT). The reverse transcription step is typically primed using specific primers, random hexamers, or oligo-dT primers, depending on the circumstances and goals of expression profiling. For example, extracted RNA can be filtered using GENEAMP according to the manufacturer's instructions. TM Reverse transcription can be performed using an RNA PCR kit (Perkin Elmer, Calif, USA). The resulting cDNA can then be used as a template in subsequent PCR reactions.

[0533] One variation of PCR technology is quantitative real-time PCR (qRT-PCR), which measures PCR product accumulation through dual-labeled fluorescent probes (ie, TAQMAN® probes). The technique of quantitative real-time polymerase chain reaction refers to a form of PCR in which the amount of PCR product is measured at each step of the PCR reaction. This technique has been documented in various publications including Cronin et al., Am. J. Pathol. 164(l):35-42 (2004); and Ma et al., Cancer Cell 5:607-616 (2004). Are listed. Real-time PCR is a quantitative competitive PCR that uses a competitor within each target sequence for normalization, and / or a quantitative comparative PCR that uses a normalization gene included within the sample, or a housekeeping gene for the PCR. Compatible with both. For further details see, eg, Held et al., Genome Research 6:986-994 (1996).

[0534] The steps of a representative protocol for profiling gene expression using fixed paraffin-embedded tissue as a source of RNA, including mRNA isolation, purification, primer extension and amplification, are described in various published journal articles (e.g., Godfrey et al., Malec. Diagnostics 2:84-91 (2000); Specht et al., Am. J. Pathol. 158:419-29 (2001)). Briefly, a typical process begins with cutting sections (eg, 10 microgram sections) of paraffin-embedded tumor tissue samples. RNA is then extracted and protein and DNA are removed. After analysis of RNA concentration, an RNA repair and / or amplification step may optionally be included in which the RNA is reverse transcribed using a gene-specific promoter, followed by PCR.

[0535] Nucleic acid expression levels determined by amplification-based methods (eg, RT-qPCR) can be expressed as cycle threshold (Ct). From this value, normalized expression levels for each gene can be determined using, for example, the delta Ct (dCt) method as follows: Ct (control / reference gene) - Ct (gene of interest) / target gene) = dCt(gene of interest / target gene). Those skilled in the art will appreciate that the dCt values ​​obtained can be negative dCt values ​​or positive dCt values. As defined herein, higher dCt values ​​indicate higher levels of expression of the gene of interest compared to the control gene. Conversely, lower dCt values ​​indicate lower levels of expression of the gene of interest compared to the control gene. If the expression levels of multiple genes have been determined, then the expression level of each gene, expressed, for example, as a dCt value, can then be combined into a single expression representing the average or composite expression level of the multiple genes (e.g., immune score expression levels). It can be used to determine the value of one. The immune score expression level can be the mean or median dCt determined for each target gene / gene of interest. Thus, in some cases, the Immunoscore expression level described herein is the mean dCt or It can be the median value. As defined herein, a higher mean dCt or median dCt indicates a higher aggregate expression level of multiple target genes compared to a control gene (or multiple control genes). A lower mean dCt or median dCt indicates lower aggregate expression levels of multiple target genes compared to a control gene (or multiple control genes). As described herein, the immune score expression level can then be compared to a reference immune score expression level, as further defined herein.

[0536] In some embodiments, nucleic acid expression levels described herein can be described using methods comprising: (a) tumor tissue samples (e.g., paraffin-embedded formalin-fixed NSCLC, UC, RCC; (b) isolating the mRNA from the sample; (c) performing reverse transcription of the mRNA into cDNA (e.g., (d) using PCR to amplify the cDNA (e.g., for one or more genes listed in any one of Tables 1-17); and (e) quantifying nucleic acid expression levels (eg, of one or more genes shown in any one of Tables 1-17).

[0537] One or more genes (eg, one or more genes shown in any one of Tables 1-17) can be detected in a single assay, depending on the primers or probes used. Additionally, assays can be performed across one or more tubes (eg, 1, 2, 3, 4, 5 or 6 or more tubes).

[0538] In some cases, the method (f) measures the nucleic acid expression level of one or more genes (e.g., one or more genes set forth in any one of Tables 1-17) in the sample by of one or more reference genes (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or more reference genes, e.g., housekeeping genes) Further comprising normalizing to expression levels. For example, immunoscore expression levels of genes described herein (e.g., one or more genes shown in any one of Tables 1-17) were analyzed using RT-qPCR and analyzed An immune score expression level can be generated that reflects the normalized mean dCT value of the gene.

