Prognostic diagnosis and treatment methods for non-small cell lung cancer

Abstract

The present invention relates to CD8 + This invention relates to a prognostic and therapeutic method for the treatment of non-small cell lung cancer (NSCLC) using the expression levels of T cell-related genes. In particular, the invention provides a method for patient selection and treatment.

Description

[Technical Field]

[0001] Sequence List This application includes a sequence listing submitted electronically in XML format, which is incorporated herein by reference in its entirety. The XML copy, created on 14 February 2024, is named 50474-320WO2_Sequence_Listing_2_14_24 and has a size of 6,606 bytes.

[0002] This invention relates to cd8 + This invention relates to a prognostic and therapeutic method for the treatment of non-small cell lung cancer (NSCLC) using the expression levels of T cell-related genes. In particular, the invention provides a method for patient selection and treatment. [Background technology]

[0003] Non-small cell lung cancer (NSCLC) is the major subtype of lung cancer, accounting for approximately 80%–85% of all cases. For advanced disease, the overall 5-year survival rate is 2%–4%. Despite improvements in first-line treatments for patients with advanced NSCLC, which have resulted in longer survival times and reduced disease-related symptoms, almost all patients experience disease progression.

[0004] Programmed cell death-1 / programmed cell death ligand-1 (PD-1 / PD-L1) blockade is effective across a wide range of malignancies. However, not all patients benefit, and a significant proportion of initial responders eventually relapse. One approach to extend and broaden the impact of cancer immunotherapy has been to target additional immune checkpoints. One such co-inhibitory checkpoint is TIGIT (T cell immune receptor with Ig and immune receptor tyrosine-based inhibitory motif (ITIM) domains).

[0005] Therefore, there is an unmet need in this field for robust prognostic diagnostic methods to identify patients who are likely to benefit from treatments including atezolizumab and / or tilagolumab, for more effective management of the disease. [Overview of the project]

[0006] In one embodiment, the present invention provides a method for identifying individuals with non-small cell lung cancer (NSCLC) who may benefit from treatment comprising atezolizumab and tilagorumab, comprising detecting the expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in a sample from the individual, wherein the expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 that is equal to or greater than the reference expression level of ccl5, cxcr3, ccr7, or cxcr6 identifies the individual as one who may benefit from treatment comprising atezolizumab and tilagorumab.

[0007] In another aspect, the present invention provides a method for selecting a treatment for an individual having NSCLC, comprising detecting the expression level of one or more of ccl5, cxcr3, ccr7, and cxcr6 in a sample from the individual, wherein the expression level of one or more of ccl5, cxcr3, ccr7, and cxcr6 being equal to or greater than the reference expression level of ccl5, cxcr3, ccr7, or cxcr6 identifies the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

[0008] In some embodiments, the individual has an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in the sample, which is equal to or greater than the reference expression level of CCL5, CXCR3, CCR7, or CXCR6, and the method further comprises administering an effective amount of atezolizumab and tilagolumab to the individual.

[0009] In another aspect, the present invention provides a method for treating an individual having NSCLC, comprising: (a) detecting the expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in a sample from the individual, wherein the expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 is equal to or greater than the reference expression level of CCL5, CXCR3, CCR7, or CXCR6, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab; and (b) administering an effective dose of atezolizumab and tilagorumab to the individual.

[0010] In another aspect, the present invention provides a method for treating an individual having NSCLC, comprising administering atezolizumab and tilagorumab to the individual, wherein it is determined that the individual has an expression level of one or more of CCL5, CXCR3, CCR7, or CXCR6 that is equal to or greater than the reference expression level of CCL5, CXCR3, CCR7, or CXCR6, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

[0011] In some embodiments, the benefit is a clinical response. In some embodiments, a clinical response is a complete response (CR) or a partial response (PR).

[0012] In some embodiments, individuals have an expression level of one or more of CCL5, CXCR3, and CCR7 in a sample that is above the reference expression level of CCL5, CXCR3, or CCR7, and the benefit is an increased overall survival (OS) hazard ratio (HR).

[0013] In some embodiments, individuals have an expression level of one or more of CCL5, CXCR3, and CXCR6 in a sample that is above the reference expression level of CCL5, CXCR3, or CXCR6, and the benefit is an increase in overall survival (OS).

[0014] In some embodiments, the reference expression level of CCL5, CXCR3, or CXCR6 is a pre-assigned expression level.

[0015] In some embodiments, the reference expression level of CCL5, CXCR3, or CXCR6 is the expression level in the reference population. In some embodiments, the expression level in the reference population is the median expression level of CCL5, CXCR3, or CXCR6 in the reference population. In some embodiments, the reference population is a population of individuals with NSCLC.

[0016] In another aspect, the present invention provides a method for identifying individuals with NSCLC who may benefit from treatment comprising atezolizumab and tilagorumab, comprising detecting the expression levels of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score equal to or greater than a reference gene signature score identifies the individual as one who may benefit from treatment comprising atezolizumab and tilagorumab.

[0017] In another aspect, the present invention provides a method for selecting a treatment for an individual having NSCLC, comprising detecting the expression levels of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score greater than or equal to a reference gene signature score identifies the individual as one that may benefit from treatment comprising atezolizumab and tilagolumab.

[0018] In some embodiments, the individual has a gene signature score in the sample that is equal to or greater than the reference gene signature score, and the method further comprises administering an effective amount of atezolizumab and tilagolumab to the individual.

[0019] In another aspect, the present invention provides a method for treating an individual having NSCLC, comprising: (a) determining a gene signature score therefrom, which is obtained by detecting the expression levels of CCL5, CXCR3, and CXCR6 in a sample from the individual, and determining a gene signature score such that the gene signature score is equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab; and (b) administering an effective dose of atezolizumab and tilagorumab to the individual.

[0020] In another aspect, the present invention provides a method for treating an individual having NSCLC, comprising administering atezolizumab and tilagorumab to the individual, wherein the individual has been determined to have a gene signature score equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab, and the gene signature score is based on the respective expression levels of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.

[0021] In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, and CXCR6 in a sample from an individual.

[0022] In some embodiments, the method includes further detection of the expression level of CCR7 in a sample from an individual. In some embodiments, the gene signature score is the average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in a sample from an individual.

[0023] In some embodiments, the expression level of CCR7 is detected in samples from individuals. In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, CXCR6, and CCR7 in samples from individuals.

[0024] In some embodiments, the benefit is a clinical response. In some embodiments, a clinical response is a complete response (CR) or partial response (PR).

[0025] In some aspects, the benefit is an increase in OS HR.

[0026] In some aspects, the benefit is an increase in the operating system.

[0027] In some embodiments, the reference gene signature score is a pre-assigned gene signature score.

[0028] In some embodiments, the reference gene signature score is the gene signature score in the reference population. In some embodiments, the gene signature score in the reference population is the median of the gene signature scores based on the respective expression levels of CCL5, CXCR3, and CXCR6 in the reference population. In some embodiments, the reference population is the population of individuals with NSCLC.

[0029] In another embodiment, the present invention relates to a method for identifying individuals having NSCLC who may benefit from treatment comprising atezolizumab and tilagormab, (a) Detect the expression levels of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X in samples from individuals, and determine the Ccr7.2 gene signature score from these levels; (b) Detect the expression levels of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB in ​​samples from individuals, and determine the Ccr7.3 gene signature score from these levels; (c) Detect the expression levels of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7 in samples from individuals, and determine the Cxcr3 gene signature score from these levels; (d) Detect the expression levels of each of the following genes in samples from individuals: CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3, and determine the Ccl5.1 gene signature score from these levels; (e) Detect the expression levels of ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1 in samples from individuals, and determine the Ifit gene signature score from these levels; (f) Detect the expression levels of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL in samples from individuals, and determine the Mitotic gene signature score from these levels; (g) Detect the expression levels of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT in a sample from an individual, and determine the Cytotox.2 gene signature score from there; or (h) detecting the expression levels of S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2 in samples from individuals, and determining the Cytotox.4 gene signature score therefrom; (i) A Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, or Mitotic gene signature score equal to or greater than the reference gene signature score identifies the individual as one who may benefit from treatment including atezolizumab and tilagolumab. (ii) A Cytotox.2 or Cytotox.4 gene signature score lower than the reference gene signature score provides a method for identifying an individual as potentially beneficial to treatment including atezolizumab and tilagorumab.

[0030] In another aspect, the present invention relates to a method for selecting a treatment for an individual having NSCLC, (a) Detect the expression levels of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X in samples from individuals, and determine the Ccr7.2 gene signature score from these levels; (b) Detect the expression levels of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB in ​​samples from individuals, and determine the Ccr7.3 gene signature score from these levels; (c) Detect the expression levels of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7 in samples from individuals, and determine the Cxcr3 gene signature score from these levels; (d) Detect the expression levels of each of the following genes in samples from individuals: CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3, and determine the Ccl5.1 gene signature score from these levels; (e) Detect the expression levels of ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1 in samples from individuals, and determine the Ifit gene signature score from these levels; (f) Detect the expression levels of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL in samples from individuals, and determine the Mitotic gene signature score from these levels; (g) Detect the expression levels of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT in a sample from an individual, and determine the Cytotox.2 gene signature score from there; or (h) detecting the expression levels of S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2 in samples from individuals, and determining the Cytotox.4 gene signature score therefrom; (i) A Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, or Mitotic gene signature score equal to or greater than the reference gene signature score identifies the individual as one who may benefit from treatment including atezolizumab and tilagolumab. (ii) A Cytotox.2 or Cytotox.4 gene signature score lower than the reference gene signature score provides a method for identifying an individual as potentially beneficial to treatment including atezolizumab and tilagorumab.

[0031] In some embodiments, an individual has (i) a Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, or Mitotic gene signature score in a sample that is equal to or greater than the reference gene signature score, or (ii) a Cytotox.2 or Cytotox.4 gene signature score that is lower than the reference gene signature score, and the method further comprises administering an effective dose of atezolizumab and tilagolumab to the individual.

[0032] In another aspect, the present invention relates to a method for treating an individual having NSCLC, (i)(a)Detecting the expression levels of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X in a sample from an individual, and determining a Ccr7.2 gene signature score therefrom, wherein the gene signature score is greater than or equal to the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab; (b) Determining the expression levels of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB in ​​samples from an individual, and thereby determining a Ccr7.3 gene signature score, wherein the gene signature score is greater than or equal to the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab; (c) Determining a gene signature score from which the expression levels of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7 are detected in a sample from an individual, and thereby determining a Cxcr3 gene signature score such that the gene signature score is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab; (d) Determining the expression levels of CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3 in samples from individuals, and thereby determining a Ccl5.1 gene signature score, wherein the gene signature score is greater than or equal to the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab; (e) Determining the gene signature score from which to detect the expression levels of ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1 in a sample from an individual, and to determine an Ifit gene signature score from which to which the gene signature score is greater than or equal to the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab; (f) Determining a Mitotic gene signature score from which the expression levels of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL are detected in a sample from an individual, and a Mitotic gene signature score is determined therefrom, wherein the gene signature score is greater than or equal to the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab; (g) Determining a Cytotox.2 gene signature score from which the expression levels of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT are detected in a sample from an individual, and thereby determining a Cytotox.2 gene signature score such that the gene signature score is lower than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab; or (h) Determining the expression levels of S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2 in a sample from an individual, and thereby determining a Cytotox.4 gene signature score, wherein the gene signature score is lower than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab; and (ii) A method comprising administering an effective amount of atezolizumab and tilagolumab to an individual.

[0033] In another embodiment, the present invention relates to a method for treating an individual having NSCLC, comprising administering atezolizumab and tilagolumab to the individual, wherein the individual is determined to have the following: (a) Ccr7.2 gene signature scores based on the expression levels of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X in samples from individuals with a reference Ccr7.2 gene signature score or higher; (b) Ccr7.3 gene signatures based on the expression levels of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB in ​​samples from individuals with a reference Ccr7.3 gene signature score or higher; (c) Cxcr3 gene signature score based on the expression levels of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7 in samples from individuals whose Cxcr3 gene signature score is equal to or greater than the reference Cxcr3 gene signature score; (d) Ccl5.1 gene signature score based on the expression levels of each of the following genes in samples from individuals whose reference Ccl5.1 gene signature score is equal to or greater than that of the reference Ccl5.1 gene signature score: Ccl5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3; (e) Ifit gene signature scores based on the expression levels of ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1 in samples from individuals whose Ifit gene signature score is equal to or greater than the reference Ifit gene signature score; (f) Mitotic gene signature scores based on the expression levels of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL in samples from individuals whose reference Mitotic gene signature score is equal to or greater than that of the reference Mitotic gene signature score; (g) Cytotox.2 gene signature score based on the expression levels of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT in samples from individuals with lower Cytotox.2 gene signature scores than the reference Cytotox.2 gene signature score; or (h) Cytotox.4 gene signature score based on the expression levels of S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2 in samples from individuals with lower Cytotox.4 gene signature scores than the reference Cytotox.4 gene signature score; This provides a method for identifying individuals who may benefit from treatment including atezolizumab and tilagormab.

[0034] In some embodiments, the gene signature score is the average expression level of members of the gene signature in a sample from an individual.

[0035] In some embodiments, the individual has a Ccr7.3, Cxcr3, or Ccl5.1 gene signature score in the sample that is equal to or greater than the reference gene signature score, and the benefit is a clinical response. In some embodiments, the clinical response is a complete response (CR) or partial response (PR).

[0036] In some embodiments, individuals have (i) a Ccr7.2, Cxcr3, Ifit, or Mitotic gene signature score in the sample that is equal to or greater than the reference gene signature score, or (ii) a Cytotox.2 or Cytotox.4 gene signature score that is lower than the reference gene signature score, and the benefit is an increase in OS HR.

[0037] In some embodiments, individuals have a Ccr7.2, Ccr7.3, or Cxcr3 gene signature score in the sample that is equal to or greater than the reference gene signature score, and the benefit is an increase in OS.

[0038] In some embodiments, the reference gene signature score is a pre-assigned gene signature score.

[0039] In some embodiments, the reference gene signature score is the gene signature score in the reference population. In some embodiments, the gene signature score in the reference population is the median of the Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox.2, or Cytotox.4 gene signature scores in the reference population. In some embodiments, the reference population is the population of individuals with NSCLC.

[0040] In another aspect, the present invention provides a method for identifying individuals with NSCLC who may benefit from treatment including atezolizumab, comprising detecting the expression levels of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score equal to or greater than a reference gene signature score identifies the individual as one who may benefit from treatment including atezolizumab.

[0041] In another aspect, the present invention provides a method for selecting a treatment for an individual having NSCLC, comprising detecting the expression levels of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score equal to or greater than a reference gene signature score identifies the individual as one that may benefit from treatment including atezolizumab.

[0042] In some embodiments, the individual has a gene signature score in the sample that is equal to or greater than the reference gene signature score, and the method further comprises administering an effective amount of atezolizumab to the individual.

[0043] In another aspect, the present invention provides a method for treating an individual having NSCLC, comprising: (a) determining a gene signature score therefrom, which is obtained by detecting the expression levels of CCL5, CXCR3, and CXCR6 in a sample from the individual, and determining a gene signature score therefrom such that the gene signature score is greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab; and (b) administering an effective dose of atezolizumab to the individual.

[0044] In another aspect, the present invention provides a method for treating an individual having NSCLC, comprising administering atezolizumab to the individual, wherein the individual has been determined to have a gene signature score equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab, and the gene signature score is based on the respective expression levels of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.

[0045] In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, and CXCR6 in a sample from an individual.

[0046] In some embodiments, the method includes further detection of the expression level of CCR7 in a sample from an individual. In some embodiments, the gene signature score is the average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in a sample from an individual.

[0047] In some embodiments, the expression level of CCR7 is detected in samples from individuals. In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, CXCR6, and CCR7 in samples from individuals.

[0048] In some aspects, the benefit is an increase in progression-free survival (PFS) or overall survival (OS).

[0049] In some embodiments, the reference gene signature score is a pre-assigned gene signature score.

[0050] In some embodiments, the reference gene signature score is the gene signature score in the reference population. In some embodiments, the gene signature score in the reference population is the median of the gene signature scores based on the respective expression levels of CCL5, CXCR3, and CXCR6 in the reference population. In some embodiments, the reference population is the population of individuals with NSCLC.

[0051] In some aspects, treatment involving atezolizumab is atezolizumab monotherapy.

[0052] In another aspect, the present invention provides a use of atezolizumab and / or tilagorumab in the manufacture of a pharmaceutical for treating an individual having NSCLC, wherein the individual is determined to have an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in a sample from the individual which is equal to or greater than the reference expression level of CCL5, CXCR3, CCR7, or CXCR6, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

[0053] In some embodiments, the benefit is a clinical response. In some embodiments, a clinical response is a complete response (CR) or a partial response (PR).

[0054] In some embodiments, individuals have been determined to have an expression level of one or more of CCL5, CXCR3, and CCR7 in the sample that is above the reference expression level of CCL5, CXCR3, or CCR7, and the benefit is an increased overall survival (OS) hazard ratio (HR).

[0055] In some embodiments, individuals have been determined to have an expression level of one or more of CCL5, CXCR3, and CXCR6 in a sample that is above the reference expression level of CCL5, CXCR3, or CXCR6, and the benefit is an increase in overall survival (OS).

[0056] In some embodiments, the reference expression level of CCL5, CXCR3, or CXCR6 is a pre-assigned expression level.

[0057] In some embodiments, the reference expression level of CCL5, CXCR3, or CXCR6 is the expression level in the reference population. In some embodiments, the expression level in the reference population is the median expression level of CCL5, CXCR3, or CXCR6 in the reference population. In some embodiments, the reference population is a population of individuals with NSCLC.

[0058] In another aspect, the present invention provides the use of atezolizumab and / or tilagorumab in the manufacture of a pharmaceutical for treating an individual having NSCLC, wherein the individual has been determined to have a gene signature score greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab, the gene signature score being based on the respective expression levels of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.

[0059] In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, and CXCR6 in a sample from an individual.

[0060] In some embodiments, the expression level of CCR7 is detected in samples from individuals. In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, CXCR6, and CCR7 in samples from individuals.

[0061] In some embodiments, the benefit is a clinical response. In some embodiments, a clinical response is a complete response (CR) or partial response (PR).

[0062] In some aspects, the benefit is an increase in OS HR.

[0063] In some aspects, the benefit is an increase in the operating system.

[0064] In some embodiments, the reference gene signature score is a pre-assigned gene signature score.

[0065] In some embodiments, the reference gene signature score is the gene signature score in the reference population. In some embodiments, the gene signature score in the reference population is the median of the gene signature scores based on the respective expression levels of CCL5, CXCR3, and CXCR6 in the reference population. In some embodiments, the reference population is the population of individuals with NSCLC.

[0066] In another aspect, the present invention relates to the use of atezolizumab and / or tilagolumab in the manufacture of a pharmacopoeci for treating an individual having NSCLC, wherein the individual is: (i) (a) A Ccr7.2 gene signature score that is equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of each of the following detected in a sample from the individual: STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X; (b) A Ccr7.3 gene signature score greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB detected in a sample from the individual; (c) A Cxcr3 gene signature score greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7 detected in a sample from the individual; (d) A Ccl5.1 gene signature score that is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of each of the following genes detected in a sample from the individual: CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3; (e) an Ifit gene signature score that is equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1 detected in a sample from the individual; (f) A Mitotic gene signature score that is equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL detected in a sample from the individual; (g) A Cytotox.2 gene signature score lower than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT detected in a sample from the individual; or (h) Provide a Cytotox.4 gene signature score lower than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is determined to have a gene signature score based on the expression levels of S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2 detected in a sample from the individual.

[0067] In some embodiments, the gene signature score is the average expression level of members of the gene signature in a sample from an individual.

[0068] In some embodiments, individuals are determined to have a Ccr7.3, Cxcr3, or Ccl5.1 gene signature score in the sample that is equal to or greater than the reference gene signature score, and the benefit is a clinical response. In some embodiments, the clinical response is a complete response (CR) or partial response (PR).

[0069] In some embodiments, individuals have been determined to have (i) a Ccr7.2, Cxcr3, Ifit, or Mitotic gene signature score in the sample that is equal to or greater than the reference gene signature score, or (ii) a Cytotox.2 or Cytotox.4 gene signature score that is lower than the reference gene signature score, with the benefit being an increase in OS HR.

[0070] In some embodiments, individuals have been determined to have a Ccr7.2, Ccr7.3, or Cxcr3 gene signature score in the sample that is equal to or greater than the reference gene signature score, and the benefit is an increase in overall survival (OS).

[0071] In some embodiments, the reference gene signature score is a pre-assigned gene signature score.

[0072] In some embodiments, the reference gene signature score is the gene signature score in the reference population. In some embodiments, the gene signature score in the reference population is the median of the Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox.2, or Cytotox.4 gene signature scores in the reference population. In some embodiments, the reference population is the population of individuals with NSCLC.

[0073] In another aspect, the present invention provides the use of atezolizumab in the manufacture of a pharmaceutical for treating an individual having NSCLC, wherein the individual has been determined to have a gene signature score greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab, and the gene signature score is based on the respective expression levels of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.

[0074] In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, and CXCR6 in a sample from an individual.

[0075] In some embodiments, the expression level of CCR7 is detected in samples from individuals. In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, CXCR6, and CCR7 in samples from individuals.

[0076] In some aspects, the benefit is an increase in progression-free survival (PFS) or overall survival (OS).

[0077] In some embodiments, the reference gene signature score is a pre-assigned gene signature score.

[0078] In some embodiments, the reference gene signature score is the gene signature score in the reference population. In some embodiments, the gene signature score in the reference population is the median of the gene signature scores based on the respective expression levels of CCL5, CXCR3, and CXCR6 in the reference population. In some embodiments, the reference population is the population of individuals with NSCLC.

[0079] In some aspects, treatment involving atezolizumab is atezolizumab monotherapy.

[0080] In another embodiment, the present invention provides atezolizumab and / or tilagorumab for use in treating individuals having NSCLC, wherein the individual has been determined to have an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in a sample from the individual which is equal to or greater than a reference expression level of CCL5, CXCR3, CCR7, or CXCR6, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

[0081] In some embodiments, the benefit is a clinical response. In some embodiments, a clinical response is a complete response (CR) or a partial response (PR).

[0082] In some embodiments, individuals have been determined to have an expression level of one or more of CCL5, CXCR3, and CCR7 in the sample that is above the reference expression level of CCL5, CXCR3, or CCR7, and the benefit is an increased overall survival (OS) hazard ratio (HR).

[0083] In some embodiments, individuals have been determined to have an expression level of one or more of CCL5, CXCR3, and CXCR6 in a sample that is above the reference expression level of CCL5, CXCR3, or CXCR6, and the benefit is an increase in overall survival (OS).

[0084] In some embodiments, the reference expression level of CCL5, CXCR3, or CXCR6 is a pre-assigned expression level.

[0085] In some embodiments, the reference expression level of CCL5, CXCR3, or CXCR6 is the expression level in the reference population. In some embodiments, the expression level in the reference population is the median expression level of CCL5, CXCR3, or CXCR6 in the reference population. In some embodiments, the reference population is a population of individuals with NSCLC.

[0086] In another embodiment, the present invention provides atezolizumab and / or tilagorumab for use in treating individuals having NSCLC, wherein the individual has been determined to have a gene signature score greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab, the gene signature score being based on the respective expression levels of CCL5, CXCR3, and CXCR6 detected in a sample from the individual, and provides atezolizumab and / or tilagorumab.

[0087] In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, and CXCR6 in a sample from an individual.

[0088] In some embodiments, the expression level of CCR7 is detected in samples from individuals. In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, CXCR6, and CCR7 in samples from individuals.

[0089] In some embodiments, the benefit is a clinical response. In some embodiments, a clinical response is a complete response (CR) or partial response (PR).

[0090] In some aspects, the benefit is an increase in OS HR.

[0091] In some aspects, the benefit is an increase in the operating system.

[0092] In some embodiments, the reference gene signature score is a pre-assigned gene signature score.

[0093] In some embodiments, the reference gene signature score is the gene signature score in the reference population. In some embodiments, the gene signature score in the reference population is the median of the gene signature scores based on the respective expression levels of CCL5, CXCR3, and CXCR6 in the reference population. In some embodiments, the reference population is the population of individuals with NSCLC.

[0094] In another embodiment, the present invention relates to atezolizumab and / or tilagorumab for use in the treatment of an individual having NSCLC, wherein the individual is: (i) (a) A Ccr7.2 gene signature score that is equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of each of the following detected in a sample from the individual: STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X; (b) A Ccr7.3 gene signature score greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB detected in a sample from the individual; (c) A Cxcr3 gene signature score greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7 detected in a sample from the individual; (d) A Ccl5.1 gene signature score that is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of each of the following genes detected in a sample from the individual: CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3; (e) an Ifit gene signature score that is equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1 detected in a sample from the individual; (f) A Mitotic gene signature score that is equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL detected in a sample from the individual; (g) A Cytotox.2 gene signature score lower than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT detected in a sample from the individual; or (h) Provided are atezolizumab and / or tilagorumab having a Cytotox.4 gene signature score lower than a reference gene signature score, thereby identifying an individual as one that may benefit from treatment including atezolizumab and tilagorumab, wherein the gene signature score has been determined to have a gene signature score based on the expression levels of each of S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2 detected in a sample from the individual.

[0095] In some embodiments, the gene signature score is the average expression level of members of the gene signature in a sample from an individual.

[0096] In some embodiments, individuals are determined to have a Ccr7.3, Cxcr3, or Ccl5.1 gene signature score in the sample that is equal to or greater than the reference gene signature score, and the benefit is a clinical response. In some embodiments, the clinical response is a complete response (CR) or partial response (PR).

[0097] In some embodiments, individuals have been determined to have (i) a Ccr7.2, Cxcr3, Ifit, or Mitotic gene signature score in the sample that is equal to or greater than the reference gene signature score, or (ii) a Cytotox.2 or Cytotox.4 gene signature score that is lower than the reference gene signature score, with the benefit being an increase in OS HR.

[0098] In some embodiments, individuals have been determined to have a Ccr7.2, Ccr7.3, or Cxcr3 gene signature score in the sample that is equal to or greater than the reference gene signature score, and the benefit is an increase in overall survival (OS).

[0099] In some embodiments, the reference gene signature score is a pre-assigned gene signature score.

[0100] In some embodiments, the reference gene signature score is the gene signature score in the reference population. In some embodiments, the gene signature score in the reference population is the median of the Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox.2, or Cytotox.4 gene signature scores in the reference population. In some embodiments, the reference population is the population of individuals with NSCLC.

[0101] In another embodiment, the present invention provides atezolizumab for use in treating individuals having NSCLC, wherein the individual has been determined to have a gene signature score equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab, and the gene signature score is based on the expression levels of CCL5, CXCR3, and CXCR6, respectively, detected in a sample from the individual.

[0102] In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, and CXCR6 in a sample from an individual.

[0103] In some embodiments, the expression level of CCR7 is detected in samples from individuals. In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, CXCR6, and CCR7 in samples from individuals.

[0104] In some aspects, the benefit is an increase in progression-free survival (PFS) or overall survival (OS).

[0105] In some embodiments, the reference gene signature score is a pre-assigned gene signature score.

[0106] In some embodiments, the reference gene signature score is the gene signature score in the reference population. In some embodiments, the gene signature score in the reference population is the median of the gene signature scores based on the respective expression levels of CCL5, CXCR3, and CXCR6 in the reference population. In some embodiments, the reference population is the population of individuals with NSCLC.

[0107] In some aspects, treatment involving atezolizumab is atezolizumab monotherapy.

[0108] In some embodiments, the expression level is either a nucleic acid expression level or a protein expression level.

[0109] In some embodiments, the expression level is the nucleic acid expression level. In some embodiments, the nucleic acid expression level is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof.

[0110] In some embodiments, nucleic acid expression levels are mRNA expression levels. In some embodiments, mRNA expression levels are determined by RNA-seq.

[0111] In some embodiments, the expression level is the protein expression level. In some embodiments, the protein expression level is determined by mass spectrometry.

[0112] In some embodiments, the sample is obtained from the individual before treatment with atezolizumab and / or tilagormab.

[0113] In some embodiments, the sample is a tissue sample, tumor sample, blood sample, plasma sample, serum sample, or a combination thereof.

[0114] In some embodiments, the sample is a tissue sample. In some embodiments, the tissue sample is a tumor tissue sample. In some embodiments, the tumor tissue sample is a biopsy sample.

[0115] In some embodiments, the tissue sample is a tumor drainage lymph node (dLN) sample.

[0116] In some embodiments, the sample is a blood sample.

[0117] In some embodiments, the sample is a stored sample, a fresh sample, or a frozen sample.

[0118] In some embodiments, the individual has PD-L1-positive NSCLC. In some embodiments, the PD-L1-positive NSCLC is determined to have a PD-L1-positive tumor cell fraction by immunohistochemistry (IHC) assay. In some embodiments, the PD-L1-positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, which is SP263, 22C3, SP142, or 28-8.

[0119] In some aspects, the individual is human.

[0120] In some cases, the individuals have never been treated for NSCLC before. [Brief explanation of the drawing]