[0539] (iii) RNA-seq In some cases, nucleic acid expression levels of genes described herein (e.g., one or more genes shown in any one of Tables 1-17) are determined using RNA-seq. can be detected. RNA-seq, also called whole-transcriptome shotgun sequencing (WTSS), refers to the use of high-throughput sequencing technology to sequence and / or quantify cDNA to obtain information about the RNA content of a sample. Point. Publications describing RNA-seq include: Wang et al. “RNA-Seq: a revolutionary tool for transcriptomics” Nature Reviews Genetics 10(1):57-63 (January 2009); Ryan et al.BioTechniques 45 (1):81-94 (2008); and Maher et al. "Transcriptome sequencing to detect gene fusions in cancer" Nature 458(7234):97-101 (January 2009).

[0540] (iv) sample A sample described herein is, for example, a cancer (eg, lung cancer (eg, NSCLC), bladder cancer (eg, UC), kidney cancer (eg, RCC), or breast cancer (eg, TNBC)) from individuals suspected of having cancer or diagnosed with cancer and thus likely to be in need of treatment, or not suspected of having cancer or not having cancer can be obtained from healthy individuals with a family history of cancer. Samples, such as samples containing cells, or proteins or nucleic acids produced by those cells, for the assessment of gene expression may be used in the methods of the invention. Gene expression levels can be determined by assessing the amount (eg, absolute amount or concentration) of the marker in a sample (eg, a tissue sample, eg, a tumor tissue sample such as a biopsy). Additionally, the level of the gene can be assessed in bodily fluids or secretions containing detectable levels of the gene. Bodily fluids or secretions useful as samples in the present invention include, for example, blood, urine, saliva, stool, pleural fluid, lymph, sputum, ascites, prostatic fluid, cerebrospinal fluid (CSF), or any other body secretion. or any derivative thereof. The term blood is meant to include whole blood, plasma, serum, or any blood derivative. Evaluation of genes in such bodily fluids or secretions may be preferable in situations where invasive sampling methods are inappropriate or inconvenient. In other embodiments, tumor tissue samples are preferred.

[0541] Samples can be frozen, fresh, fixed (eg, formalin-fixed), centrifuged, and / or embedded (eg, paraffin-embedded), and the like. Cell samples may be subjected to various well-known post-collection preparation and storage techniques (e.g., nucleic acid and / or protein extraction, fixation, storage, freezing, ultrafiltration, concentration, evaporation, centrifugation, etc.). Similarly, biopsies may be subjected to post-collection preparation and storage techniques, eg, fixation such as formalin fixation.

[0542] In some embodiments the sample is a clinical sample. In another instance, the sample is used in a diagnostic assay, eg, a diagnostic assay or diagnostic method of the invention. In some cases, samples are obtained from primary or metastatic tumors. A tissue biopsy is often used to obtain a representative piece of tumor tissue. Alternatively, tumor cells can be obtained indirectly in the form of tissues or fluids known or believed to contain the tumor cells of interest. For example, lung cancer lesion samples may be obtained by resection, bronchoscopy, fine needle aspiration, bronchial scraping, or from sputum, pleural fluid, or blood. Genes or gene products can be detected from cancer or tumor tissue, or from other body samples such as urine, sputum, serum, or plasma. The same techniques described above for detection of target genes or gene products in cancerous samples can be applied to other body...

Claims

1. 1. A method for identifying an individual with non-small cell lung cancer (NSCLC) who may benefit from a therapy comprising an anti-PD-L1 antagonist antibody, the method comprising determining the expression levels of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 in a sample from the individual, wherein an Immunoscore expression level of said genes that exceeds a reference Immunoscore expression level for said genes identifies the individual as one who may benefit from a therapy comprising an anti-PD-L1 antagonist antibody, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain comprising the HVR-H1 sequence of SEQ ID NO: 1, the HVR-H2 sequence of SEQ ID NO: 2, and the HVR-H3 sequence of SEQ ID NO: 3, and a light chain comprising the HVR-L1 sequence of SEQ ID NO: 4, the HVR-L2 sequence of SEQ ID NO: 5, and the HVR-L3 sequence of SEQ ID NO:

6.