[0121] [Figure 1a] This is a set of graphs showing the time course of tumor volume (mm3) (log2 scale) in balb / c mice treated with or without fty720, an isotype control, anti-PD-L1, anti-tigit, or a combination of anti-PD-L1 and anti-tigit antibodies, after subcutaneous inoculation of syngeneic ct26 tumor cells. Grouped analysis (left panel) and growth curves for each individual animal (n=10 / group) (right panel) are shown. The tumor growth efficacy studies are representative of three independent experiments. [Figure 1b] Figure 1b is a set of bar graphs showing the frequency of CD8+ T cells with positive staining for gp70-specific tetramers in dln (left panel); the number of CD8+ T cells with positive staining for gp70-specific tetramers in blood (right panel); and the frequency of CD8+ T cells with positive staining for gp70-specific tetramers in tumors (right panel) in balb / c ct26 tumor model mice treated with isotype control, anti-PD-L1, anti-tigit, and / or fty720. The p-values ​​where the difference between the two groups was determined to be statistically significant by an unpaired two-way Student's t-test are shown. [Figure 1c] This bar graph quantifies IFN-G and TNF-α-producing CD8+ T cells as a percentage of total CD8+ tumor-infiltrating lymphocytes (TIL) in BALB / C CT26 tumor model mice treated with isotype controls, anti-PD-L1, anti-TIGIT, and / or FTY720. Pharmacodynamic data are representative of three independent experiments (n=5 / group). P-values ​​are shown where the difference between two groups was determined to be statistically significant by an unpaired two-way Student's t-test. [Figure 1d]This is a set of graphs showing the time course of tumor volume (mm3) (log2 scale) in balb / c mice, inoculated subcutaneously with syngeneic ct26 tumor cells, treated with isotype control or a combination of anti-PD-L1 antibody and anti-tigit antibody, and treated with fty720 on day 0, day 1 day before the start of treatment, or day 7, one week after treatment (delayed fty720). Group analysis (left panel) and growth curves for each individual animal (n=10 / group) (right panel) are shown. The tumor growth efficacy studies are representative of three independent experiments. [Figure 2a] This is a homogeneous manifold approximation and projection (UMAP) showing 174,514 CD8+ T cells isolated from tumor, dln, and blood of a CT26 tumor model mouse, with cluster shading. [Figure 2b] Figure 2a is a heatmap showing the relative average expression of selected marker genes associated with the phenotype, function, or differentiation state of cd8+ T cells in each cluster identified in umap. [Figure 2c] This is a set of stacked bar graphs showing the cd8+ T cell cluster composition in lymph nodes and blood under the indicated treatment conditions. In each stacked bar, white (open) bars represent single clusters, solid bars indicate the number of clones with fewer than 100 cells, and diagonal bars indicate the number of clones with 100 or more cells. [Figure 2d] This is a set of stacked bar graphs showing the cd8+ T cell cluster composition in blood (day 7) and tumors under the indicated treatment conditions. In each stacked bar, white (open) bars represent a single cluster, solid bars indicate the number of clones with fewer than 100 cells, and diagonal bars indicate the number of clones with 100 or more cells. [Figure 3a] Figure 2a shows an image illustrating the relative clonal size projected onto cd8+ T cell umap. Clonal diversity was determined by T cell receptor sequencing (TCR-seq). [Figure 3b]An image showing antibody-derived tag (adt) counts measured from cell indices of transcriptomes and epitopes (cite-seq) projected onto the cd8+ T cell umap shown in Fig. 2a. [Figure 3c] An image showing the specificity of clones to gp70 subdivided by high (≧100) or low (<100) adt counts projected onto the cd8+ T cell umap shown in Fig. 2a, and a stacked bar graph showing the proportion of cells in each cluster that are gp70+ or gp70- and have high (≧100) or low (<100) adt counts. [Figure 3d] A set of scatter plots showing primary clusters of each individual clone type in dLN (upper panel) or tumor (lower panel). The shading of the circles indicates cluster designation. The size of the circles represents the number of clone types detected in the blood on day 7. [Figure 3e] A set of scatter plots showing gp70 specificity and ADT counts for individual clones. [Figure 3f] A set of stacked bar graphs showing the cluster composition of the top 50 largest clones in tumors with matching clone types in absolute numbers based on the same TCR usage in dln and blood. The identity of the clusters is indicated by shading. [Figure 4a] A set of umaps showing cluster co-occurrence analysis in dln (lymph), blood, and tumor samples from CT26 tumor model mice treated with control anti-gp120 treatment. The lines within the UMAP indicate co-occurrence between different clusters within the indicated tissue. The lines between UMAPs indicate co-occurrence between the same clusters in different tissues. The thickness of the line indicates the relative strength of co-occurrence, with the thickest line indicating the strongest co-occurrence. For lines between tissues, the shading of the line indicates the cluster. [Figure 4b] A set of umaps showing cluster co-occurrence analysis in dln (lymph), blood, and tumor samples from ct26 tumor model mice treated with anti-PD-L1 antibody. [Figure 4c]A set of UMAPs showing cluster co-occurrence analysis in dln (lymph), blood, and tumor samples from CT26 tumor model mice treated with anti-Tigit antibody. [Figure 4d] A set of UMAPs showing cluster co-occurrence analysis in dln (lymph), blood, and tumor samples from ct26 tumor model mice treated with anti-Tigit antibody and anti-PD-L1 antibody. [Figure 4e] A set of UMAPs showing cluster co-occurrence analysis in dln (lymph), blood, and tumor samples from ct26 tumor model mice treated with anti-Tigit antibody, anti-PD-L1 antibody, and FTY720. [Figure 5a] A plot showing the percentage of gp70+CD8+ T cells from dln of CT26 tumor-bearing mice treated with anti-PD-L1, anti-Tigit, or anti-PD-L1 + anti-Tigit with or without FTY720 (FTY) that express CD226. P-values determined to be statistically significant for differences between two groups by unpaired two-tailed Student's t-test are shown. [Figure 5b] A set of plots showing the percentage of CD226+(left panel) or CD226-(right panel) gp70+CD8+ T cells from dln of CT26 tumor-bearing mice treated with anti-PD-L1, anti-Tigit, or anti-PD-L1 + anti-Tigit with or without FTY720 (FTY) that express Ki67. [Figure 5c] A set of plots showing the percentage of CD226+(left panel) or CD226-(right panel) gp70+CD8+ T cells from dln of CT26 tumor-bearing mice treated with anti-PD-L1, anti-Tigit, or anti-PD-L1 + anti-Tigit with or without FTY720 (FTY) that have a naive phenotype. [Figure 5d]This is a set of plots showing the percentage of CD226+ (left panel) or CD226- (right panel) GP70+CD8+ T cells derived from DLN in CT26 tumor-bearing mice treated with anti-PD-L1, anti-TIGIT, or anti-PD-L1+anti-TIGIT with or without FTY720 (FTY), exhibiting a cytotoxic CD8+ T effector / memory cell (Teff / TEM) phenotype. [Figure 5e] This is a set of plots showing the percentage of dln-derived CD226+ (left panel) or CD226- (right panel) gp70+ CD8+ T cells from ct26 tumor-bearing mice that express pd-1 and were treated with anti-PD-L1, anti-tigit, or anti-PD-L1+anti-tigit with or without fty720(fty). [Figure 5f] This is a set of plots showing the percentage of dln-derived CD226+ (left panel) or CD226- (right panel) gp70+ CD8+ T cells from ct26 tumor-bearing mice treated with anti-PD-L1, anti-tigit, or anti-PD-L1+anti-tigit with or without fty720(fty), expressing tcf1 and tim3. [Figure 5g] This is a set of plots showing the percentage of dln-derived CD226+ (left panel) or CD226- (right panel) gp70+ CD8+ T cells from ct26 tumor-bearing mice that expressed tox and were treated with anti-PD-L1, anti-tigit, or anti-PD-L1+anti-tigit with or without fty720(fty). [Figure 5h] This plot shows the percentage of gp70+cd8+ T cells derived from tumor tissue of ct26 tumor-bearing mice expressing cd226 and treated with anti-PD-L1, anti-tigit, or anti-PD-L1+anti-tigit, with or without fty720(fty). [Figure 5i] This is a set of plots showing the percentage of cd226+ (left panel) or cd226- (right panel) gp70+cd8+ T cells derived from tumor tissue of ct26 tumor-bearing mice that expressed ki67 and were treated with anti-PD-L1, anti-tigit, or anti-PD-L1+anti-tigit with or without fty720(fty). [Figure 5j]This is a set of plots showing the percentage of cd226+ (left panel) or cd226- (right panel) gp70+cd8+ T cells derived from tumor tissue of ct26 tumor-bearing mice that expressed tcf1 and tim3 and were treated with anti-PD-L1, anti-tigit, or anti-PD-L1+anti-tigit with or without fty720(fty). [Figure 5k] This is a set of plots showing the percentage of cd226+ (left panel) or cd226- (right panel) gp70+cd8+ T cells derived from tumor tissue of ct26 tumor-bearing mice that expressed tox and were treated with anti-PD-L1, anti-tigit, or anti-PD-L1+anti-tigit with or without fty720(fty). [Figure 5l] This is a set of plots showing the percentage of dln (left panel) or tumor (right panel) gp70+cd8+ T cells from ct26 tumor-bearing mice treated with anti-PD-L1+anti-tigit, anti-PD-L1+anti-tigit+anti-cd226, or control, expressing tcf1 and tim3. [Figure 5m] This is a set of plots showing the percentage of dln (left panel) or tumor (right panel) gp70+cd8+ T cells from ct26 tumor-bearing mice treated with tox, anti-PD-L1+anti-tigit, anti-PD-L1+anti-tigit+anti-cd226, or control. [Figure 6a] This is a set of box plots showing the association between the level of human genetic signature score demonstrated in baseline tumor bulk RNA-seq samples from the Phase 2 Cityscape non-small cell lung cancer (NSCLC) trial and the clinical response to tilagolumab + atezolizumab. Patients were separated based on clinical response (CRPR, complete response / partial response; SDPD, stable disease / progressive disease) regardless of the treatment arm. Statistically significant differences are shown using two-sided t-tests. [Figure 6b]This is a set of box plots showing the associations between the expression levels of individual human genes shown in baseline tumor bulk RNA-seq samples from Phase 2 cityscape NSCLC trial patients treated with tiragolumab + atezolizumab or placebo + atezolizumab, isolated based on clinical response. [Figure 6c] This is a forest plot showing the association between high or low expression of individual human genes and overall survival (OS) hazard ratios (HR) in the tilagolumab + atezolizumab (T+A) or placebo + atezolizumab (p+a) treatment groups. Mean HR and p-values ​​with 95% confidence intervals are shown. [Figure 6d] This is a set of Kaplan-Meier (KM) curves showing the probability of os in p+a or T+A treatment groups, which are divided based on high or low expression of the indicated gene. The p-values ​​are from log-rank tests with the null hypothesis that there is no difference between the groups. [Figure 6e] This is a set of box plots showing gene scores calculated using the mean expression of a CD8 gene panel consisting of ccr7, cxcr3, cxcr6, and ccl5 (top) or cxcr3, cxcr6, and ccl5 (bottom) in tumor bulk RNA-seq samples from patients treated with tiragolumab + atezolizumab, isolated based on clinical response. [Figure 6f] This is a forest plot showing the association between high or low expression of the composite gene score and os hr in the T+A or p+a treatment group. Mean HR and p-values ​​with 95% confidence intervals are shown. [Figure 6g] This is a set of km curves showing the probability of os in p+a or T+A treatment groups, which are bifurcated based on high or low composite gene scores. The p-values ​​are from log-rank tests with the null hypothesis that there is no difference between the groups. [Figure 7a] This is a set of figures showing experimental outlines of tumor growth and pharmacodynamic (PD) analysis in ct26 and eo771 studies (left); delayed fty720 treatment in the ct26 model (center); and multi-omic analysis of T cells in the ct26 tumor model (right). [Figure 7b] This is a set of graphs showing the time course of tumor volume (mm3) (log2 scale) in c57bl / 6 mice inoculated with eo771 tumor cells into mammary fat pads and treated with isotype control, anti-PD-L1, anti-tigit, or a combination of anti-PD-L1 and anti-tigit antibodies, with or without fty720. Grouped analysis (left panel) and growth curves for each individual animal (n=10 / group) (right panel) are shown. The data shown are representative of two independent experiments. [Figure 7c] This is a set of plots showing the total number of CD8+ T cells, CD4+ T cells, or Tregs in the dln (upper panel) or tumor (lower panel) of ct26 tumor-bearing mice treated with or without fty720, isotype control, anti-PD-L1, anti-tigit, or a combination thereof. n = 5 mice / group, mean ± SD, represented by bars and whiskers. The data are representative of three independent experiments. [Figure 7d] This is a set of bar graphs showing the frequency of CD8+ T cells with positive staining for gp70-specific tetramers in dLN (left panel); the number of CD8+ T cells with positive staining for gp70-specific tetramers in blood (right panel); and the frequency of CD8+ T cells with positive staining for gp70-specific tetramers in tumors (right panel) in balb / c ct26 tumor model mice treated with or without fty720, isotype control, anti-PD-L1 (denoted as apdl1 or ap), anti-tigit (denoted as atigit or at), or a combination of anti-PD-L1 and anti-tigit antibodies. The data are summaries of two (blood) or three (dLN, tumor) independent experiments (n=5 / group / experiment), and each dot represents one animal. Bars represent the mean and whiskers represent the standard deviation. The p-values ​​where the difference between two selected groups was determined to be statistically significant by the Mann-Whitney test are shown. *,p<0.05;**,p<0.01;***,p<0.001;****,p<0.0001. [Figure 7e]This bar graph quantifies IFN-G and TNF-α-producing CD8+ T cells as a percentage of total CD8+ tumor-infiltrating lymphocytes (TIL) in BALB / C CT26 tumor model mice treated with isotype control, anti-PD-L1, anti-TIGIT, and / or FTY720. The data are a summary of two independent experiments (n=5 / group / experiment). The p-values ​​where the difference between two selected groups was determined to be statistically significant by the Mann-Whitney test are shown: *,p<0.05;**,p<0.01;***,p<0.001;****,p<0.0001. [Figure 8a] This is a representative set of dot plots showing intracellular staining of ifn-G and TNF-A in cd8+ T cells from tumors. [Figure 8b] This is a set of representative dot plots showing the co-expression of cd226 and pd-1 on cd8+ T cells in dln (top) and the co-expression of tim3 and pd-1 on cd8+ T cells in dln (bottom). [Figure 8c] This is a set of representative dot plots showing the co-expression of cd226 and lag3 on cd8+ T cells in tumors (top) and the co-expression of tim3 and pd-1 on cd8+ T cells in tumors (bottom). [Figure 8d] This is a set of representative dot plots showing tcf1 and tox co-expression on cd8+ T cells in dln (top) or tumor (bottom). [Figure 8e] This is a set of representative dot plots showing slamf6 and tcf1 co-expression on cd8+ T cells in tumors. [Figure 8f] This is a set of representative dot plots for co-expression of cd226 and gp70 tetramers on cd8+ T cells in dln (top) or tumor (center), or for gp70 tetramer staining on cd8+ T cells in blood (bottom). [Figure 9a]A set of images showing T cell clusters representing CD8+ T cells, CD4+ T cells, and regulatory T cells in 305,908 total T cells pooled from CT26 tumors, dLNs, and blood from 31 mice. Ten CD8+ T cell clusters (Ccl5-1, ribo-2, Ccl5-3, CD8-4, CD8-5, mitotic-9, mitotic-12, Xcl1-13, IFN-15, and Ly6a-16), four conventional CD4+ T cell clusters (CD40ig-0, CD40ig-7, vim-11, and Stat1-14), two regulatory T (Treg) cell clusters (Treg-6, Treg-8), three mitotic cell clusters (mitotic-9, mitotic-12, mitotic-20), two dead cell clusters (dying-10 and dying-17), and several clusters with no clear phenotype (Gxp1-19, CD74-18, and CD74-21) were classified. As shown, CD8a expression, granzyme B expression, tissue source, treatment group (group), clone size, ADT count, and gp70 antigen specificity projection on UMAP are shown. [Figure 9b] A set of images showing CITE-seq relative expression levels for the indicated markers projected onto UMAP. [Figure 10A] A set of images showing the relative expression levels of the indicated markers measured by CITE-seq and projected onto UMAP composed of CD8+ T cells from CT26 tumors, dLNs, and blood. [Figure 10B] A heatmap showing the relative CITE-seq marker expression levels in the indicated tissues under various treatment conditions. [Figure 11a]This is a set of heatmaps showing the cross-labeling of cd8+ T cell clusters (rows) to reference gene signatures (columns), obtained from analyses of huang et al., cell, 185:1-18, 2022; deak et al., nature, 610:173-181, 2022; hashimoto et al., nature, 610:173-181, 2022; and daniel et al., nat immunol, 23:1614-1627, 2022, where intensity represents normalized frequency. [Figure 11b] This is a set of umaps showing cluster composition in dln (lymph), tumors, and blood from ct26 tumor-bearing mice treated with isotype controls, anti-PD-L1, anti-tigit, combinations, or combinations with fty720. [Figure 12A] This is a set of scatter plots showing the primary clusters of each individual clone type shown in dLN and blood on day 7. The shading of the circles indicates cluster designations as shown in Figure 3D. [Figure 12b] This is a set of stacked bar graphs showing the absolute number of cluster compositions of the 50 largest clonal types derived from tumors (top panel), lymph nodes (middle panel), or blood on day 7 (bottom panel) of ct26 tumor-bearing mice treated with isotype control, anti-PD-L1, anti-tigit, a combination, or a combination with fty720. Cluster identity is indicated by light or dark gray. [Figure 12c] This is a set of stacked bar graphs showing the cluster composition of 50 largest clonal types derived from tumors (top panel), lymph nodes (middle panel), or blood on day 7 (bottom panel) of ct26 tumor-bearing mice treated with isotype control, anti-PD-L1, anti-tigit, a combination, or a combination with fty720, normalized to the total number of cells for each individual clonal type (total cell count = 1). Cluster identity is indicated by light or dark shades. [Figure 13a]This heatmap shows the relative co-occurrence relationships of CD8+ T cell clusters derived from ct26 tumor-bearing mice in dln, blood, and within or between tumors. A higher intensity of co-occurrence between two clusters indicates greater similarity and suggests a shared differentiation trajectory. [Figure 13b] This heatmap shows defined clusters using metadata from li et al., j exp med, 219:e20210749, 2022, where cd8t2 is likely naive, cd8t2 has Tscm / memory characteristics, cd8t4 has activated effector cell characteristics, and cd8t5 has an exhausted phenotype. CD8T2 and CD8T5 were described as recently entered tumor T cells, while CD8T4 and CD8T5 were resident cells in the tumor. CD8T2 also has the ability to recirculate from tumor to dLN. [Figure 14a] This is a set of charts showing the frequency of CD8+ T cells in dln (left) or tumor (right) mice as a percentage of CD45+ cells in mice with established eo771 tumors treated with isotype control ab or anti-tigit combined with anti-PD-L1. dln and tumor mice were collected 7 days post-treatment for phenotypic characterization of CD8+ T cells by flow cytometry. n=4 / group; mean and sd are shown as bars and whiskers; data represent one of two independent experiments. P-values ​​are shown where the difference was determined to be statistically significant by an unpaired t-test. [Figure 14b] This is a set of charts showing the frequency of CD8+ T cells expressing CD226 in dln (left) or tumor (right) mice, as a percentage of CD45+ cells in mice with established eo771 tumors treated with isotype control ab or anti-tigit combined with anti-PD-L1. dln and tumor cells were collected 7 days post-treatment for phenotypic characterization of CD8+ T cells by flow cytometry. n=4 / group; mean and sd are shown as bars and whiskers; data represent one of two independent experiments. P-values ​​are shown where the difference was determined to be statistically significant by an unpaired t-test. [Figure 14c] This is a set of charts showing the frequency of cd8+ T cells stained positive with the eo771-specific antigen p15e as a tetramer in dln (left) or tumor (right) mice with established eo771 tumors treated with isotype control ab or anti-tigit in combination with anti-PD-L1, as a percentage of cd45+ cells. dln and tumor cells were collected 7 days post-treatment for phenotypic characterization of cd8+ T cells by flow cytometry. n=4 / group; mean and sd are shown as bars and whiskers; data represent one of two independent experiments. p-values ​​are shown where the difference was determined to be statistically significant by an unpaired t-test. [Figure 14d] This is a set of charts showing the frequency of p15e+cd8+ T cells expressing cd226 in dln (left) or tumor (right) mice, as a percentage of cd45+ cells in mice with established eo771 tumors treated with isotype control ab or anti-tigit combined with anti-PD-L1. dln and tumor cells were collected 7 days post-treatment for phenotypic characterization of cd8+ T cells by flow cytometry. n=4 / group; mean and sd are shown as bars and whiskers; data represent one of two independent experiments. P-values ​​are shown where the difference was determined to be statistically significant by an unpaired t-test. [Figure 14e] This is a set of charts showing the frequency of CD226+ (left) or CD226- (right) p15e+cd8+ Teff / TEM cells co-expressing TCF1 and tim3 in dln (left) or tumor (right) mice, as a percentage of CD45+ cells in mice with established eo771 tumors treated with isotype control ab or anti-tigit combined with anti-pd-l1. dln and tumor cells were collected 7 days post-treatment for phenotypic characterization of CD8+ T cells by flow cytometry. n=4 / group; mean and sd are shown as bars and whiskers; data represent one of two independent experiments. P-values ​​are shown where the difference was determined to be statistically significant by an unpaired t-test. [Figure 14f]This is a set of charts showing the frequency of CD226+ (left) or CD226- (right) p15e+ CD8+ Teff / TEM cells co-expressing tox in dln (left) or tumor (right) mice, as the percentage of CD45+ cells in dln (left) or tumor (right) mice treated with anti-tigit combined with isotype control ab or anti-pd-l1. dln and tumor cells were collected 7 days post-treatment for phenotypic characterization of CD8+ T cells by flow cytometry. n=4 / group; mean and sd are shown as bars and whiskers; data represent one of two independent experiments. P-values ​​are shown where the difference was determined to be statistically significant by an unpaired t-test. [Figure 15a] This image shows scrna-seq of 144,413 human CD8+ T cells derived from patient blood in a tiragolumab + atezolizumab (T+A) ph1b nsclc study, where human genes were renamed to their mouse orthologues (if any) and gene expression was normalized before sample integration and projection onto mouse CD8+ T cell reference umap. [Figure 15b] This is a set of plots showing the predicted cell type scores of human cd8+ T cells mapped to each assigned mouse cd8+ T cell reference cluster. [Figure 15C] This is a set of box plots showing the frequency of human predictive clusters in patients with complete or partial response (CRPR) compared to stable or progressive disease (SDPD) on day 1 of cycle 2 of T+A treatment in the Ph1b study. The percentage sum was calculated as the percentage of clusters in the total cd8+ T cells for each patient. [Figure 15d] This is a forest plot showing the association between high or low expression of the top corresponding human 18-20 signature genes (signature gene score) from each mouse CD8+ T cell cluster or CD8a in the ph2 cityscape study and the overall survival (OS) hazard ratio (HR) in the T+A or placebo + atezolizumab (P+A) treatment groups. Mean HR and p-values ​​with 95% confidence intervals are shown. [Figure 15E]This is a set of Kaplan-Meier curves showing the OS probability in the P+A treatment group or the T+A treatment group, which are bifurcated based on high or low CD8+ T cell cluster gene scores from each reference cluster. The p-values ​​are from a log-rank test with the null hypothesis that there is no difference between the groups. [Figure 15F] This is a set of Kaplan-Meier curves comparing progression-free survival (PFS, left) or overall survival (OS, right) in patients from the Phase 3 NSCLC OAK study who received atezolizumab monotherapy. Patients were bifurcated by a median genetic score calculated using the mean expression of a CD8 gene panel consisting of CCR7, CXCR3, CXCR6, and CCL5. [Figure 16] This figure shows a model of the combined effect of anti-TIgit and anti-PD-L1 on tumor-specific CD8+ T cell differentiation in a syngeneic mouse CT26 tumor model. The combined treatment drives the dual expansion of tumor-specific gp70+cd8+ T cell clones in both the dln and the tumor, requiring initial export from the dln and transport to the tumor until the tumor is sufficiently disseminated by infiltrating cells. The dual-expanded gp70+cd8+ T cell clones highly express CD226 and CCL5, possess stem cell-like memory / precursor-exhausted (TSCM / Tpex) cell characteristics such as TCF-1 expression, and reduce exhaustion programming as characterized by reduced TOX expression, thereby increasing the pool of CD8+ T cells with antitumor effector activity at the expense of exhaustion. Anti-TIgit alone phenotypicly mimics gp70+cd8+ T cells that respond to the combined treatment but does not drive robust dual expansion. Anti-PD-L1 alone does not promote dual expansion and does not provide protection from the exhaustion pathway. [Figure 17] This is a set of Kaplan-Meier curves showing progression-free survival (PFS, left) or OS (OS) in the pd-L1-positive subset (TPS ≥ 1%) of patients from the imppower110 study who received atezolizumab monotherapy. Patients were bifurcated by median genetic scores calculated using mean expression of a CD8 gene panel consisting of CCR7, CXCR3, CXCR6, and CCL5. [Modes for carrying out the invention]

[0122] I. General Techniques and Definitions The techniques and procedures described or referenced herein are generally well understood and commonly employed by those skilled in the art using conventional methodologies, such as the widely used methodologies described below: Sambrook et al., Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (FMAusubel, et al., eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (MJ MacPherson, BD Hames and GRTaylor eds. (1995)), Harlow and Lane, eds. (1988); Antibodies, A Laboratory Manual, and Animal Cell Culture (RI Freshney, ed. (1987)); Oligonucleotide Synthesis (MJ Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (JECellis, ed., 1998) Academic Press; Animal Cell Culture (RIFreshney), ed., 1987); Introduction to Cell and Tissue Culture (JP Mather and PE Roberts, 1998) Plenum Press; DG Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (DM Weir and CC Blackwell, eds.);Gene Transfer Vectors for Mammalian Cells(JMMiller and MPCalos,eds.,1987);PCR: The Polymerase Chain Reaction,(Mullis et al.,eds.,1994);Current Protocols in Immunology(JEColigan et al.,eds.,1991);Short Protocols in Molecular Biology(Wiley and Sons, 1999); Immunobiology (CA Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Press,2000);Using Antibodies:A Laboratory Manual(E.Harlow and D.Lane(Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and JDCapra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (VTDeVita et al., eds., JBLippincott Company, 1993). .

[0123] The aspects and embodiments of the present invention described herein are understood to include "a," "consisting of," and "essentially consisting of." As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated.

[0124] As used herein, the term “about” refers to the normal range of error for each value, as readily understood by those skilled in the art. References to “about” values ​​or parameters herein include (and describe) embodiments relating to the value or parameter itself. For example, a statement referring to “about X” includes a statement of “X”.

[0125] As used interchangeably herein, “quantity,” “level,” or “expression level” of a biomarker refers to a detectable level in a biological sample. “Expression” generally refers to the process by which information (e.g., genetic coding information and / or epigenetic information) is translated into structures that exist and function within a cell. Therefore, as used herein, “expression” may refer to transcription to polynucleotides, translation to polypeptides, or further to polynucleotide and / or polypeptide modifications (e.g., post-translational modifications of polypeptides). Fragments of transcribed polynucleotides, translated polypeptides, or polynucleotide and / or polypeptide modifications (e.g., post-translational modifications of polypeptides) should also be considered expressed, regardless of whether they originate from transcripts produced by alternative splicing or degraded transcripts, or from post-translational processing of polypeptides, for example, by proteolysis. “Expressed genes” include those transcribed as mRNA into polynucleotides and subsequently translated into polypeptides, and those transcribed into RNA but not translated into polypeptides (e.g., transfer and ribosomal RNAs). The expression level can be measured by methods known to those skilled in the art and disclosed herein.

[0126] The terms “detect” and “detect” are used most broadly herein to include both qualitative and quantitative measurements of a target molecule. Detection includes simply identifying the presence of a target molecule in a sample, as well as determining whether the target molecule is present in the sample at a detectable level. Detection may be direct or indirect.

[0127] The presence and / or expression levels / amounts of the various biomarkers described herein in a sample can be analyzed by several methodologies, many of which are known in the art and understood by those skilled in the art, including immunohistochemistry ("IHC"), Western blotting, immunoprecipitation, molecular binding assays, ELISA, ELIFA, fluorescence-activated cell sorting ("FACS"), MassARRAY, proteomics, quantitative blood-based assays (e.g., serum ELISA), biochemical enzyme activity assays, in situ hybridization, and fluorescence in This includes, but is not limited to, any one of the wide variety of assays that can be performed by situ hybridization (FISH), Southern blotting, Northern blotting, whole-genome sequencing, large-scale parallel DNA sequencing (e.g., next-generation sequencing), NANOSTRING®, polymerase chain reaction (PCR) including quantitative real-time PCR (qRT-PCR) and other amplification-type detection methods such as branched DNA, SISBA, TMA, RNA-seq, microarray analysis, gene expression profiling, and / or gene expression serial analysis ("SAGE"), as well as protein, gene, and / or tissue array analysis. Typical protocols for assessing the status of genes and gene products can be found, for example, in Part 2 (Northern blotting), Part 4 (Southern blotting), Part 15 (Immunoblotting), and Part 18 (PCR analysis) of Ausubel et al., eds., 1995, Current Protocols In Molecular Biology. Multiplexed immunoassays, such as those available from Rules Based Medicine or Meso Scale Discovery ("MSD"), may also be used.

[0128] As used herein, the terms “CC motif chemokine 5” or “CCL5” broadly refer to any native CCL5 from any mammalian source, including primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. The term encompasses full-length CCL5 and isolated regions or domains of CCL5, e.g., CCL5 ECD. The term also encompasses naturally occurring variants of CCL5, e.g., splice variants or allele variants. An exemplary human CCL5 amino acid sequence is shown under UniProt accession number P13501. Minor sequence variations of CCL5 that do not affect the function and / or activity of CCL5, in particular conservative amino acid substitutions, are also contemplated by this invention.

[0129] As used herein, the terms “CXC chemokine receptor type 3” or “CXCR3” broadly refer to any native CXCR3 from any mammalian source, including primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. The term encompasses full-length CXCR3 and isolated regions or domains of CXCR3, e.g., CXCR3 ECD. The term also encompasses naturally occurring variants of CXCR3, e.g., splice variants or allele variants. An exemplary human CXCR3 amino acid sequence is shown under UniProt accession number P49682. Minor sequence variations of CXCR3 that do not affect the function and / or activity of CXCR3, in particular conservative amino acid substitutions, are also contemplated by this invention.

[0130] As used herein, the terms “CXC chemokine receptor type 6” or “CXCR6” broadly refer to any native CXCR6 from any mammalian source, including primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. The term encompasses full-length CXCR6 and isolated regions or domains of CXCR6, e.g., CXCR6 ECD. The term also encompasses naturally occurring variants of CXCR6, e.g., splice variants or allele variants. An exemplary human CXCR6 amino acid sequence is shown under UniProt accession number O00574. Minor sequence variations of CXCR6 that do not affect the function and / or activity of CXCR6, particularly conserved amino acid substitutions, are also contemplated by this invention.

[0131] As used herein, the terms “CC chemokine receptor type 7” or “CCR7” broadly refer to any native CCR7 from any mammalian source, including primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. The term encompasses full-length CCR7 and isolated regions or domains of CCR7, e.g., CCR7 ECD. The term also encompasses naturally occurring variants of CCR7, e.g., splice variants or allele variants. An exemplary human CCR7 amino acid sequence is shown under UniProt accession number P32248. Minor sequence variations of CCR7 that do not affect the function and / or activity of CCR7, in particular conservative amino acid substitutions, are also contemplated by this invention.

[0132] As used herein, the terms “TIGIT” or “T-cell immune receptor having Ig and ITIM domains” refer to any native TIGIT from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. TIGIT is also known in the art as DKFZp667A205, FLJ39873, V-set and immunoglobulin domain-containing protein 9, V-set and transmembrane domain-containing protein 3, VSIG9, VSTM3, and WUCAM. The term encompasses “full-length” untreated TIGIT (e.g., full-length human TIGIT having the amino acid sequence of SEQ ID NO: 1), as well as any form of TIGIT resulting from intracellular processing (e.g., processed human TIGIT lacking a signal sequence and having the amino acid sequence of SEQ ID NO: 2). The term also encompasses naturally occurring variants of TIGIT, such as splice variants or allele variants. An exemplary human TIGIT amino acid sequence can be found under UniProt accession number Q495A1.

[0133] The terms “PD-L1” or “Programmed Cell Death Ligand 1” refer, unless otherwise specified herein, to any native PD-L1 from any vertebrate source, including mammals, e.g., primates (e.g., humans) and rodents (e.g., mice and rats). PD-L1 is also known in the Art as the CD274 molecule, CD274 antigen, B7 homolog 1, PDCD1 ligand 1, PDCD1LG1, PDCD1L1, B7H1, PDL1, programmed cell death ligand 1, B7-H1, and B7-H. The terms also encompass naturally occurring variants of PD-L1, e.g., splice variants or allele variants. An exemplary human PD-L1 amino acid sequence may be found under UniProt accession number Q9NZQ7 (SEQ ID NO: 3).

[0134] As used herein, the term "atezolizumab" refers to an anti-PD-L1 antagonist antibody with International Name of Drug (INN) List 112 (WHO Drug Information, Vol. 28, No. 4, 2014, p. 488) or CAS Registry Number 1380723-44-3.

[0135] As used herein, “tiragolumab” is a fully human IgG1 / kappa mAb conjugated to TIGIT and containing the heavy chain sequence of SEQ ID NO: 4 and the light chain sequence of SEQ ID NO: 5. Tiragolumab contains two N-linked glycosylation sites (N306) in its Fc domain. Tiragolumab is also listed in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 117, Vol. 31, No. 2 (published June 9, 2017) (see page 343). Tiragolumab (Genentech) is also known as MTIG7192A, RG6058, or RO7092284. Tiragolumab is published in International Publication No. 2003072305A8, International Publication No. 2004024068A3, International Publication No. 2004024072A3, International Publication No. 2009126688A2, International Publication No. 2015009856A2, International Publication No. 2016011264A1, International Publication No. 2016109546A2, International Publication No. 2017053748A2 and International Publication No. 2019165434A1; U.S. Patent Application Publication No. 2017 / 0044256, 2017 / 00 U.S. Patent Nos. 37127, 2017 / 0145093, 2017 / 260594, 2017 / 0088613, 2018 / 0186875, 2019 / 0119376; and as described in U.S. Patent Nos. 9873740B2, 10626174B2, 10611836B2, 9499596B2, 8431350B2, 10047158B2, and 10017572B2.

[0136] As used herein, “administer” means a method of giving a subject a dose of a compound (e.g., tiragolumab and / or atezolizumab) or a composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition comprising tiragolumab and / or atezolizumab). The compounds and / or compositions used in the methods described herein may be administered, for example, intravenously (e.g., by intravenous infusion), subcutaneously, intramuscularly, intradermally, percutaneously, intra-arterially, intraperitoneally, intra-articularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreously, intravaginally, intrarectally, topically, intratumorally, intraperitoneally, subconjunctivally, intravesically, transmucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, injection, infusion, continuous infusion, local perfusion directly into target cells, by catheter, lavage, cream, or lipid composition. The method of administration may vary depending on various factors (e.g., the compound or composition being administered, and the severity of the symptoms, disease, or disorder being treated).

[0137] As used herein, “systemic treatment” refers to a treatment that travels through the bloodstream and can reach multiple organ systems in a single administration. The term “systemic treatment” is well understood by those skilled in the art and is equivalent to systemic therapy.

[0138] In this specification, a “fixed” or “flat” dose of a therapeutic agent (e.g., tiragolumab or atezolizumab) refers to the dose administered to a patient regardless of their body weight or body surface area (BSA). Therefore, a fixed or flat dose is expressed in mg / kg or mg / m². 2 It is provided as an absolute amount of the therapeutic agent (e.g., mg), not as a dosage.

[0139] As used herein, the terms “treatment” or “treating” refer to a clinical intervention designed to alter the natural course of an individual or cells being treated during the course of a clinical lesion. Desired effects of treatment include slowing or reducing the rate of disease progression, recovery or mitigation of the disease state, and remission or improvement of the prognosis. For example, an individual is considered to have received a “treatment” if one or more cancer-related symptoms are reduced or eliminated, including but not limited to reduced proliferation (or destruction) of cancer cells, a decrease in symptoms resulting from the disease, an improvement in the quality of life of the person with the disease, a reduction in the dosage of other medications required to treat the disease, slowing of disease progression, and / or an extension of the individual’s survival time.

[0140] As used herein, "in conjunction with" refers to the administration of one treatment regimen in addition to another treatment regimen. Therefore, "in conjunction with" refers to the application of another treatment regimen before, during, or after the application of one treatment regimen to an individual.

[0141] "Disorder" or "disease" is any condition that benefits from treatment for a disorder associated with some degree of abnormal cell proliferation, including, but not limited to, cancer, lung cancer, or non-small cell lung cancer (NSCLC).

[0142] The terms “cancer” and “malignant” refer to or describe physiological conditions in mammals typically characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemias or lymphoid malignancies. More specific examples of such cancers include, but are not limited to, lung cancer, including non-small cell lung cancer (NSCLC), which includes squamous cell NSCLC or non-squamous cell NSCLC, and also includes locally advanced, unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC).

[0143] The term “tumor” refers to the growth and proliferation of all neoplastic cells, whether malignant or benign, as well as all precancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” “proliferative disorder,” “proliferative disorder,” and “tumor” are not mutually exclusive when used herein.

[0144] As used herein, “metastasis” refers to the spread of cancer from its primary site to other parts of the body. Cancer cells may detach from the primary tumor, infiltrate the lymphatic and vascular systems, circulate through the bloodstream, and grow (metastasize) at distal foci in normal tissues elsewhere in the body. Metastasis can be local or distal. Metastasis is a sequential process in which tumor cells detach from the primary tumor, travel through the bloodstream, and halt at a distal site. At the new site, the cells can establish a blood supply, grow, and form a life-threatening mass. Both stimulative and inhibitory molecular pathways within tumor cells control this behavior, and interactions between tumor cells and host cells at the distant site are also important.

[0145] The “effective dose” of a compound, e.g., tiragolumab or atezolizumab, or a composition thereof (e.g., a pharmaceutical composition), is the minimum amount necessary to achieve a desired therapeutic outcome, e.g., a measurable increase in overall survival or progression-free survival for a particular disease or disorder (e.g., cancer, e.g., lung cancer (e.g., NSCLC)). The effective dose as used herein may vary depending on factors such as the patient’s disease status, age, sex, and weight, as well as the antibody’s ability to induce the desired response in the subject. The effective dose is also the amount at which the therapeutically beneficial effect outweighs any toxic or adverse effects of the treatment. Beneficial or desired outcomes for prophylactic use include outcomes such as the elimination or reduction of risk, reduction of severity, or delay of disease onset, including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that appear during the onset of the disease.For therapeutic use, beneficial or desired outcomes include reduction of one or more symptoms caused by the disease (e.g., cancer-related pain, reduction or delay of symptomatic skeletal events (SSEs)), and the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC). Clinical outcomes such as a reduction in symptoms measured by the QLQ-C30 (e.g., fatigue, nausea, vomiting, pain, dyspnea, insomnia, loss of appetite, constipation, diarrhea, or general levels of physical, emotional, cognitive, or social functioning), a reduction in pain as measured by the Numerical Rating Scale (NRS) for Pain Severity (measured in the worst case) on a 10-point scale, and / or a reduction in lung cancer-related symptoms as measured by the Health-Related Quality of Life (HRQoL) questionnaire, assessed by the Symptoms in Lung Cancer (SILC) scale (e.g., time to worsening of cough, dyspnea, and chest pain (TTD)), an increase in the quality of life of the person with the disease, a reduction in the dose of other medications needed to treat the disease, an enhancement of the effect of another medication through targeting, etc., a delay in disease progression (e.g., progression-free survival or radiation-induced progression-free survival (rPFS)); clear clinical progression (e.g., progression of cancer-related pain, symptomatic skeletal-related events, Eastern Cooperative Group Oncology Group (ECOG) Performance This includes a decline in Status (PS) (e.g., how the disease affects a patient's ability to perform daily activities), and / or a delay in the initiation of the next systemic anticancer therapy, and / or a delay in the time to lung-specific antigen progression, and / or an extension of survival. In the case of cancer or tumors, an effective dose of the drug may have the effect of reducing the number of cancer cells, reducing tumor size, inhibiting (i.e., delaying to some extent, or preferably stopping) the invasion of cancer cells into peripheral organs, inhibiting (i.e., delaying to some extent, or preferably stopping) tumor metastasis, inhibiting tumor growth to some extent, and / or alleviating to some extent one or more of the symptoms associated with the disability. An effective dose may be administered in one or more doses. In this invention, an effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve a prophylactic or therapeutic measure.As understood in the clinical field, the effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Therefore, “effective dose” may be considered in relation to the administration of one or more therapeutic agents, and a monotherapy agent may be considered to be given in an effective dose if, in combination with one or more other agents, the desired outcome can or would be achieved.

[0146] "Individual response" or "response" may be assessed using any endpoint demonstrating a benefit to the subject, including, but not limited to, (1) some degree of inhibition of disease progression (e.g., progression of cancer, e.g., lung cancer (e.g., NSCLC)), including slowing and complete cessation; (2) reduction of tumor size; (3) inhibition of cancer cell invasion into adjacent peripheral organs and / or tissues (i.e., reduction, slowing, or complete cessation); (4) inhibition of metastasis (i.e., reduction, slowing, or complete cessation); (5) some degree of alleviation of one or more symptoms associated with the disease or disorder (e.g., cancer, e.g., lung cancer (e.g., NSCLC)); (6) an increase or extension of the length of survival, including overall survival and progression-free survival; and / or (9) a reduction in mortality at a given time point after treatment.

[0147] As used herein, “complete response” or “CR” refers to the disappearance of all target lesions.

[0148] As used herein, “partial response” or “PR” refers to a reduction of at least 30% in the sum of the longest diameters (SLD) of the target lesions, with reference to the baseline SLD.

[0149] As used herein, "objective response rate" (ORR) refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

[0150] The terms "effective response" or "responsiveness" and similar phrases to a treatment using a pharmacokinetic agent refer to the clinical or therapeutic benefit bestowed upon a subject who is at risk of or suffering from a disease or disorder such as cancer. In one embodiment, such benefit may include one or more of the following: extension of survival (including overall survival and progression-free survival), achieving an objective response (including complete or partial response), or improving the signs or symptoms of cancer.

[0151] A patient who "does not show an effective response" to the treatment is defined as a patient who does not experience any of the following: an extension of survival time (including overall survival and progression-free survival), an objective response (including complete or partial response), or an improvement in signs or symptoms of cancer.

[0152] As used herein, the term “survival” means the period during which a patient is alive, and includes overall survival and progression-free survival.

[0153] As used herein, “overall survival” (OS) refers to the percentage of subjects who are still alive at a specific time, for example, one year or five years after diagnosis or treatment.

[0154] As used herein, “progression-free survival” (PFS) refers to the length of time during and after treatment in which the treated disease (e.g., cancer, e.g., lung cancer (e.g., NSCLC)) does not worsen. Progression-free survival may include the amount of time the patient experienced a complete or partial response, as well as the amount of time the patient experienced stable disease.

[0155] As used herein, “stable disease” or “SD” refers to a state where, based on the minimum SLD since the start of treatment, there is neither a sufficient reduction in the target lesion to be considered a partial response (PR) nor a sufficient increase to be considered a progressive disease (PD).

[0156] As used herein, “progressive disease” or “PD” means an increase of at least 20% in the SLD of the target lesion, based on the minimum SLD recorded since the start of treatment or the presence of one or more new lesions.

[0157] As used herein, “delaying the progression” of a disorder or disease means delaying, hindering, slowing, stabilizing, and / or delaying the development of a disease or disorder (e.g., cancer, e.g., lung cancer (e.g., NSCLC)). This delay may be of varying duration depending on the disease history and / or the subject being treated. As will be apparent to those skilled in the art, a sufficient or significant delay may substantially encompass prevention in that the subject does not develop the disease. For example, in late-stage cancer, the development of central nervous system (CNS) metastases may be delayed.

[0158] "Extending survival" means an increase in overall survival or progression-free survival in treated patients compared to untreated patients (e.g., patients not treated with a drug), or patients not expressing a specified level of biomarker, and / or patients treated with an approved antitumor agent. Objective response refers to measurable responses, including complete response (CR) or partial response (PR).

[0159] As used herein, “hazard ratio” or “HR” is a statistical definition of the incidence rate of an event. For the purposes of the present invention, the hazard ratio is defined as the probability of an event (e.g., PFS or OS) in the experimental (e.g., treatment) group / arm divided by the probability of the event in the control group / arm at any given time point. An HR value of 1 indicates that the relative risk of the endpoint (e.g., death) is equal in both the “treatment” group and the “control” group; a value greater than 1 indicates that the risk in the treatment group is greater than in the control group, and a value less than 1 indicates that the risk in the control group is greater than in the treatment group. In progression-free survival analysis, the “hazard ratio” (i.e., PFS HR) is a summary of the difference between two progression-free survival curves and represents the reduction in the risk of death in the treatment compared to the control over the follow-up period. In overall survival analysis, the “hazard ratio” (i.e., OS HR) is a summary of the difference between two overall survival curves and represents the reduction in the risk of death in the treatment compared to the control over the follow-up period.

[0160] When used herein, the "Ventana SP263 IHC assay" (also referred herein as the Ventana SP263 CDx assay) is performed in accordance with the Ventana PD-L1 (SP263) assay insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.

[0161] When used herein, the "Ventana SP142 IHC assay" is performed in accordance with the Ventana PD-L1 (SP142) assay insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.

[0162] When used herein, the "pharmDx 22C3 IHC assay" is performed in accordance with the PD-L1 IHC 22C3 pharmDx Pre-authorized Document (Carpinteria, CA:Dako, Agilent Pathology Solutions), which is incorporated herein by reference in its entirety.

[0163] "Tumor-infiltrating immune cells," as used herein, refers to any immune cells present in a tumor or a sample thereof. Tumor-infiltrating immune cells include, but are not limited to, intratumor immune cells, peritumor immune cells, other tumor stromal cells (e.g., fibroblasts), or any combination thereof. Such tumor-infiltrating immune cells may include, for example, T lymphocytes (such as CD8+ T lymphocytes and / or CD4+ T lymphocytes), B lymphocytes, or granulocytes (e.g., neutrophils, eosinophils, and basophils), monocytes, macrophages, dendritic cells (e.g., finger-shaped dendritic cells), histiocytes, and other myeloid cells, including natural killer cells.

[0164] As used herein, the term “biomarker” refers to an indicator that may be detected in a sample, such as a predictive indicator, a diagnostic indicator, and / or a prognostic indicator. In some embodiments, the biomarker is a gene. Examples of biomarkers include, but are not limited to, polypeptides, polynucleotides (e.g., DNA and / or RNA), polynucleotide copy number changes (e.g., DNA copy number), polypeptide and polynucleotide modifications (e.g., post-translational modifications), carbohydrates, and / or glycolipid-based molecular markers.

[0165] As used herein, “subject” or “individual” means a mammal, including but not limited to humans or non-human mammals such as cattle, horses, dogs, sheep, or cats. In some embodiments, the subject is human. A patient is also a subject as used herein.

[0166] As used herein, the term “sample” refers to a composition obtained from or derived from the subject and / or individual of interest that contains cellular and / or other molecular entities characterized and / or identified, for example, based on physical, biochemical, chemical, and / or physiological properties. For example, the terms “tumor sample,” “disease sample,” and their variations refer to any sample obtained from the subject of interest that is expected to contain, or is known to contain, the characterized cellular and / or molecular entities. In some embodiments, the sample is a tumor tissue sample (e.g., a lung cancer sample (e.g., a NSCLC sample)). Other samples include, but are not limited to, primary or cultured cells or cell lines, cell supernatant, cell lysates, platelets, serum, plasma, vitreous fluid, lymph, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, sweat, mucus, feces, tumor lysates, and tissue culture media, tissue extracts, such as homogenized tissue, cell extracts, and combinations thereof. In some embodiments, the sample is a tumor dissipation lymph node (dLN) sample.

[0167] The terms “tissue sample” and “cell sample” refer to a collection of similar cells obtained from the tissue of a subject or individual. Sources of tissue or cell samples may include solid tissues such as fresh, frozen, and / or preserved organs, tissue samples, biopsy materials, and / or aspirates; blood or any blood components such as plasma; bodily fluids such as cerebrospinal fluid, amniotic fluid, ascites, or interstitial fluid; and cells at any stage in the subject's pregnancy or development. Tissue samples may be primary or cultured cells or cell lines. Optionally, tissue or cell samples may be obtained from diseased tissue / organs. Tissue samples may contain compounds not naturally mixed with natural tissues, such as preservatives, anticoagulants, buffers, fixatives, nutrients, and antibiotics.

[0168] As used herein, “reference sample,” “reference cell,” “reference tissue,” “control sample,” “control cell,” or “control tissue” refers to a sample, cell, tissue, standard, or level used for comparative purposes. In one embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and / or non-disease portion (e.g., tissue or cell) of the same body of the subject. For example, tissue adjacent to healthy and / or non-disease cells or diseased cells or tissue (e.g., cells or tissue adjacent to a tumor). In another embodiment, the reference sample is obtained from untreated tissue and / or cells of the same body of the subject. In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and / or non-disease portion (e.g., tissue or cell) of a body of a non-subject. 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 a body of a non-subject individual.

[0169] Unless otherwise specified, the term “protein” as used herein refers to any native protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice, rats), unless otherwise specified. The term also includes any form of protein resulting from “full length,” untreated protein, and intracellular processing. The term also encompasses naturally occurring variants of proteins, such as splice variants or allele variants.

[0170] As used herein, “polynucleotide” or “nucleic acid” refers to a polymer of nucleotides of any length, including DNA and RNA. The nucleotides may be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or analogs thereof, or any substrate that can be incorporated into the polymer by DNA or RNA polymerase or by synthetic reactions. Therefore, examples of polynucleotides as defined herein include, but are not limited to, single-stranded and double-stranded DNA, DNA containing single-stranded and double-stranded regions, single-stranded and double-stranded RNA, RNA containing single-stranded and double-stranded regions, and hybrid molecules containing single-stranded or more typically double-stranded DNA and RNA, or potentially containing single-stranded and double-stranded regions. In addition, as used herein, the term “polynucleotide” refers to a triple-stranded region containing RNA or DNA, or both RNA and DNA. The strands within such a region may originate from the same molecule or from different molecules. These regions may contain all of one or more of these molecules, but more typically, only some of these molecules. One of the molecules in a triple helix region is often an oligonucleotide. The terms "polynucleotide" and "nucleic acid" specifically include mRNA and cDNA.

[0171] Polynucleotides may include modified nucleotides, such as methylated nucleotides and their analogues. If present, modifications to the nucleotide structure may be applied before or after polymer assembly. The nucleotide sequence may be interrupted by non-nucleotide components. Polynucleotides may be further modified after synthesis, such as by conjugation with labels. Other types of modifications include, for example, "caps," substitution of one or more naturally occurring nucleotides with analogs, internucleotide modifications, such as those by uncharged bonds (e.g., methylphosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and those by charged bonds (e.g., phosphorothioates, phosphorodithioates, etc.), suspensions, such as those involving proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those involving intercalators (e.g., acridine, psoralens, etc.), those involving chelating agents (e.g., metals, radioactive metals, boron, metal oxides, etc.), those involving alkylating agents, those involving modified bonds (e.g., alpha-anomeric nucleic acids, etc.), and the unmodified form of polynucleotides. Furthermore, any of the hydroxyl groups normally present in the sugar may be replaced, for example, by a phosphonic acid group or a phosphate group, protected by a standard protecting group, or activated to prepare for additional binding to additional nucleotides, or conjugated to a solid or semi-solid support. The 5' and 3' terminal OH groups may be phosphorylated or substituted with amines or organic capping groups of 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups. Polynucleotides may also include analogous forms of ribose sugars or deoxyribose sugars known in the art, which include, for example, 2'-O-methyl-, 2'-O-allyl-, 2'-fluoro-, or 2'-azid-ribose, carbocyclic sugar analogs, α-anomeric sugars, epimeric sugars, such as arabinose, xylose, or lyxose, pyranose sugars, furanose sugars, sedoheptulose, acyclic analogs, and nonbasic nucleoside analogs, such as methylriboside.One or more phosphodiester bonds may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments in which the phosphate is replaced by P(O)S ("thioate"), P(S)S ("dithioate"), (O)NR2 ("amidate"), P(O)R, P(O)OR', CO, or CH2 ("formacetal"), where each R or R' is independently H, or a substituted or unsubstituted alkyl (1-20C) (optionally including an ether (-O-) bond), aryl, alkenyl, cycloalkyl, cycloalkenyl, or araluzyl. Not all bonds in a polynucleotide need to be identical. The foregoing description applies to all polynucleotides referred to herein, including RNA and DNA.