2. 1. A method of selecting a therapy for an individual with NSCLC, comprising determining the expression levels of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 in a sample from the individual, wherein an Immunoscore expression level of said genes that exceeds a reference Immunoscore expression level for said genes identifies the individual as one who may benefit from therapy comprising an anti-PD-L1 antagonist antibody, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain comprising the HVR-H1 sequence of SEQ ID NO: 1, the HVR-H2 sequence of SEQ ID NO: 2, and the HVR-H3 sequence of SEQ ID NO: 3, and a light chain comprising the HVR-L1 sequence of SEQ ID NO: 4, the HVR-L2 sequence of SEQ ID NO: 5, and the HVR-L3 sequence of SEQ ID NO:

6.

3. A medicament for treating an individual with NSCLC, comprising an effective amount of an anti-PD-L1 antagonist antibody; determining the expression levels of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 in a sample from the individual; determining that the immunoscore expression level of said gene in the sample is greater than a reference immunoscore expression level of said gene, thereby identifying the individual as one who may benefit from a treatment comprising an anti-PD-L1 antagonist antibody; A pharmaceutical agent, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain comprising the HVR-H1 sequence of SEQ ID NO: 1, the HVR-H2 sequence of SEQ ID NO: 2, and the HVR-H3 sequence of SEQ ID NO: 3, and a light chain comprising the HVR-L1 sequence of SEQ ID NO: 4, the HVR-L2 sequence of SEQ ID NO: 5, and the HVR-L3 sequence of SEQ ID NO:

6.

4. 1. A medicament for treating NSCLC in an individual wherein the immunoscore expression levels of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 in a sample from the individual have been determined to be above reference immunoscore expression levels for said genes, thereby identifying the individual as one who would benefit from therapy comprising an anti-PD-L1 antagonist antibody, the medicament comprising an effective amount of an anti-PD-L1 antagonist antibody, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain comprising the HVR-H1 sequence of SEQ ID NO: 1, the HVR-H2 sequence of SEQ ID NO: 2, and the HVR-H3 sequence of SEQ ID NO: 3, and a light chain comprising the HVR-L1 sequence of SEQ ID NO: 4, the HVR-L2 sequence of SEQ ID NO: 5, and the HVR-L3 sequence of SEQ ID NO:

6.

5. The method of claim 1 or 2, wherein the immunoscore expression level of the gene in the sample is greater than a reference immunoscore expression level.

6. The method of any one of claims 1, 2 and 5, wherein the reference immune score expression level is the immune score expression level of the gene in a reference population.

7. 7. The method of claim 6, wherein the reference population is a population of individuals with NSCLC.

8. 8. The method of claim 7, wherein the population of individuals comprises a first subset of individuals treated with a PD-L1 axis binding antagonist and a second subset of individuals treated with a therapy that does not include a PD-L1 axis binding antagonist.

9. 9. The method of claim 8, wherein the reference immunoscore expression level significantly separates each of the first and second subsets of individuals based on a significant difference between the individual's responsiveness to treatment with the PD-L1 axis binding antagonist and the individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist that is greater than the reference immunoscore expression level, and wherein the individual's responsiveness to treatment with the PD-L1 axis binding antagonist is significantly improved compared to the individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist.

10. 10. The method of claim 8 or 9, wherein the PD-L1 axis-binding antagonist-free therapy comprises an anti-tumor agent, a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, radiation therapy, a cytotoxic agent, or a combination thereof.

11. 11. The method of claim 10, wherein the PD-L1 axis binding antagonist-free therapy comprises a chemotherapeutic agent.

12. 12. The method of claim 11, wherein the chemotherapeutic agent is docetaxel.

13. 13. The method of any one of claims 9 to 12, wherein responsiveness to treatment comprises an increase in OS, an increase in progression-free survival (PFS), or an increase in best confirmed overall response (BCOR).

14. 14. The method of claim 13, wherein responsiveness to treatment comprises prolongation of OS.

15. The method of any one of claims 6 to 14, wherein the reference immunoscore expression level is the median expression level of each of said genes in a reference population.

16. 16. The method of any one of claims 1, 2, and 5-15, wherein the benefit comprises an extension of the individual's OS compared to treatment without the anti-PD-L1 antagonist antibody.

17. A pharmaceutical described in claim 3 or 4, wherein the reference immune score expression level is the immune score expression level of the gene in a reference population.

18. The pharmaceutical described in claim 17, wherein the reference population is a population of individuals with NSCLC.

19. The pharmaceutical composition of claim 18, wherein the population of individuals comprises a first subset of individuals treated with a PD-L1 axis binding antagonist and a second subset of individuals treated with a therapy that does not include a PD-L1 axis binding antagonist.