[0172] As used herein, “carrier” includes pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to cells or mammals to which they are exposed at the doses and concentrations used. In many cases, physiologically acceptable carriers are pH-buffered aqueous solutions. Examples of physiologically acceptable carriers include buffers such as phosphoric acid, citrate, and other organic acids; antioxidants, including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN®, polyethylene glycol (PEG), and PLURONICS®.

[0173] The phrase "pharmaceutically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other components of the formulation and / or the mammal being treated with it.

[0174] The term "pharmaceutical preparation" refers to a preparation in which the biological activity of the active ingredient contained therein is effective, and which does not contain any further components that are unacceptably toxic to the person to whom the preparation is administered.

[0175] II. Prognostic diagnostic methods and assays for tilagolmab + atezolizumab A. CCL5, CXCR3, CCR7, and CXCR6 Methods for identifying individuals who may benefit from treatment In one embodiment, the present invention provides a method for identifying an individual having non-small cell lung cancer (NSCLC) that may benefit from treatment comprising atezolizumab and tilagorumab, comprising detecting the expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 (e.g., one, two, three, or all four of CCL5, CXCR3, CCR7, and CXCR6) in a sample from the individual, wherein the expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 (e.g., the expression level of one, two, three, or all four of CCL5, CXCR3, CCR7, and CXCR6) that is equal to or greater than the reference expression level of CCL5, cxcr3, ccr7, or cxcr6 identifies the individual as an individual that may benefit from treatment comprising atezolizumab and tilagorumab.

[0176] For example, in one embodiment, the present invention provides a method for identifying individuals having NSCLC who may benefit from treatment comprising atezolizumab and tilagorumab, the method comprising detecting the expression level of ccl5 in a sample from the individual, wherein the ccl5 expression level is equal to or greater than the reference expression level of ccl5, thereby identifying the individual as one who may benefit from treatment comprising atezolizumab and tilagorumab.

[0177] In another embodiment, the present invention provides a method for identifying individuals with NSCLC who may benefit from treatment comprising atezolizumab and tilagorumab, the method comprising detecting the expression level of cxcr3 in a sample from the individual, wherein the expression level of cxcr3 is equal to or greater than the reference expression level of cxcr3, thereby identifying the individual as one who may benefit from treatment comprising atezolizumab and tilagorumab.

[0178] In another embodiment, the present invention provides a method for identifying individuals with NSCLC who may benefit from treatment comprising atezolizumab and tilagorumab, the method comprising detecting the expression level of ccr7 in a sample from the individual, wherein the expression level of ccr7 is equal to or greater than the reference expression level of ccr7, thereby identifying the individual as one who may benefit from treatment comprising atezolizumab and tilagorumab.

[0179] In another embodiment, the present invention provides a method for identifying individuals with NSCLC who may benefit from treatment comprising atezolizumab and tilagorumab, the method comprising detecting the expression level of cxcr6 in a sample from the individual, wherein the expression level of cxcr6 is equal to or greater than the reference expression level of cxcr6, thereby identifying the individual as one who may benefit from treatment comprising atezolizumab and tilagorumab.

[0180] In some embodiments, the individual has an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in the sample, which is equal to or greater than the reference expression level of CCL5, CXCR3, CCR7, or CXCR6, and the method further comprises administering an effective dose of atezolizumab and tilagorumab (e.g., an effective dose of atezolizumab and tilagorumab as described in Section III of this Spec.)

[0181] Treatment options In another embodiment, the present invention provides a method for selecting a treatment for an individual having NSCLC, comprising detecting the expression level of one or more ccl5, cxcr3, ccr7, and cxcr6 (e.g., one, two, three, or all four of ccl5, cxcr3, ccr7, and cxcr6) in a sample from the individual, wherein the expression level of one or more ccl5, cxcr3, ccr7, and cxcr6 (e.g., the expression levels of one, two, three, or all four of ccl5, cxcr3, ccr7, and cxcr6) is equal to or greater than the reference expression level of ccl5, cxcr3, ccr7, or cxcr6, thereby identifying the individual as one that may benefit from a treatment comprising atezolizumab and tilagorumab.

[0182] For example, in one embodiment, the present invention provides a method for selecting a treatment for an individual having NSCLC that may benefit from a treatment comprising atezolizumab and tilagorumab, the method comprising detecting the expression level of ccl5 in a sample from the individual, wherein the expression level of ccl5 is equal to or greater than the reference expression level of ccl5, thereby identifying the individual as one that may benefit from a treatment comprising atezolizumab and tilagorumab.

[0183] In another embodiment, the present invention provides a method for selecting a treatment for an individual having NSCLC who may benefit from a treatment comprising atezolizumab and tilagorumab, the method comprising detecting the expression level of cxcr3 in a sample from the individual, wherein the expression level of cxcr3 is equal to or greater than the reference expression level of cxcr3, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tilagorumab.

[0184] In another embodiment, the present invention provides a method for selecting a treatment for an individual having NSCLC who may benefit from a treatment comprising atezolizumab and tilagorumab, the method comprising detecting the expression level of ccr7 in a sample from the individual, wherein the expression level of ccr7 is equal to or greater than the reference expression level of ccr7, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tilagorumab.

[0185] In another embodiment, the present invention provides a method for selecting a treatment for an individual having NSCLC who may benefit from a treatment comprising atezolizumab and tilagorumab, the method comprising detecting the expression level of cxcr6 in a sample from the individual, wherein the expression level of cxcr6 is equal to or greater than the reference expression level of cxcr6, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tilagorumab.

[0186] In some embodiments, the individual has an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in the sample, which is equal to or greater than the reference expression level of CCL5, CXCR3, CCR7, or CXCR6, and the method further comprises administering an effective dose of atezolizumab and tilagorumab (e.g., an effective dose of atezolizumab and tilagorumab as described in Section III of this Spec.)

[0187] Treatment method In another embodiment, the present invention provides a method for treating an individual having NSCLC, comprising: (a) detecting the expression level of one or more ccl5, cxcr3, ccr7, and cxcr6 (one, two, three, or all four of ccl5, cxcr3, ccr7, and cxcr6) in a sample from the individual, wherein the expression level of one or more of ccl5, cxcr3, ccr7, and cxcr6 is equal to or greater than the reference expression level of ccl5, cxcr3, ccr7, or cxcr6, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab; and (b) administering an effective dose of atezolizumab and tilagorumab to the individual.

[0188] For example, in one embodiment, the present invention provides a method for treating an individual having NSCLC, comprising: (a) detecting the expression level of ccl5 in a sample from the individual, wherein the expression level of ccl5 is equal to or greater than the reference expression level of ccl5, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab; and (b) administering an effective amount of atezolizumab and tilagorumab to the individual.

[0189] In another aspect, the present invention provides a method for treating an individual having NSCLC, comprising: (a) detecting the expression level of cxcr3 in a sample from the individual, wherein the expression level of cxcr3 is equal to or greater than the reference expression level of cxcr3, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab; and (b) administering an effective amount of atezolizumab and tilagorumab to the individual.

[0190] In another aspect, the present invention provides a method for treating an individual having NSCLC, comprising: (a) detecting the expression level of ccr7 in a sample from the individual, wherein the expression level of ccr7 is equal to or greater than the reference expression level of ccr7, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab; and (b) administering an effective amount of atezolizumab and tilagorumab to the individual.

[0191] In another aspect, the present invention provides a method for treating an individual having NSCLC, comprising: (a) detecting the expression level of cxcr6 in a sample from the individual, wherein the expression level of cxcr6 is equal to or greater than the reference expression level of cxcr6, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab; and (b) administering an effective amount of atezolizumab and tilagorumab to the individual.

[0192] In another embodiment, the present invention provides a method for treating an individual having NSCLC, comprising administering atezolizumab and tilagorumab to the individual, wherein it is determined that the individual has one or more expression levels of ccl5, cxcr3, ccr7, and cxcr6 (e.g., expression levels of one, two, three, or all four of ccl5, cxcr3, ccr7, and cxcr6) that are equal to or above the reference expression level of ccl5, cxcr3, ccr7, or cxcr6, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

[0193] For example, in one embodiment, the present invention provides a method for treating an individual having NSCLC, comprising administering atezolizumab and tilagorumab to the individual, wherein the individual is determined to have a CCL5 expression level equal to or greater than the reference expression level of CCL5, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

[0194] In another aspect, the present invention provides a method for treating an individual having NSCLC, comprising administering atezolizumab and tilagorumab to the individual, wherein the individual is determined to have a CXCR3 expression level equal to or greater than the reference expression level of CXCR3, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

[0195] In another aspect, the present invention provides a method for treating an individual having NSCLC, comprising administering atezolizumab and tilagorumab to the individual, wherein the individual is determined to have a CCR7 expression level equal to or greater than the reference expression level of CCR7, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

[0196] In another embodiment, the present invention provides a method for treating an individual having NSCLC, comprising administering atezolizumab and tilagorumab to the individual, wherein the individual is determined to have a CXCR6 expression level equal to or greater than the reference expression level of CXCR6, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

[0197] In another aspect, the present invention provides a use of atezolizumab and / or tilagorumab in the manufacture of a pharmaceutical for treating an individual having NSCLC, wherein the individual is determined to have an expression level of one or more of ccl5, cxcr3, ccr7, and cxcr6 in a sample from an individual whose expression level is equal to or greater than a reference expression level of ccl5, cxcr3, ccr7, or cxcr6, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

[0198] In another embodiment, the present invention provides atezolizumab and / or tilagorumab for use in treating individuals having NSCLC, wherein the individual has been determined to have an expression level of one or more of ccl5, cxcr3, ccr7, and cxcr6 in a sample from an individual whose reference expression level is equal to or greater than that of ccl5, cxcr3, ccr7, or cxcr6, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

[0199] profit Individuals who benefit from treatment with atezolizumab and tilagolumab may experience, for example, delayed or prevention of the onset or recurrence of NSCLC, relief of cancer symptoms, reduction of direct or indirect pathological consequences of cancer, prevention of metastasis, slower rate of disease progression, improvement or relief of disease status, or remission or improved prognosis.

[0200] In some embodiments, the benefit achieved by treatment including atezolizumab and tilagolumab is a clinical response, e.g., a complete response (CR) or a partial response (PR) (e.g., individuals treated with this method are more likely to achieve a CR or PR, and / or the frequency of CR or PR is higher in the population of individuals treated according to this method).

[0201] In some embodiments, individuals have an expression level of one or more of CCL5, CXCR3, and CCR7 in the sample that is equal to or greater than the reference expression level of CCL5, CXCR3, or CCR7 (e.g., expression levels of one, two, or all three of CCL5, CXCR3, and CCR7), and the benefit is an increase in the overall survival (os) hazard ratio (hr) (e.g., an increase in the mean os hr of the individual population treated according to this method).

[0202] In some embodiments, individuals have an expression level of one or more of CCL5, CXCR3, and CXCR6 in a sample (e.g., an expression level of one, two, or all three of CCL5, CXCR3, and CXCR6) that is equal to or greater than the reference expression level of CCL5, CXCR3, or CXCR6, and the benefit is an increase in overall survival (OS) (e.g., an increase in the duration of OS experienced by individuals treated according to the Method or an increase in the mean OS of a population of individuals treated according to the Method).

[0203] The likelihood of clinical response, OS HR, and / or increased OS may be determined by comparison with, for example, an untreated reference individual and / or a reference population of individuals; a reference individual and / or a reference population of individuals that have received a control treatment, e.g., one or more previously approved treatments, or a commercially available product for the treatment of cancer; and / or a reference individual and / or a reference population of individuals treated with atezolizumab or tiragolumab as monotherapy. In some embodiments, the likelihood of clinical response, OS HR, and / or increased OS are determined by comparison with a reference individual and / or a reference population of individuals with cancer treated with treatments including atezolizumab and tiragolumab, where each individual in the reference individual and / or reference population has expression levels of CCL5, CXCR3, CCR7, and CXCR6 that are lower than their respective reference expression levels. The reference expression levels are described herein and may, for example, be the median expression levels of CCL5, CXCR3, CCR7, or CXCR6 in a reference population of individuals with NSCLC.

[0204] Those skilled in the art can easily determine whether a given clinical outcome is improved according to the present invention. For example, “improvement” in this context means that the clinical outcome resulting from treatment of individuals having expression levels of one or more of CCL5, CXCR3, CCR7, and CXCR6 above their respective reference expression levels with treatment comprising atezolizumab and tilagolumab is at least 3%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 100%, or at least 120% higher than the clinical outcome resulting from the comparative treatment described above.

[0205] For example, in some embodiments, the duration of OS experienced by individuals treated according to the Method, or the mean OS of a population of individuals treated according to the Method, increases by at least 3%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 100%, or at least 120%.

[0206] The time at which clinical outcomes / clinical endpoints are assessed can be easily determined by those skilled in the art. In principle, it is determined when the difference in clinical outcomes / clinical endpoints between the two treatments becomes apparent. This time could be, for example, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, or at least 48 months after the start of treatment.

[0207] Genetic signatures including B.CCL5, CXCR3, and CXCR6 A method for identifying individuals who may benefit from treatment with atezolizumab and tilagorumab. In one embodiment, the present invention provides a method for identifying individuals having nsclc that may benefit from treatment comprising atezolizumab and tilagorumab, comprising detecting the expression levels of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score equal to or greater than a reference gene signature score identifies the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

[0208] In some embodiments, the individual has a gene signature score in the sample that is equal to or greater than the reference gene signature score, and the method further comprises administering an effective dose of atezolizumab and tilagolumab (e.g., an effective dose of atezolizumab and tilagolumab as described in Section III of this Spec.)

[0209] In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, and CXCR6 in a sample from an individual.

[0210] In other embodiments, the method further includes detecting the expression level of ccr7 in a sample from an individual, and the gene signature score is the average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in a sample from an individual. Thus, in one embodiment, the present invention provides a method for identifying an individual having NSCLC that may benefit from treatment comprising atezolizumab and tilagorumab, comprising detecting the expression levels of ccl5, cxcr3, cxcr6, and ccr7 in a sample from an individual and determining a gene signature score therefrom, wherein a gene signature score greater than or equal to a reference gene signature score identifies the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

[0211] A method for identifying individuals who may benefit from treatment with atezolizumab. In another embodiment, the present invention provides a method for identifying individuals having NSCLCs (e.g., PD-L1 positive NSCLCs, e.g., NSCLCs having a PD-L1 tumor percentage score (TPS) ≥ 1% as determined using the Ventana(SP263) PD-L1 IHC assay) that may benefit from treatment including atezolizumab (e.g., atezolizumab monotherapy), comprising detecting the expression levels of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score greater than or equal to a reference gene signature score identifies the individual as one that may benefit from treatment including atezolizumab.

[0212] In some embodiments, the individual has a gene signature score in the sample that is equal to or greater than the reference gene signature score, and the method further comprises administering an effective dose of atezolizumab (e.g., an effective dose of atezolizumab as described in Section III of this specification) to the individual.

[0213] In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, and CXCR6 in a sample from an individual.

[0214] In other embodiments, the method further includes detecting the expression level of ccr7 in a sample from an individual, and the gene signature score is the average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in a sample from an individual. Thus, in one embodiment, the present invention provides a method for identifying an individual with NSCLC that may benefit from treatment including atezolizumab (e.g., atezolizumab monotherapy), comprising detecting the expression levels of ccl5, cxcr3, cxcr6, and ccr7 in a sample from an individual and determining a gene signature score therefrom, wherein a gene signature score greater than or equal to a reference gene signature score identifies the individual as one that may benefit from treatment including atezolizumab.

[0215] In some embodiments, the individual has never been treated for NSCLC before (for example, never been treated for stage IV NSCLC).

[0216] A method for selecting treatment for individuals who may benefit from treatment with atezolizumab and tilagolumab. In another aspect, the present invention provides a method for selecting a treatment for an individual having nsclc, comprising detecting the expression levels of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score greater than or equal to a reference gene signature score identifies the individual as one that may benefit from treatment comprising atezolizumab and tilagolumab.

[0217] In some embodiments, the individual has a gene signature score in the sample that is equal to or greater than the reference gene signature score, and the method further comprises administering an effective dose of atezolizumab and tilagolumab (e.g., an effective dose of atezolizumab and tilagolumab as described in Section III of this Spec.)

[0218] In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, and CXCR6 in a sample from an individual.

[0219] In other embodiments, the method further includes detecting the expression level of ccr7 in a sample from an individual, and the gene signature score is the average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in a sample from an individual. Thus, in one embodiment, the present invention provides a method for selecting a treatment for an individual having NSCLC, comprising detecting the expression levels of ccl5, cxcr3, cxcr6, and ccr7 in a sample from an individual and determining a gene signature score therefrom, wherein a gene signature score greater than or equal to a reference gene signature score identifies the individual as one that may benefit from treatment comprising atezolizumab and tilagolumab.

[0220] A method for selecting treatment for individuals who may benefit from atezolizumab treatment. In another aspect, the present invention provides a method for selecting a treatment for an individual having an NSCLC (e.g., a PD-L1 positive NSCLC, e.g., an NSCLC having a PD-L1 tumor percentage score (TPS) ≥ 1% as determined using the Ventana(SP263) PD-L1 IHC assay), comprising detecting the expression levels of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score greater than or equal to a reference gene signature score identifies the individual as one that may benefit from treatment including atezolizumab (e.g., atezolizumab monotherapy).

[0221] In some embodiments, the individual has a gene signature score in the sample that is equal to or greater than the reference gene signature score, and the method further comprises administering an effective dose of atezolizumab (e.g., an effective dose of atezolizumab as described in Section III of this specification) to the individual.

[0222] In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, and CXCR6 in a sample from an individual.

[0223] In other embodiments, the method further includes detecting the expression level of ccr7 in a sample from an individual, and the gene signature score is the average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in a sample from an individual. Thus, in one embodiment, the present invention provides a method for selecting a treatment for an individual having NSCLC, comprising detecting the expression levels of ccl5, cxcr3, cxcr6, and ccr7 in a sample from an individual and determining a gene signature score therefrom, wherein a gene signature score greater than or equal to a reference gene signature score identifies the individual as one that may benefit from treatment including atezolizumab (e.g., atezolizumab monotherapy).

[0224] In some embodiments, the individual has never been treated for NSCLC before (for example, never been treated for stage IV NSCLC).

[0225] Treatment methods including atezolizumab and tilagolumab In another aspect, the present invention provides a method for treating an individual having nsclc, comprising: (a) determining a gene signature score therefrom, which is obtained by detecting the expression levels of CCL5, CXCR3, and CXCR6 in a sample from the individual, and determining a gene signature score therefrom such that the gene signature score is greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab; and (b) administering an effective dose of atezolizumab and tilagorumab to the individual.

[0226] In another aspect, the present invention provides a method for treating an individual having nsclc, comprising administering atezolizumab and tilagorumab to the individual, wherein the individual has been determined to have a gene signature score equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab, and the gene signature score is based on the respective expression levels of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.

[0227] In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, and CXCR6 in a sample from an individual.

[0228] In other embodiments, the expression level of CCR7 is detected in a sample from an individual, and the gene signature score is the average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual. Accordingly, in one embodiment, the present invention provides a method for treating an individual having NSCLC, comprising: (a) detecting the expression levels of each of ccl5, cxcr3, cxcr6, and ccr7 in a sample from an individual and determining a gene signature score therefrom, wherein the gene signature score is greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab; and (b) administering an effective dose of atezolizumab and tilagorumab to the individual. In another aspect, the present invention provides a method for treating an individual having NSCLC, comprising administering atezolizumab and tilagorumab to the individual, wherein the individual has been determined to have a gene signature score equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab, and the gene signature score is based on the expression levels of CCL5, CXCR3, CXCR6, and CCR7, respectively, detected in a sample from the individual.

[0229] In another aspect, the present invention provides the use of atezolizumab and / or tilagorumab in the manufacture of a pharmaceutical for treating an individual having nsclc, wherein the individual has been determined to have a gene signature score greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab, the gene signature score being based on the respective expression levels of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.