20. The pharmaceutical composition of claim 19, wherein the reference immunoscore expression level significantly separates each of the first and second subsets of individuals based on a significant difference between the individual's responsiveness to treatment with a PD-L1 axis binding antagonist and the individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist that exceeds the reference immunoscore expression level, and wherein the individual's responsiveness to treatment with the PD-L1 axis binding antagonist is significantly improved compared to the individual's responsiveness to treatment with a therapy that does not include a PD-L1 axis binding antagonist.

21. The pharmaceutical described in claim 19 or 20, wherein the treatment that does not include a PD-L1 axis binding antagonist comprises an antitumor agent, a chemotherapeutic agent, a growth inhibitor, an antiangiogenic agent, radiation therapy, a cytotoxic agent, or a combination thereof.

22. The pharmaceutical described in claim 21, wherein the treatment method not including a PD-L1 axis binding antagonist includes a chemotherapeutic agent.

23. The pharmaceutical described in claim 22, wherein the chemotherapeutic agent is docetaxel.

24. The pharmaceutical agent according to any one of claims 20 to 23, wherein responsiveness to treatment includes an extension of OS, an extension of progression-free survival (PFS), or an increase in best confirmed overall response (BCOR).

25. The pharmaceutical described in claim 24, wherein responsiveness to treatment includes prolongation of OS.

26. A pharmaceutical described in any one of claims 17 to 25, wherein the reference immune score expression level is the median of the expression levels of each of the genes in the reference population.

27. The method of any one of claims 1, 2, and 5 to 16, wherein the gene expression level is a nucleic acid expression level.

28. 28. The method of claim 27, wherein the nucleic acid expression level is an mRNA expression level.

29. The method of any one of claims 1, 2, and 5 to 16, wherein the gene expression level is a protein expression level.

30. 30. The method of any one of claims 1, 2, 5-16 and 27-29, wherein the expression level of the gene is detected in tumor cells, tumor-infiltrating immune cells, stromal cells, normal adjacent tissue (NAT) cells, or a combination thereof.

31. A pharmaceutical described in any one of claims 3, 4, and 17 to 26, wherein the gene expression level is a nucleic acid expression level.

32. The pharmaceutical described in claim 31, wherein the nucleic acid expression level is an mRNA expression level.

33. A pharmaceutical described in any one of claims 3, 4, and 17 to 26, wherein the gene expression level is a protein expression level.

34. A pharmaceutical described in any one of claims 3, 4, 17 to 26 and 31 to 33, wherein the expression level of the gene is detected in tumor cells, tumor-infiltrating immune cells, stromal cells, normal adjacent tissue (NAT) cells, or a combination thereof.

35. 31. The method of any one of claims 1, 2, 5-16 and 27-30, wherein the sample is a tissue sample, a cell sample, a whole blood sample, a plasma sample, a serum sample, or a combination thereof.

36. 36. The method of claim 35, wherein the tissue sample is a tumor tissue sample.

37. 37. The method of claim 36, wherein the tumor tissue sample comprises tumor cells, tumor-infiltrating immune cells, stromal cells, NAT cells, or a combination thereof.

38. 38. The method of claim 36 or 37, wherein the tumor tissue sample is a formalin-fixed, paraffin-embedded (FFPE) sample, an archived sample, a fresh sample, or a frozen sample.

39. 39. The method of any one of claims 1, 2, 5-16, 27-30, and 35-38, wherein the NSCLC is non-squamous NSCLC.

40. 39. The method of any one of claims 1, 2, 5-16, 27-30, and 35-38, wherein the NSCLC is squamous NSCLC.

41. The method of any one of claims 1, 2, 5-16, 27-30, and 35-40, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

8.

42. 42. The method of claim 41, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:

10.

43. 43. The method of claim 42, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

44. 44. The method of any one of claims 1, 2, 5-16, 27-30, and 35-43, wherein the individual has not previously received treatment for NSCLC.

45. 45. The method of claim 44, wherein the individual has not previously been administered a PD-L1 axis binding antagonist.

46. 46. ​​The method of claim 44 or 45, wherein the individual does not have an EGFR or ALK genomic tumor abnormality.

47. 44. The method of any one of claims 1, 2, 5-16, 27-30, and 35-43, wherein the individual has previously received treatment for NSCLC.

48. 48. The method of claim 47, wherein the individual has previously been treated for NSCLC by administering to the individual a platinum-containing chemotherapy agent, and the individual did not respond to the chemotherapy agent.

49. A pharmaceutical described in any one of claims 3, 4, 17 to 26 and 31 to 34, wherein the sample is a tissue sample, a cell sample, a whole blood sample, a plasma sample, a serum sample, or a combination thereof.