[0230] In another embodiment, the present invention provides atezolizumab and / or tilagorumab for use in treating individuals having nsclc, wherein the individual has been determined to have a gene signature score greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab, and the gene signature score is based on the expression levels of CCL5, CXCR3, and CXCR6, respectively, detected in a sample from the individual.

[0231] Treatment methods including atezolizumaba In another embodiment, the present invention provides a method for treating an individual having an NSCLC (e.g., a PD-L1 positive NSCLC, e.g., an NSCLC having a PD-L1 tumor percentage score (TPS) ≥ 1% as determined using the Ventana(SP263) PD-L1 IHC assay), comprising: (a) detecting the expression levels of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein the gene signature score is greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab (e.g., atezolizumab monotherapy); and (b) administering an effective dose of atezolizumab to the individual.

[0232] In another aspect, the present invention provides a method for treating an individual having an NSCLC (e.g., a PD-L1 positive NSCLC), comprising administering atezolizumab to the individual, wherein the individual has been determined to have a gene signature score equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab (e.g., atezolizumab monotherapy), and the gene signature score is based on the respective expression levels of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.

[0233] In some embodiments, the gene signature score is the average expression level of CCL5, CXCR3, and CXCR6 in a sample from an individual.

[0234] In other embodiments, the expression level of CCR7 is detected in a sample from an individual, and the gene signature score is the average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual. Thus, in one embodiment, the present invention provides a method for treating an individual having NSCLC, comprising: (a) detecting the expression levels of each of ccl5, cxcr3, cxcr6, and ccr7 in a sample from an individual and determining a gene signature score therefrom, wherein the gene signature score is greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab (e.g., atezolizumab monotherapy); and (b) administering an effective dose of atezolizumab to the individual. In some embodiments, the present invention provides a method for treating an individual having NSCLC, comprising administering atezolizumab to the individual, wherein the individual has been determined to have a gene signature score equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab (e.g., atezolizumab monotherapy), and the gene signature score is based on the expression levels of CCL5, CXCR3, CXCR6, and CCR7, respectively, detected in a sample from the individual.

[0235] In some embodiments, the individual has never been treated for NSCLC before (for example, never been treated for stage IV NSCLC).

[0236] In another aspect, the present invention provides the use of atezolizumab in the manufacture of a pharmaceutical for treating an individual having nsclc, wherein the individual has been determined to have a gene signature score greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab, and the gene signature score is based on the respective expression levels of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.

[0237] In another embodiment, the present invention provides atezolizumab for use in treating individuals having nsclc, wherein the individual has been determined to have a gene signature score equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab, and the gene signature score is based on the respective expression levels of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.

[0238] Benefits of treatments including atezolizumab and tilagolumab In some embodiments, the benefit achieved by treatment including atezolizumab and tilagolumab is a clinical response, e.g., a complete response (CR) or a partial response (PR) (e.g., individuals treated with this method are more likely to achieve a CR or PR, and / or the frequency of CR or PR is higher in the population of individuals treated according to this method).

[0239] In some embodiments, the benefit achieved by treatments including atezolizumab and tilagormab is an increase in the overall survival (OS) hazard ratio (HR) (e.g., an increase in the mean OS HR of the population of individuals treated according to this method).

[0240] In some embodiments, the benefit achieved by treatments including atezolizumab and tilagormab is an increase in overall survival (OS) (e.g., an increase in the duration of OS experienced by individuals treated according to the method or an increase in the mean OS of a population of individuals treated according to the method).

[0241] The likelihood of clinical response, OS HR, and / or OS increase may be determined by comparison with, for example, an untreated reference individual and / or a reference population of individuals; a reference individual and / or a reference population of individuals that have received a control treatment, e.g., one or more previously approved treatments, or a commercially available product for the treatment of cancer; and / or a reference individual and / or a reference population of individuals treated with atezolizumab or tilagolumab as monotherapy. In some embodiments, the likelihood of clinical response, OS HR, and / or OS increase is determined by comparison with a reference individual and / or a reference population of individuals with cancer treated with treatments including atezolizumab and tilagolumab, each individual in the reference individual and / or reference population having a gene signature score, based on (a) the expression levels of each of CCL5, CXCR3, and CXCR6 or (b) the expression levels of each of CCL5, CXCR3, CXCR6, and CCR7 that are lower than their respective reference gene signature scores.

[0242] Those skilled in the art can easily determine whether a given clinical outcome is improved according to the present invention. For example, “improvement” in this context means that the clinical outcome resulting from treatment of an individual having a gene signature score is at least 3%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 100%, or at least 120% higher than the clinical outcome resulting from the above comparative treatment, based on the expression levels of each of ccl5, cxcr3, cxcr6, and ccr7 exceeding the respective reference expression levels from treatment comprising atezolizumab and tilagolumab.

[0243] For example, in some embodiments, the duration of OS experienced by individuals treated according to the Method, or the mean OS of a population of individuals treated according to the Method, increases by at least 3%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 100%, or at least 120%.

[0244] The time at which clinical outcomes / clinical endpoints are assessed can be easily determined by those skilled in the art. In principle, it is determined when the difference in clinical outcomes / clinical endpoints between the two treatments becomes apparent. This time could be, for example, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, or at least 48 months after the start of treatment.

[0245] Benefits of treatments including atezolizumab In some embodiments, the benefit achieved by treatment including atezolizumab (e.g., atezolizumab monotherapy) is an increase in overall survival (OS) (e.g., an increase in the duration of OS experienced by individuals treated according to the method or an increase in the mean OS of a population of individuals treated according to the method).

[0246] In some embodiments, the benefit achieved by treatment including atezolizumab (e.g., atezolizumab monotherapy) is an increase in progression-free survival (PFS) (e.g., an increase in the duration of PFS experienced by individuals treated according to this method or an increase in the mean PFS of a population of individuals treated according to this method).

[0247] Increases in OS and / or PFS may be determined by comparison with, for example, an untreated reference individual and / or a reference population of individuals; a control treatment, e.g., one or more previously approved treatments, or a commercially available product for the treatment of cancer. In some embodiments, increases in OS and / or PFS are determined by comparison with a reference individual and / or a reference population of individuals having cancer treated with a treatment including a PD-1 axis-binding antagonist (e.g., atezolizumab), where each individual in the reference individual and / or reference population has a gene signature score, based on (a) the expression levels of each of CCL5, CXCR3, and CXCR6 or (b) the expression levels of each of CCL5, CXCR3, CXCR6, and CCR7 being lower than their respective reference gene signature scores.

[0248] Those skilled in the art can easily determine whether a given clinical outcome is improved according to the present invention. For example, “improvement” in this context means that the clinical outcome resulting from treatment of an individual having a gene signature score is at least 3%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 100%, or at least 120% higher than the clinical outcome resulting from the above comparative treatment, based on the expression levels of each of ccl5, cxcr3, cxcr6, and ccr7 exceeding the respective reference expression levels from treatment comprising atezolizumab and tilagolumab.

[0249] For example, in some embodiments, the duration of OS experienced by individuals treated according to the Method, or the mean OS of a population of individuals treated according to the Method, increases by at least 3%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 100%, or at least 120%.

[0250] In some embodiments, the duration of PFS experienced by individuals treated according to the Method, or the mean PFS of a population treated according to the Method, increases by at least 3%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 100%, or at least 120%.

[0251] The time at which clinical outcomes / clinical endpoints are assessed can be easily determined by those skilled in the art. In principle, it is determined when the difference in clinical outcomes / clinical endpoints between the two treatments becomes apparent. This time could be, for example, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, or at least 48 months after the start of treatment.

[0252] C.Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic Cytotox.2, and Cytotox.4 gene signatures Methods for identifying individuals who may benefit from treatment In another embodiment, the present invention relates to a method for identifying individuals having NSCLC who may benefit from treatment comprising atezolizumab and tilagormab, (a) At least two of the following in a sample from an individual (e.g., STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X) Detect the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 of the RPS4X genes (e.g., STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and each of the RPS4X genes) and determine the Ccr7.2 gene signature score from there; (b) At least two of the following in the sample from an individual (e.g., DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB) Detect the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 of the RFLNBs (e.g., DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and each of the RFLNBs) and determine the Ccr7.3 gene signature score from there; (c) At least two of the following in a sample from an individual (e.g., CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7) To detect the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or all 19 of the GIMAP7 genes (e.g., each of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7) and determine the Cxcr3 gene signature score from there; (d) At least two of the following in the sample from an individual (e.g., CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3) Detect the expression levels of at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or all sixteen of the EL3 genes (e.g., each of CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3) and determine the Ccl5.1 gene signature score from there; (e) At least two of the following in the sample from an individual (e.g., ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1) Detect the expression levels of FI16 and all 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 of IFIH1 (for example, ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1) and determine the Ifit gene signature score from there; (f) At least two of the following in the sample from the individual (e.g., HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL (for example, HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, Detect the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or all 19 of the FTLs (e.g., each of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL) and determine the Mitotic gene signature score from there; (g) At least two of the following in a sample from an individual (e.g., HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT) Detect the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all 15 of the T genes (e.g., each of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT) and determine the Cytotox.2 gene signature score from there; or (h) At least two of the following in a sample from an individual (e.g., S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2) This includes detecting the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 of FITM2 (for example, S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and each of IFITM2) and determining the Cytotox.4 gene signature score from there; (i) A Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, or Mitotic gene signature score equal to or greater than the reference gene signature score identifies the individual as one who may benefit from treatment including atezolizumab and tilagolumab. (ii) A Cytotox.2 or Cytotox.4 gene signature score lower than the reference gene signature score provides a method for identifying an individual as potentially beneficial to treatment including atezolizumab and tilagorumab.

[0253] In some embodiments, an individual has (i) a Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, or Mitotic gene signature score in a sample that is equal to or greater than the reference gene signature score, or (ii) a Cytotox.2 or Cytotox.4 gene signature score that is lower than the reference gene signature score, and the method further comprises administering an effective dose of atezolizumab and tilagorumab (e.g., an effective dose of atezolizumab and tilagorumab as described in Section III of the present invention) to the individual.

[0254] In some embodiments, the gene signature score is the average expression level of members of the gene signature in a sample from an individual.

[0255] In some embodiments, the reference gene signature score is a pre-assigned gene signature score and / or gene signature score in a reference population (e.g., a population of individuals with NSCLC). In some embodiments, the gene signature score in the reference population is the median of the Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox.2, or Cytotox.4 gene signature scores in the reference population.

[0256] Treatment options In another aspect, the present invention relates to a method for selecting a treatment for an individual having NSCLC, (a) At least two of the following in a sample from an individual (e.g., STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X) Detect the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 of the RPS4X genes (e.g., STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and each of the RPS4X genes) and determine the Ccr7.2 gene signature score from there; (b) At least two of the following in the sample from an individual (e.g., DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB) Detect the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 of the RFLNBs (e.g., DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and each of the RFLNBs) and determine the Ccr7.3 gene signature score from there; (c) At least two of the following in a sample from an individual (e.g., CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7) To detect the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or all 19 of the GIMAP7 genes (e.g., each of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7) and determine the Cxcr3 gene signature score from there; (d) At least two of the following in the sample from an individual (e.g., CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3) Detect the expression levels of at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or all sixteen of the EL3 genes (e.g., each of CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3) and determine the Ccl5.1 gene signature score from there; (e) At least two of the following in the sample from an individual (e.g., ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1) Detect the expression levels of FI16 and all 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 of IFIH1 (for example, ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1) and determine the Ifit gene signature score from there; (f) At least two of the following in the sample from the individual (e.g., HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL (for example, HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, Detect the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or all 19 of the FTLs (e.g., each of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL) and determine the Mitotic gene signature score from there; (g) At least two of the following in a sample from an individual (e.g., HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT) Detect the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all 15 of the T genes (e.g., each of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT) and determine the Cytotox.2 gene signature score from there; or (h) At least two of the following in a sample from an individual (e.g., S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2) This includes detecting the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 of FITM2 (for example, S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and each of IFITM2) and determining the Cytotox.4 gene signature score from there; (i) A Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, or Mitotic gene signature score equal to or greater than the reference gene signature score identifies the individual as one who may benefit from treatment including atezolizumab and tilagolumab. (ii) A Cytotox.2 or Cytotox.4 gene signature score lower than the reference gene signature score provides a method for identifying an individual as potentially beneficial to treatment including atezolizumab and tilagorumab.

[0257] In some embodiments, an individual has (i) a Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, or Mitotic gene signature score in a sample that is equal to or greater than the reference gene signature score, or (ii) a Cytotox.2 or Cytotox.4 gene signature score that is lower than the reference gene signature score, and the method further comprises administering an effective dose of atezolizumab and tilagorumab (e.g., an effective dose of atezolizumab and tilagorumab as described in Section III of the present invention) to the individual.

[0258] In some embodiments, the gene signature score is the average expression level of members of the gene signature in a sample from an individual.

[0259] In some embodiments, the reference gene signature score is a pre-assigned gene signature score and / or gene signature score in a reference population (e.g., a population of individuals with NSCLC). In some embodiments, the gene signature score in the reference population is the median of the Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox.2, or Cytotox.4 gene signature scores in the reference population.

[0260] Treatment method In another aspect, the present invention relates to a method for treating an individual having NSCLC, (i) (a) At least two of the following in the sample from an individual (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 of the following STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X, Determining the expression levels of 15, 16, 17, or all 18 genes (e.g., each of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X) and thereby determining a Ccr7.2 gene signature score, wherein the gene signature score is greater than or equal to the reference gene signature score, thereby identifying the individual as one who may benefit from treatment including atezolizumab and tilagolumab; (b) At least two of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB in ​​the sample from the individual (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB, Detecting the expression levels of 15, 16, or 17 of the following genes (e.g., each of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB) and determining a Ccr7.3 gene signature score therefrom, wherein the gene signature score is greater than or equal to the reference gene signature score, thereby identifying the individual as one who may benefit from treatment including atezolizumab and tilagolumab; (c) At least two of the following in the sample from an individual (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 of the following CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7) , or all 15, 16, 17, 18, or 19 genes (e.g., each of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7), by detecting the expression levels of each gene and determining a Cxcr3 gene signature score therefrom, wherein the gene signature score is greater than or equal to a reference gene signature score, thereby identifying the individual as one who may benefit from treatment including atezolizumab and tilagolumab; (d) At least two of the following in the sample from the individual (e.g., at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen of the following CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3) Detecting the expression levels of one, fifteen, or all sixteen of the following gene signatures (e.g., each of CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3), and determining a Ccl5.1 gene signature score therefrom, wherein the gene signature score is greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab; (e) At least two of the following in the sample from an individual (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 1 ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, GBP2, IFITM3, STAT1, IFI16, and IFIH1) Detecting the expression levels of 3, 14, 15, 16, 17, 18, or 19 of the following genes (e.g., each of ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1), and determining an Ifit gene signature score therefrom, wherein the gene signature score is greater than or equal to the reference gene signature score, thereby identifying the individual as one who may benefit from treatment including atezolizumab and tilagolumab; (f) At least two of the following in the sample from an individual (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 1) HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL) Determining a Mitotic gene signature score therefrom, which involves detecting the expression levels of 5, 16, 17, 18, or 19 genes (for example, each of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL), and determining a gene signature score such that the gene signature score is greater than or equal to the reference gene signature score, thereby identifying the individual as one who may benefit from treatment including atezolizumab and tilagolumab; (g) At least two of the following in a sample from an individual (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of the following: HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT) Detecting the expression levels of each individual (e.g., HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT) and determining a Cytotox.2 gene signature score therefrom, wherein the gene signature score is lower than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab; or (h) At least two of the following in a sample from an individual (e.g., S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2) Detect the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 of IFITM2 (e.g., S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and each of IFITM2) and determine the Cytotox.4 gene signature score from there; and (ii) A method is provided which includes administering an effective dose of atezolizumab and tilagolumab to an individual.

[0261] In another embodiment, the present invention relates to a method for treating an individual having NSCLC, comprising administering atezolizumab and tilagolumab to the individual, wherein the individual is determined to have the following: (a) At least two of the following genes in a sample from an individual with a reference Ccr7.2 gene signature score or higher (e.g., STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X) Ccr7.2 gene signature score based on the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 of the following genes: DAPL1, SMC6, RFLNB, and RPS4X (e.g., STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X); (b) At least two of the following genes in a sample from an individual with a reference Ccr7.3 gene signature score or higher (e.g., DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB) 1. A gene signature score of Ccr7.3 based on the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 of the following: IZUMO1R, INPP4B, and RFLNB (e.g., each of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB); (c) At least two of the following genes in a sample from an individual having a reference Cxcr3 gene signature score or higher (e.g., CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7) 2. Cxcr3 gene signature score based on the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or all 19 of SOCS2, CD82, CD4, and GIMAP7 (e.g., each of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7); (d) At least two of the following genes in a sample from an individual having a reference Ccl5.1 gene signature score or higher (e.g., CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3) 3. Ccl5.1 gene signature score based on the expression levels of at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or all sixteen of MS4A4A, DGKA, and YPEL3 (e.g., each of CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3); (e) At least two of the following in a sample from an individual having a reference Ifit gene signature score of or higher (e.g., ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1 (e.g., ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, G Ifit gene signature score based on the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or all 19 of the following genes: BP2, IFITM3, STAT1, IFI16, and IFIH1 (e.g., ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1); (f) At least two of the following in a sample from an individual having a reference Mitotic gene signature score of or higher (e.g., HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL (e.g., HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, Mitotic gene signature score based on the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or all 19 of the following MCM3, TPI1, MCM5, DUT, and FTL (e.g., HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL); (g) At least two of the following genes in a sample from an individual with a lower Cytotox.2 gene signature score than the reference Cytotox.2 gene signature score (e.g., HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT (e.g., HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMG Cytotox.2 gene signature score based on the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all 15 of N2, TUBA1B, LY6E, and DUT (for example, each of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT); or (h) At least two of the following genes in a sample from an individual with a lower reference Cytotox.4 gene signature score (e.g., S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2) Cytotox.4 gene signature score based on the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 of the following: S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2 (each of these); This provides a method for identifying individuals who may benefit from treatment including atezolizumab and tilagormab.

[0262] In some embodiments, the gene signature score is the average expression level of members of the gene signature in a sample from an individual.

[0263] In some embodiments, the reference gene signature score is a pre-assigned gene signature score and / or gene signature score in a reference population (e.g., a population of individuals with NSCLC). In some embodiments, the gene signature score in the reference population is the median of the Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox.2, or Cytotox.4 gene signature scores in the reference population.

[0264] In another aspect, the present invention relates to the use of atezolizumab and / or tilagolumab in the manufacture of a pharmacopoeci for treating an individual having NSCLC, wherein the individual is: (i) (a) A Ccr7.2 gene signature score that is equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of each of the following detected in a sample from the individual: stat1, lef1, irgm, ccr7, sell, rps24, rps27, gbp2, rps29, rps3a, rps20, klf2, rplp1, rpl13, dapl1, smc6, rflnb, and rps4x; (b) A Ccr7.3 gene signature score that is equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of dapl1, ccr7, smc4, rgcc, mxd4, cd8a, tcf7, itgae, rgs10, znrf1, chd3, cd52, ddit4, lef1, izumo1r, inpp4b, and rflnb detected in a sample from the individual; (c) A cxcr3 gene signature score greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7 detected in a sample from the individual; (d) A ccl5.1 gene signature score that is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of each of the following genes detected in a sample from the individual: CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3; (e) an Ifit gene signature score that is equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of each of the following genes detected in a sample from the individual: isg15, ifit1b, ifit3, isg20, ifi27l2, samhd1, zbp1, slfn5, irf7, rtp4, usp18, pf11, lgals3bp, bst2, gbp2, ifitm3, stat1, ifi16, and ifih1; (f) A mitotic gene signature score that is equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL detected in a sample from the individual; (g) A cytotox.2 gene signature score lower than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT detected in a sample from the individual; or (h) Provide a use for a cytotox.4 gene signature score lower than a reference gene signature score, thereby identifying an individual as one that may benefit from treatment including atezolizumab and tilagolumab, wherein the gene signature score is determined to have a gene signature score based on the expression levels of S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2 detected in a sample from the individual.