50. The pharmaceutical described in claim 49, wherein the tissue sample is a tumor tissue sample.

51. The pharmaceutical described in claim 50, wherein the tumor tissue sample comprises tumor cells, tumor-infiltrating immune cells, stromal cells, NAT cells, or a combination thereof.

52. The pharmaceutical described in claim 50 or 51, wherein the tumor tissue sample is a formalin-fixed paraffin-embedded (FFPE) sample, an archived sample, a fresh sample, or a frozen sample.

53. A pharmaceutical described in any one of claims 3, 4, 17 to 26, 31 to 34, and 49 to 52, wherein the NSCLC is non-squamous NSCLC.

54. A pharmaceutical described in any one of claims 3, 4, 17 to 26, 31 to 34, and 49 to 52, wherein the NSCLC is squamous NSCLC.

55. A pharmaceutical described in any one of claims 3, 4, 17 to 26, 31 to 34, and 49 to 54, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

8.

56. The pharmaceutical described in claim 55, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO:

10.

57. The pharmaceutical described in claim 56, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

58. A pharmaceutical described in any one of claims 3, 4, 17-26, 31-34, and 49-57, wherein the individual has not previously received treatment for NSCLC.

59. The pharmaceutical composition of claim 58, wherein the individual has not previously been administered a PD-L1 axis binding antagonist.

60. The pharmaceutical described in claim 58 or 59, wherein the individual does not have an EGFR or ALK genomic tumor abnormality.

61. A pharmaceutical described in any one of claims 3, 4, 17-26, 31-34, and 49-57, wherein the individual has previously received treatment for NSCLC.

62. The pharmaceutical described in claim 61, wherein the individual has previously been treated for NSCLC by administering to the individual a platinum-containing chemotherapy agent, and the individual did not respond to the chemotherapy agent.

63. The pharmaceutical agent according to any one of claims 3, 4, 17 to 26, 31 to 34, and 49 to 62, wherein the anti-PD-L1 antagonist antibody is administered as a monotherapy.

64. The pharmaceutical composition of any one of claims 3, 4, 17 to 26, 31 to 34, and 49 to 63, further comprising an effective amount of one or more additional therapeutic agents.

65. 65. The pharmaceutical of claim 64, wherein the one or more additional therapeutic agents comprise an anti-tumor agent, a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, radiation therapy, a cytotoxic agent, an immunomodulatory agent, or a combination thereof.

66. 10. The method of any one of claims 1, 2, 5-16, 27-30, and 35-48, wherein the individual is a human.

67. A pharmaceutical described in any one of claims 3, 4, 17 to 26, 31 to 34, and 49 to 65, wherein the individual is a human.

68. 1. A kit for identifying an individual with NSCLC who may benefit from a therapy comprising an anti-PD-L1 antagonist antibody, the kit comprising reagents for determining expression levels of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 in a sample from the individual, wherein an Immunoscore expression level of said genes that exceeds a reference Immunoscore expression level for said genes identifies the individual as one who may benefit from a therapy comprising an anti-PD-L1 antagonist antibody, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain comprising the HVR-H1 sequence of SEQ ID NO: 1, the HVR-H2 sequence of SEQ ID NO: 2, and the HVR-H3 sequence of SEQ ID NO: 3, and a light chain comprising the HVR-L1 sequence of SEQ ID NO: 4, the HVR-L2 sequence of SEQ ID NO: 5, and the HVR-L3 sequence of SEQ ID NO:

6.

69. A kit for selecting a therapy for an individual with NSCLC, comprising reagents for determining the expression levels of the genes CD79A, CD19, BANK1, JCHAIN, SLAMF7, BTK, TNFRSF17, IGJ, IGLL5, RBPJ, and MZB1 in a sample from the individual, wherein an immunoscore expression level of said genes that exceeds a reference immunoscore expression level for said genes identifies the individual as one that may benefit from a therapy comprising an anti-PD-L1 antagonist antibody, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain comprising the HVR-H1 sequence of SEQ ID NO:1, the HVR-H2 sequence of SEQ ID NO:2, and the HVR-H3 sequence of SEQ ID NO:3, and a light chain comprising the HVR-L1 sequence of SEQ ID NO:4, the HVR-L2 sequence of SEQ ID NO:5, and the HVR-L3 sequence of SEQ ID NO:

6.

70. The kit of claim 68 or 69, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

8.

71. 71. The kit of claim 70, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:

10.

72. The kit of claim 71, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

Images