[0265] In another embodiment, the present invention relates to atezolizumab and / or tilagorumab for use in the treatment of an individual having NSCLC, wherein the individual is: (i) (a) A Ccr7.2 gene signature score that is equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of each of the following detected in a sample from the individual: stat1, lef1, irgm, ccr7, sell, rps24, rps27, gbp2, rps29, rps3a, rps20, klf2, rplp1, rpl13, dapl1, smc6, rflnb, and rps4x; (b) A Ccr7.3 gene signature score that is equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of dapl1, ccr7, smc4, rgcc, mxd4, cd8a, tcf7, itgae, rgs10, znrf1, chd3, cd52, ddit4, lef1, izumo1r, inpp4b, and rflnb detected in a sample from the individual; (c) A cxcr3 gene signature score greater than or equal to a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7 detected in a sample from the individual; (d) A ccl5.1 gene signature score that is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of each of the following genes detected in a sample from the individual: CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3; (e) an Ifit gene signature score that is equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of each of the following genes detected in a sample from the individual: isg15, ifit1b, ifit3, isg20, ifi27l2, samhd1, zbp1, slfn5, irf7, rtp4, usp18, pf11, lgals3bp, bst2, gbp2, ifitm3, stat1, ifi16, and ifih1; (f) A mitotic gene signature score that is equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL detected in a sample from the individual; (g) A cytotox.2 gene signature score lower than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the expression levels of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT detected in a sample from the individual; or (h) Provided are atezolizumab and / or tilagorumab having a cytotox.4 gene signature score lower than a reference gene signature score, thereby identifying an individual as one that may benefit from treatment including atezolizumab and tilagorumab, wherein the gene signature score has been determined to have a gene signature score based on the expression levels of S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2 detected in a sample from the individual.

[0266] profit In some embodiments, individuals have a CCR7.3, CXCR3, or CCL5.1 gene signature score in the sample that is equal to or greater than the reference gene signature score, and the benefit achieved by treatment including atezolizumab and tilagolumab is a clinical response, e.g., a complete response (CR) or a partial response (PR) (e.g., individuals treated by this method are more likely to achieve CR or PR, and / or the frequency of CR or PR is high in the population of individuals treated according to this method).

[0267] In some embodiments, individuals have (i) a Ccr7.2, Cxcr3, Ifit, or Mitotic gene signature score in the sample that is equal to or greater than the reference gene signature score, or (ii) a cytotox.2 or cytotox.4 gene signature score that is lower than the reference gene signature score, and the benefit achieved by treatment including atezolizumab and tilagorumab is an increase in the overall survival (os) hazard ratio (hr) (e.g., an increase in the mean os hr of a population of individuals treated according to this method).

[0268] In some embodiments, individuals have a CCR7.2, CCR7.3, or Cxcr3 gene signature score in a sample that is equal to or greater than a reference gene signature score, and the benefit achieved by treatment including atezolizumab and tilagolumab is an increase in overall survival (OS) (e.g., an increase in the duration of OS experienced by individuals treated according to the Method or an increase in the mean OS of a population of individuals treated according to the Method).

[0269] The likelihood of clinical response, OS HR, and / or increased OS may be determined by comparison with, for example, untreated reference individuals and / or a reference population of individuals; reference individuals and / or a reference population of individuals who have received a control treatment, e.g., one or more previously approved treatments, or commercially available products for the treatment of cancer; and / or reference individuals and / or a reference population of individuals treated with atezolizumab or tiragolumab as monotherapy. In some embodiments, the likelihood of clinical response, OS HR, and / or increase in OS are determined by comparison with a reference individual and / or a reference population of individuals with cancer treated with treatment including atezolizumab and tilagolumab, where each individual in the reference individual and / or reference population has (i) a Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, or Mitotic gene signature score lower than the reference gene signature score, and / or (ii) a Cytotox.2 or Cytotox.4 gene signature score greater than or equal to the reference gene signature score.

[0270] Those skilled in the art can easily determine whether a given clinical outcome is improved according to the present invention. For example, “improvement” in this context means that the clinical outcome resulting from treatment of individuals having a Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, or Mitotic gene signature score equal to or greater than the reference gene signature score, and / or (ii) a Cytotox.2 or Cytotox.4 gene signature score lower than the reference gene signature score achieved by treatment comprising atezolizumab and tilagolumab, is at least 3% higher, at least 5% higher, at least 7% higher, at least 10% higher, at least 15% higher, at least 20% higher, at least 25% higher, at least 30% higher, at least 40% higher, at least 50% higher, at least 75% higher, at least 100% higher, or at least 120% higher than the clinical outcome resulting from the comparative treatment described above.

[0271] For example, in some embodiments, the duration of OS experienced by individuals treated according to the Method, or the mean OS of a population of individuals treated according to the Method, increases by at least 3%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 100%, or at least 120%.

[0272] The time at which clinical outcomes / clinical endpoints are assessed can be easily determined by those skilled in the art. In principle, it is determined when the difference in clinical outcomes / clinical endpoints between the two treatments becomes apparent. This time could be, for example, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, or at least 48 months after the start of treatment.

[0273] D. Sample, expression level, and PD-L1 status sample Expression levels of one or more of CCL5, CXCR3, CCR7, or CXCR6; one member and / or gene signature score of any of the gene signatures of Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox.2, and Cytotox.4 can be determined from any suitable sample. Exemplary sample types include, but are not limited to, tissue samples, tumor samples, blood samples (e.g., whole blood samples), plasma samples, serum samples, and combinations thereof. Samples may be fresh, stored, or frozen.

[0274] In some embodiments, the sample is a tissue sample, such as a tumor tissue sample. In some embodiments, the tumor tissue sample is a biopsy sample, such as a biopsy sample of NSCLC.

[0275] In some embodiments, the sample is a tumor drainage lymph node (dLN) sample.

[0276] In some embodiments, the sample is obtained from the individual prior to treatment with atezolizumab and tilagorumab, for example, immediately before the first dose of atezolizumab and / or tilagorumab, or at least one day, at least one week, or at least one month before the first dose of atezolizumab and / or tilagorumab.

[0277] Expression level The expression levels of one or more genes detected by the methods provided herein may be, for example, nucleic acid expression levels or protein expression levels.

[0278] In some embodiments, the expression level is the nucleic acid expression level, e.g., the mRNA expression level. The nucleic acid expression level can be detected using any suitable method known in the art, for example, by RNA-seq, reverse transcriptase quantitative PCR (RT-qPCR), quantitative PCR (qPCR), real-time PCR, quantitative real-time PCR (qRT-PCR), multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, in situ hybridization (ISH), or a combination thereof. 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, e.g., bDNA.

[0279] In some cases, the nucleic acid expression levels of the genes described herein may be measured by sequencing-based techniques such as RNA-seq, gene expression linkage analysis (SAGE), high-throughput sequencing techniques (e.g., large-scale parallel sequencing), and Sequenom MassARRAY®. Nucleic acid expression levels may also be measured by, for example, NanoString nCounter and high-coverage expression profiling (HiCEP). Additional protocols for evaluating the state of genes and gene products can be found, for example, in Part 2 (Northern blotting), Part 4 (Southern blotting), Part 15 (Immunoblotting), and Part 18 (PCR analysis) of Ausubel et al., eds., 1995, Current Protocols In Molecular Biology.

[0280] Other methods for detecting the nucleic acid level of genes described herein include protocols for examining or detecting mRNA, such as target mRNA, in tissue or cell samples using microarray technology.

[0281] Other methods for detecting the nucleic acid expression levels of genes described herein include electrophoresis, Northern blotting and Southern blotting, in situ hybridization (e.g., single or multiple nucleic acid in situ hybridization), RNAse protection assays, and microarrays (e.g., Illumina BEADARRAY® technology; bead arrays for detecting gene expression (BADGE)).

[0282] In some embodiments, the expression level is the protein expression level, for example, the protein expression level determined by mass spectrometry, Western blotting, ELISA, immunoprecipitation, immunohistochemistry, immunofluorescence, radioimmunoassay, dot blotting, immunodetection, surface plasmon resonance, optical spectroscopy, mass spectrometry, or HPLC.

[0283] Normalization of expression levels In some embodiments, the expression levels of one or more genes detected in the methods provided herein are normalized expression levels, for example, the gene signature score is the average of the normalized expression levels of one or more genes in a sample from an individual.

[0284] The detected gene expression levels can be normalized using one of the standard normalization methods known in the art. Those skilled in the art will understand that the normalization method used may depend on the gene expression methodology used (for example, one or more housekeeping genes may be used for normalization from the perspective of the RT-qPCR methodology, while the whole genome or substantially the whole genome may be used as the normalization baseline from the perspective of the RNA-seq methodology). For example, the detected expression levels of each assayed gene can be normalized for differences in the quantity of assayed genes, variability in the quality of the samples used, and / or variability between assay runs.

[0285] In some cases, normalization can be achieved by detecting the expression of one or more specific normalization genes, including reference genes (e.g., housekeeping genes (e.g., β-actin)). For example, in some cases, nucleic acid expression levels detected using the methods described herein (e.g., for at least one of the genes described herein) can be normalized to the expression levels of one or more reference genes (e.g., one, two, three, four, five, six, seven, eight, nine or more reference genes, e.g., housekeeping genes (e.g., β-actin)). Alternatively, normalization can be performed based on the mean or median of the signals of all assayed genes. For each gene, the measured amount of normalized mRNA can be compared to the amount found at the reference expression level. The measured presence and / or expression level / amount in a particular sample of interest being analyzed is expressed at a percentile within this range, which can be determined by methods well known in the art.

[0286] In other cases, the detected expression levels of each assayed gene are not normalized in order to determine the expression level.

[0287] The expression level of each gene can be determined using any statistical approach known in the art. For example, the expression level may reflect the median expression level, the median normalized expression level, or the mean expression level, or the mean normalized expression level.

[0288] Reference expression level and gene signature score The terms “reference expression level” and “reference gene signature score” refer to an expression level or gene signature score that is compared to another expression level or gene signature score, for example, to make decisions regarding diagnosis, prediction, prognosis, and / or treatment.

[0289] In some embodiments, the reference expression level or reference gene signature score is a pre-assigned reference expression level or reference gene signature score.

[0290] In some embodiments, the reference expression level or reference gene signature score is the expression level or gene signature score in a reference population (e.g., a population of individuals with NSCLC).

[0291] In some embodiments, the expression level or gene signature score in the reference population is the median of the expression levels or gene signature scores of the reference population.

[0292] In other embodiments, the expression level or gene signature score in the reference population is the average expression level or gene signature score of the reference population.

[0293] In still other embodiments, the expression level or gene signature score is the 25 th percentile, 26 th percentile, 27 th percentile, 28 th percentile, 29 th percentile, 30 th percentile, 31 st percentile, 32 nd percentile, 33 rd percentile, 34 th percentile, 35 th percentile, 36 th percentile, 37 th percentile, 38 th percentile, 39 th percentile, 40 th percentile, 41 st percentile, 42 nd percentile, 43 rd percentile, 44 th percentile, 45 th percentile, 46 th percentile, 47 th percentile, 48 th percentile, 49th Percentile, 50 th Percentile, 51 st Percentile, 52 nd Percentile, 53 rd Percentile, 54 th Percentile, 55 th Percentile, 56 th Percentile, 57 th Percentile, 58 th Percentile, 59 th Percentile, 60 th Percentile, 61 st Percentile, 62 nd Percentile, 63 rd Percentile, 64 th Percentile, 65 th Percentile, 66 th Percentile, 67 th Percentile, 68 th Percentile, 69 th Percentile, 70 th Percentile, 71 st Percentile, 72 nd Percentile, 73 rd Percentile, 74 th Percentile, 75 th Percentile, 76 th Percentile, 77 th Percentile, 78 th Percentile, 79 th Percentile, 80 th Percentile, 81 st Percentile, 82 nd Percentile, 83 rd Percentile, 84 th Percentile, 85 th Percentile, 86 th Percentile, 87 th Percentile, 88 th Percentile, 89 th Percentile, 90 th Percentile, 91 st Percentile, 92 ndPercentile, 93 rd Percentile, 94 th Percentile, 95 th Percentile, 96 th Percentile, 97 th Percentile, 98 th Percentile, or 99th percentile th It is defined as a percentile.

[0294] In some cases, the reference expression level or reference gene signature score is a cutoff value that significantly separates a first and second subset of individuals treated with atezolizumab and tilagolumab within the same reference population, based on a significant difference between the responsiveness of individuals to atezolizumab and tilagolumab treatment above or below the cutoff value. In some embodiments, the responsiveness of individuals to atezolizumab and tilagolumab treatment is significantly improved compared to the responsiveness of individuals to atezolizumab and tilagolumab treatment above the cutoff value.

[0295] In some cases, the reference expression level or reference gene signature score is a cutoff value that significantly separates a first and second subset of individuals treated with atezolizumab (e.g., atezolizumab monotherapy) in the same reference population, based on a significant difference between the response of individuals to atezolizumab treatment above or below the cutoff value. In some embodiments, the response of individuals to atezolizumab treatment is significantly improved compared to the response of individuals to atezolizumab treatment above the cutoff value.

[0296] PD-L1 status In some embodiments, the expression level of PD-L1 is assessed in samples from subjects described herein. In some embodiments, the samples are determined to have a PD-L1-positive tumor cell fraction (e.g., by immunohistochemistry (IHC) assay, for example, by positive staining with an anti-PD-L1 antibody (the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8)).

[0297] Exemplary methods for assessing PD-L1 expression levels are provided in Section II(F).

[0298] E.TIGIT expression assessment In some embodiments, TIGIT expression is assessed in the individuals described herein. Methods provided herein may include determining the level of TIGIT expression in biological samples (e.g., tumor samples) obtained from individuals. In other examples, the level of TIGIT expression in biological samples (e.g., tumor samples) obtained from individuals is determined before or after the commencement of treatment. TIGIT expression can be determined using any suitable method. Any suitable tumor sample, such as formalin-fixed paraffin-embedded (FFPE) tumor samples, stored tumor samples, fresh tumor samples, or frozen tumor samples, may be used.

[0299] For example, TIGIT expression can be determined as the percentage of tumor-infiltrating immune cells in a tumor sample expressing a detectable level of TIGIT, and / or as the percentage of tumor cells in a tumor sample expressing a detectable level of TIGIT, with respect to the percentage of tumor-infiltrating immune cells in the tumor sample expressing a detectable level of TIGIT. In any of the above examples, it should be understood that the percentage of tumor sample composed of tumor-infiltrating immune cells may be, for example, the percentage of tumor area covered by tumor-infiltrating immune cells in a section of tumor sample obtained from an individual, when assessed by IHC using an anti-TIGIT antibody. Any suitable anti-TIGIT antibody may be used. In some examples, the anti-TIGIT antibody is 10A7 (International Publication No. 2009 / 126688A3; U.S. Patent No. 9,499,596). In other examples, the anti-TIGIT antibody is the anti-human TIGIT rabbit monoclonal antibody clone SP410 (Roche Tissue Diagnostics, Pleasanton, CA). In some embodiments, the anti-TIGIT antibody (e.g., SP410) is detected using the VENTANA OptiView DAB IHC detection kit on the automated VENTANA BenchMark ULTRA platform.

[0300] F. PD-L1 expression assessment In some embodiments, PD-L1 expression is assessed in the individuals described herein. Methods provided herein may include determining the expression level of PD-L1 in biological samples (e.g., tumor samples) obtained from individuals. In other examples, the expression level of PD-L1 in biological samples (e.g., tumor samples) obtained from individuals is determined before or after the initiation of treatment. PD-L1 expression may be determined using any suitable approach. For example, PD-L1 expression may be determined as described in U.S. Patent Application Publication No. 20180030138A1 and U.S. Patent Application Publication No. 20180037655A1. Any suitable tumor sample, such as formalin-fixed paraffin-embedded (FFPE) tumor samples, stored tumor samples, fresh tumor samples, or frozen tumor samples may be used.

[0301] For example, PD-L1 expression can be determined as the percentage of tumor-infiltrating immune cells in a tumor sample expressing a detectable level of PD-L1, and / or as the percentage of tumor cells in a tumor sample expressing a detectable level of PD-L1, with respect to the percentage of tumor-infiltrating immune cells in the tumor sample expressing a detectable level of PD-L1. In any of the above examples, it should be understood that the percentage of tumor sample composed of tumor-infiltrating immune cells may be related to the percentage of tumor area covered by tumor-infiltrating immune cells in a section of tumor sample obtained from an individual (e.g., as assessed by IHC using an anti-PD-L1 antibody (e.g., SP142 antibody)). For example, any suitable anti-PD-L1 antibody may be used, including SP142 (Ventana), SP263 (Ventana), 22C3 (Dako), 28-8 (Dako), E1L3N (Cell Signaling Technology), 4059 (ProSci, Inc.), h5H1 (Advanced Cell Diagnostics), and 9A11. In some examples, the anti-PD-L1 antibody is SP142. In other examples, the anti-PD-L1 antibody is SP263. In some examples, the anti-PD-L1 antibody is 22C3. In some examples, the anti-PD-L1 antibody is 28-8.

[0302] In some cases, tumor samples obtained from individuals have detectable PD-L1 expression levels in less than 1% of tumor cells, more than 1% of tumor cells, 1% to less than 5% of tumor cells, more than 5% of tumor cells, 5% to less than 50% of tumor cells, or more than 50% of tumor cells.

[0303] In some cases, tumor samples obtained from individuals have detectable PD-L1 expression levels in tumor-infiltrating immune cells that constitute less than 1% of the tumor sample, more than 1% of the tumor sample, 1% to less than 5% of the tumor sample, more than 5% of the tumor sample, 5% to less than 10% of the tumor sample, or more than 10% of the tumor sample.

[0304] In some embodiments, tumor samples obtained from an individual have a detectable PD-L1 expression level in tumor-infiltrating immune cells constituting 5% to 19% (e.g., 5% to 19% TIC) of the tumor sample, for example, a low PD-L1 expression level. In some embodiments, tumor samples obtained from an individual have a detectable PD-L1 expression level in tumor-infiltrating immune cells constituting ≥20% (e.g., ≥20% TIC) of the tumor sample, for example, a high PD-L1 expression level. In some embodiments, tumor samples determined to have 5% or more TIC are equivalent to 1 or more CPS.

[0305] In some cases, tumor specimens may be scored for PD-L1 positivity in tumor-infiltrating immune cells and / or tumor cells, according to the diagnostic assessment criteria shown in Table 1 and / or Table 2, respectively. [Table 1] [Table 2]

[0306] In some cases, in any of the methods, uses, or compositions for use described herein, the individual has a PD-L1 selective tumor (for example, the percentage of tumor area occupied by PD-L1-expressing tumor-infiltrating immune cells (ICs) is 5% or more in the tumor sample, as determined by IHC using SP142 antibody). In some cases, a PD-L1 selective tumor is a tumor determined by an immunohistochemistry (IHC) assay to have a percentage of tumor area occupied by PD-L1-expressing immune cells (ICs) of 5% or more. In some cases, the IHC assay uses anti-PD-L1 antibodies SP142, SP263, 22C3, or 28-8. In some cases, the IHC assay uses anti-PD-L1 antibody SP142. In some cases, the IHC assay uses anti-PD-L1 antibody SP263. In some cases, the IHC assay uses anti-PD-L1 antibody 22C3. In some cases, the IHC assay uses anti-PD-L1 antibody 22C3. In some cases, the IHC assay uses the anti-PD-L1 antibody 28-8.

[0307] In some cases, the IC score was determined to be 5% or higher (for example, when determined using the Ventana(SP142)PD-L1 IHC assay). In some cases, the IC score was determined to be 2 or 3 (for example, when determined using the Ventana(SP142)PD-L1 IHC assay). In some cases, the IC score was determined to be 1% or higher (for example, when determined using the Ventana(SP142)PD-L1 IHC assay). In some cases, the IC score was determined to be 10% or higher (for example, when determined using the Ventana(SP142)PD-L1 IHC assay). In some cases, the IC score was determined to be between 1% and less than 50% (for example, when determined using the Ventana(SP142)PD-L1 IHC assay). In some cases, the IC score was determined to be between 1% and less than 30% (for example, when determined using the Ventana(SP142)PD-L1 IHC assay).

[0308] In some cases, tumor samples obtained from an individual using any of the methods, uses, or compositions for use described herein have a detectable level of PD-L1 protein expression. In some cases, the detectable level of PD-L1 protein expression is determined by an IHC assay. In some cases, the IHC assay uses the anti-PD-L1 antibody SP142. In some cases, it has been determined that tumor samples have a detectable level of PD-L1 expression in tumor-infiltrating immune cells constituting 5% or more of the tumor sample. In some cases, it has been determined that tumor samples have a detectable level of PD-L1 expression in tumor-infiltrating immune cells constituting 1% or more of the tumor sample. In some cases, it has been determined that tumor samples have a detectable level of PD-L1 expression in tumor-infiltrating immune cells constituting 1% or more but less than 5% of the tumor sample. In some cases, it has been determined that tumor samples have a detectable level of PD-L1 expression in tumor-infiltrating immune cells constituting 5% or more but less than 10% of the tumor sample. In some cases, tumor samples have been found to have detectable levels of PD-L1 expression in tumor-infiltrating immune cells constituting more than 10% of the tumor sample. In some cases, tumor samples have been found to have detectable levels of PD-L1 expression in more than 1% of tumor cells in the sample. In some cases, tumor samples have been found to have detectable levels of PD-L1 expression in more than 1% but less than 5% of tumor cells in the sample. In some cases, tumor samples have been found to have detectable levels of PD-L1 expression in more than 5% but less than 50% of tumor cells in the sample. In some cases, tumor samples have been found to have detectable levels of PD-L1 expression in more than 50% of tumor cells in the sample.

[0309] In some cases, in any of the methods, uses, or compositions for use described herein, an individual has a PD-L1 selective tumor (e.g., a PD-L1 "high" selective tumor (e.g., a PD-L1 tumor percentage score (TPS) of 50% or more in a tumor sample, as determined by IHC using SP263 antibody)). In some cases, a PD-L1 selective tumor is a PD-L1 "high" selective tumor. In some cases, a PD-L1 selective tumor is a PD-L1 tumor with a PD-L1 tumor percentage score of 50% or more as determined by immunohistochemistry (IHC) assay. This is a tumor determined to have S. In some cases, the IHC assay uses anti-PD-L1 antibodies SP263, SP142, 22C3, or 28-8. In some cases, the IHC assay uses anti-PD-L1 antibody SP263. In some cases, the IHC assay uses anti-PD-L1 antibody SP142. In some cases, the IHC assay uses anti-PD-L1 antibody 22C3. In some cases, TPS is used (e.g., Ventana(SP263)PD-L1 In some cases, TPS has been determined to be 50% or higher (when determined using an IHC assay). In some cases, TPS has been determined to be less than 50% (for example, when determined using a Ventana(SP263)PD-L1 IHC assay). In some cases, TPS has been determined to be 1% or higher (for example, when determined using a Ventana(SP263)PD-L1 IHC assay). In some cases, TPS has been determined to be between 1% and 50% (for example, when determined using a Ventana(SP263)PD-L1 IHC assay).

[0310] In some cases, tumor samples obtained from an individual using any of the methods, uses, or compositions for use described herein have a detectable level of PD-L1 protein expression. In some cases, the detectable level of PD-L1 protein expression is determined by an IHC assay. In some cases, the IHC assay uses the anti-PD-L1 antibody SP263. In some cases, the tumor sample is determined to have a PD-L1-positive tumor cell fraction of 50% or more of the tumor sample. In some cases, the tumor sample is determined to have a PD-L1-positive tumor cell fraction of less than 50% of the tumor sample. In some cases, the tumor sample is determined to have a PD-L1-positive tumor cell fraction of 1% or more but less than 50% of the tumor sample.

[0311] In some cases, the IHC assay uses the anti-PD-L1 antibody 22C3. In some cases, the IHC assay is the pharmDx 22C3 IHC assay. In some cases, the PD-L1-positive tumor cell fraction is 50% or more, as determined by positive staining with the anti-PD-L1 antibody 22C3. In some embodiments, the tumor sample is determined to have a composite positive score (cps) of 10 or more or a tumor percentage score (TPS) of 1% or more, as determined using the anti-PD-L1 antibody 22C3 as part of the pharmdx 22C3 IHC assay. In some embodiments, the tumor sample is determined to have a composite positive score (cps) of 10 or more or a TPS of 1% or more but less than 50%, as determined using the anti-PD-L1 antibody 22C3 as part of the pharmDx 22C3 IHC assay. In some embodiments, when a tumor sample is determined using the anti-PD-L1 antibody 22C3 as part of, for example, the pharmDx 22C3 IHC assay, it is determined that the tumor sample has 20 or more CPS or 50% or more TPS. In some embodiments, a tumor sample determined to have 1 or more CPS is equivalent to 5% or more TIC.

[0312] In some cases, the IHC assay uses the anti-PD-L1 antibody 28-8. In some cases, the IHC assay is the pharmDx 28-8 IHC assay. In some cases, the PD-L1-positive tumor cell fraction is greater than 50% when determined by positive staining with the anti-PD-L1 antibody 28-8.

[0313] In some cases, tumor samples obtained from an individual using any of the methods, uses, or compositions for use described herein have a detectable level of PD-L1 nucleic acid expression. In some cases, the detectable level of PD-L1 nucleic acid expression is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof. In some cases, the sample is selected from the group consisting of tissue samples, whole blood samples, serum samples, and plasma samples. In some cases, the tissue sample is a tumor sample. In some cases, the tumor sample includes tumor-infiltrating immune cells, tumor cells, stromal cells, and any combination thereof.

[0314] III. Tiragolumab and atezolizumab Tiragolumab (an anti-TIGIT antagonist antibody) and atezolizumab (an anti-PD-L1 antibody), useful for treating individuals (e.g., humans) with non-small cell lung cancer (NSCLC), according to the methods, uses, and compositions for use of the present invention, are described herein.

[0315] A. Tiragolumab Tiragolumab (CAS Registry Number: 1918185-84-8) is a fully human IgG1 / kappa mAb that binds to TIGIT and contains the heavy chain sequence of SEQ ID NO: 4 and the light chain sequence of SEQ ID NO: 5. Tiragolumab contains two N-linked glycosylation sites (N306) in its Fc domain. Tiragolumab is listed in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 117, Vol. 31, No. 2 (published June 9, 2017) (see page 343).

[0316] Tiragolumab (Genentech) is also known as MTIG7192A, RG6058, or RO7092284. Tiragolumab is published in International Publication No. 2003072305A8, International Publication No. 2004024068A3, International Publication No. 2004024072A3, International Publication No. 2009126688A2, International Publication No. 2015009856A2, International Publication No. 2016011264A1, International Publication No. 2016109546A2, International Publication No. 2017053748A2 and International Publication No. 2019165434A1; U.S. Patent Application Publication No. 2017 / 0044256, 2017 / 00 U.S. Patent Nos. 37127, 2017 / 0145093, 2017 / 260594, 2017 / 0088613, 2018 / 0186875, 2019 / 0119376; and as described in U.S. Patent Nos. 9873740B2, 10626174B2, 10611836B2, 9499596B2, 8431350B2, 10047158B2, and 10017572B2.

[0317] B. Atezolizumab Atezolizumab is an anti-PD-L1 antagonist monoclonal antibody (mAb) with International Name of Drug (INN) List 112 (WHO Drug Information, Vol.28.No.4, 2014, p.488) or CAS Registry Number 1380723-44-3.

[0318] C. Delivery method The compositions used in the methods described herein (e.g., tiragolumab and atezolizumab) may be administered by any preferred method, such as intravenously, intramuscularly, subcutaneously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumorally, intraperitoneally, subconjunctivally, intravesicularly, intramucosa, intrapericardially, intraumbilically, intraorbitally, orally, orally, topically, percutaneously, intravitreally (e.g., by intravitreal injection), by eye drops, by inhalation, by injection, by implantation, by infusion, by continuous infusion, by local perfusion directly immersing target cells, by catheter, by lavage, in a cream, or in a lipid composition. The compositions used in the methods described herein may also be administered systemically or topically. The method of administration may vary depending on various factors (e.g., the compound or composition being administered, and the severity of the symptom, disease, or disorder being treated). In some embodiments, tiragolumab and / or atezolizumab may be administered intravenously, intramuscularly, subcutaneously, topically, orally, percutaneously, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. Dosage may be by any preferred route, e.g., by injection, such as intravenous or subcutaneous injection, depending in part whether the administration is short-term or long-term. Various dosing schedules, including but not limited to single doses, multiple doses over various time points, bolus doses, and pulse infusions, are contemplated herein.

[0319] Tiragolumab and / or atezolizumab (and any additional therapeutic agents) may be formulated, administered, and given in a manner consistent with good medical practice. Factors to consider in this regard include the specific disorder being treated, the specific mammal being treated, the individual patient's clinical symptoms, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to the healthcare professional. Tiragolumab and / or atezolizumab may, optionally but not required, be formulated and / or administered concurrently with one or more agents currently used to prevent or treat the disorder in question, e.g., one or more agents described herein. The effective dose of such other agents depends on the amount of tiragolumab or atezolizumab present in the formulation, the type of disorder or treatment, and the other factors mentioned above. These are generally used in the same doses and routes of administration as described herein, or in approximately 1% to 99% of the doses described herein, or in any dose, by any route empirically / clinically determined to be appropriate.

[0320] For the treatment of NSCLC, the appropriate dose of tiragolumab and atezolizumab, or any combination thereof, as described herein (when used alone or in combination with one or more other additional therapeutic agents) depends on the type of disease being treated, the severity and course of the disease, whether tiragolumab and / or atezolizumab are administered for prophylactic or therapeutic purposes, previous treatments, the patient's medical history and response to tiragolumab and / or atezolizumab, and the discretion of the attending physician. Tiragolumab and / or atezolizumab are administered appropriately to the patient, either as a single dose or over a series of treatments. A typical daily dose may range from approximately 1 μg / kg to 100 mg / kg or more, depending on the factors mentioned above. In repeated administrations over several days or more, treatment is usually continued, depending on the symptoms, until the desired suppression of disease symptoms occurs. Such doses may be administered intermittently, for example, weekly or every three weeks (for example, so that the patient receives approximately 2 to 20 doses, or approximately 6 doses, of tiragolumab and / or atezolizumab). A higher initial loading dose may be administered, followed by one or more lower doses. However, other dosage regimens may also be useful. The progress of this treatment is readily monitored by conventional techniques and assays.

[0321] D. Medication i. Administration of tilagolumab As a general suggestion, the therapeutically effective dose of tiragolumab administered to humans would be in the range of approximately 0.01 to approximately 50 mg / kg (patient weight), whether administered in one or more doses. In some embodiments, the therapeutically effective dose of tiragolumab administered to humans is in the range of 0.01 to 50 mg / kg (patient weight), whether administered in one or more doses.

[0322] In some exemplary embodiments, tiragolumab is administered in doses of approximately 0.01 to 45 mg / kg, approximately 0.01 to 40 mg / kg, approximately 0.01 to 35 mg / kg, approximately 0.01 to 30 mg / kg, approximately 0.01 to 25 mg / kg, approximately 0.01 to 20 mg / kg, approximately 0.01 to 15 mg / kg, approximately 0.01 to 10 mg / kg, approximately 0.01 to 5 mg / kg, or approximately 0.01 to 1 mg / kg, for example, daily, weekly, every two weeks, every three weeks, or every four weeks. In exemplary embodiments, tiragolumab is administered in doses of 0.01–45 mg / kg, 0.01–40 mg / kg, 0.01–35 mg / kg, 0.01–30 mg / kg, 0.01–25 mg / kg, 0.01–20 mg / kg, 0.01–15 mg / kg, 0.01–10 mg / kg, 0.01–5 mg / kg, or 0.01–1 mg / kg, for example, daily, weekly, every two weeks, every three weeks, or every four weeks.

[0323] In some cases, tiragolumab is administered around day 1 of the medication cycle (e.g., day -3, day -2, day -1, day 1, day 2, or day 3).

[0324] In some cases, tiragolumab is administered in a stepwise dosing regimen (e.g., based on the subject's body weight (BW) or body surface area (BSA)) (e.g., every three weeks). Such dosing regimens can be used to treat subjects with relatively low body weight (e.g., 40 kg or less (e.g., 5 kg–40 kg, 15 kg–40 kg, or 5 kg–15 kg)) and have been developed through biosimulation studies based on extrapolation of pharmacokinetic parameters estimated from adult data.

[0325] In some cases, the effective dose of tiragolumab to treat a patient with cancer is a graded dose based on the patient's weight. In some cases, the effective dose of tiragolumab is a graded dose based on the patient's weight, such as (a) if the patient weighs 15 kg or less, tiragolumab is administered in doses between approximately 10 mg and approximately 1000 mg every three weeks (e.g., approximately 300 mg every three weeks); (b) if the patient weighs more than 15 kg but 40 kg or less, tiragolumab is administered in doses between approximately 10 mg and approximately 1000 mg every three weeks (e.g., approximately 400 mg every three weeks); or (c) if the patient weighs more than 40 kg, tiragolumab is administered in doses between approximately 30 mg and approximately 1200 mg every three weeks (e.g., approximately 600 mg every three weeks). In some cases, the effective dose of tiragolumab is a stepwise dose based on the patient's body weight, where (a) if the patient weighs 15 kg or less, tiragolumab is administered in doses between approximately 250 mg and approximately 350 mg every three weeks (e.g., approximately 300 mg every three weeks); (b) if the patient weighs more than 15 kg but 40 kg or less, tiragolumab is administered in doses between approximately 350 mg and approximately 450 mg every three weeks (e.g., approximately 400 mg every three weeks); or (c) if the patient weighs more than 40 kg, tiragolumab is administered in doses between approximately 550 mg and approximately 650 mg every three weeks (e.g., approximately 600 mg every three weeks). In some cases, the effective dose of tiragolumab is a graded dose based on the patient's body weight, such as (a) if the patient weighs 15 kg or less, tiragolumab is administered at a dose of approximately 300 mg every three weeks; (b) if the patient weighs between 15 kg and 40 kg, tiragolumab is administered at a dose of approximately 400 mg every three weeks; or (c) if the patient weighs more than 40 kg, tiragolumab is administered at a dose of approximately 600 mg every three weeks.In some cases, the effective dose of tiragolumab is a stepwise dose based on the patient's body weight, where (a) if the patient weighs 15 kg or less, tiragolumab is administered in doses between 10 mg and 1000 mg every three weeks (e.g., 300 mg every three weeks); (b) if the patient weighs more than 15 kg but 40 kg or less, tiragolumab is administered in doses between 10 mg and 1000 mg every three weeks (e.g., 400 mg every three weeks); or (c) if the patient weighs more than 40 kg, tiragolumab is administered in doses between 30 mg and 1200 mg every three weeks (e.g., 600 mg every three weeks). In some cases, the effective dose of tiragolumab is a stepwise dose based on the patient's body weight, where (a) if the patient weighs 15 kg or less, tiragolumab is administered at a dose between 250 mg and 350 mg every three weeks (e.g., 300 mg every three weeks); (b) if the patient weighs more than 15 kg but 40 kg or less, tiragolumab is administered at a dose between 350 mg and 450 mg every three weeks (e.g., 400 mg every three weeks); or (c) if the patient weighs more than 40 kg, tiragolumab is administered at a dose between 550 mg and 650 mg every three weeks (e.g., 600 mg every three weeks). In some cases, the effective dose of tilagolumab is a graded dose based on the patient's body weight, such as (a) if the patient weighs 15 kg or less, tilagolumab is administered at a dose of 300 mg every three weeks; (b) if the patient weighs between 15 kg and 40 kg, tilagolumab is administered at a dose of 400 mg every three weeks; or (c) if the patient weighs more than 40 kg, tilagolumab is administered at a dose of 600 mg every three weeks.

[0326] In some cases, the effective dose of tiragolumab for patients weighing over 40 kg (e.g., 40.5 kg, 41 kg, 42 kg, 43 kg, 44 kg, 45 kg, 46 kg, 47 kg, 48 kg, 49 kg, 50 kg, 51 kg, 52 kg, 53 kg, 54 kg, 55 kg, 56 kg, 57 kg, 58 kg, 59 kg, 60 kg, 61 kg, 62 kg, 63 kg, 64 kg, 65 kg, 66 kg, 67 kg, 68 kg, 69 kg, 70 kg, 75 kg, 80 kg, 85 kg, 90 kg, 95 kg, 100 kg, 110 kg, 120 kg, 130 kg, 140 kg, 150 kg or more) is between approximately 30 mg and approximately 1200 mg every three weeks (Q3W) (e.g. For example, the dosage is between approximately 30 mg and approximately 1100 mg, between approximately 60 mg and approximately 1000 mg, between approximately 100 mg and approximately 900 mg, between approximately 200 mg and approximately 800 mg, between approximately 300 mg and approximately 800 mg, between approximately 400 mg and approximately 800 mg, between approximately 400 mg and approximately 750 mg, between approximately 450 mg and approximately 750 mg, between approximately 500 mg and approximately 700 mg, between approximately 550 mg and approximately 650 mg, for example, 600 mg ± 10 mg, for example, 600 ± 6 mg, for example, 600 ± 5 mg, for example, 600 ± 3 mg, for example, 600 ± 1 mg, for example, 600 ± 0.5 mg, for example, 600 mg). In some cases, the effective dose of tiragolumab is approximately 600 mg every three weeks for subjects weighing more than 40 kg.In some cases, the effective dose of tiragolumab for patients weighing over 40 kg (e.g., 40.5 kg, 41 kg, 42 kg, 43 kg, 44 kg, 45 kg, 46 kg, 47 kg, 48 kg, 49 kg, 50 kg, 51 kg, 52 kg, 53 kg, 54 kg, 55 kg, 56 kg, 57 kg, 58 kg, 59 kg, 60 kg, 61 kg, 62 kg, 63 kg, 64 kg, 65 kg, 66 kg, 67 kg, 68 kg, 69 kg, 70 kg, 75 kg, 80 kg, 85 kg, 90 kg, 95 kg, 100 kg, 110 kg, 120 kg, 130 kg, 140 kg, 150 kg or more) was 30 mg every three weeks (Q3W) plus 1 The effective dose is between 200 mg (for example, between 30 mg and 1100 mg, between 60 mg and 1000 mg, between 100 mg and 900 mg, between 200 mg and 800 mg, between 300 mg and 800 mg, between 400 mg and 800 mg, between 400 mg and 750 mg, between 450 mg and 750 mg, between 500 mg and 700 mg, between 550 mg and 650 mg, for example, 600 mg ± 10 mg, for example, 600 ± 6 mg, for example, 600 ± 5 mg, for example, 600 ± 3 mg, for example, 600 ± 1 mg, for example, 600 ± 0.5 mg, for example, 600 mg). In some cases, the effective dose of tiragolumab for subjects weighing more than 40 kg is 600 mg every three weeks.

[0327] In some cases, the effective dose of tilagolumab is for patients weighing more than 15 kg but less than or equal to 40 kg (for example, 15.1 kg, 15.2 kg, 15.3 kg, 15.4 kg, 15.5 kg, 16 kg, 17 kg, 18 kg, 19 kg, 20 kg, 21 kg, 22 kg, 23 kg, 24 kg, 25 kg, 26 kg, 27 kg, 28 kg, 29 kg, 30 kg, 31 kg, 32 kg, 33 kg, 34 kg, 35 kg, 36 kg, 37 kg, 38 kg, 39 kg, or 39.5 kg). For subjects weighing (kg), the dosage is between approximately 10 mg and approximately 1000 mg every three weeks (Q3W) (for example, between approximately 20 mg and approximately 1000 mg, between approximately 50 mg and approximately 900 mg, between approximately 100 mg and approximately 850 mg, between approximately 200 mg and approximately 700 mg, between approximately 250 mg and approximately 600 mg, between approximately 300 mg and approximately 500 mg, between approximately 350 mg and approximately 450 mg, between approximately 390 mg and approximately 410 mg, or approximately 400 mg). In some cases, the effective dose of tiragolumab for subjects weighing more than 15 kg but less than or equal to 40 kg is approximately 400 mg every three weeks (for example, 400 mg ± 10 mg, 400 ± 6 mg, 400 ± 5 mg, 400 ± 3 mg, 400 ± 1 mg, 400 ± 0.5 mg, or 400 mg every three weeks). In some cases, the effective dose of tiragolumab is found to be between 15 kg and 40 kg of body weight (for example, 15.1 kg, 15.2 kg, 15.3 kg, 15.4 kg, 15.5 kg, 16 kg, 17 kg, 18 kg, 19 kg, 20 kg, 21 kg, 22 kg, 23 kg, 24 kg, 25 kg, 26 kg, 27 kg, 28 kg, 29 kg, 30 kg, 31 kg, 32 kg, 33 kg, 34 kg, 35 kg, 36 kg, 37 kg, 38 kg, 39 kg). For subjects weighing 39.5 kg or less, the dosage is between 10 mg and 1000 mg every three weeks (Q3W) (for example, between 20 mg and 1000 mg, between 50 mg and 900 mg, between 100 mg and 850 mg, between 200 mg and 700 mg, between 250 mg and 600 mg, between 300 mg and 500 mg, between 350 mg and 450 mg, between 390 mg and 410 mg, or 400 mg).In some cases, the effective dose of tiragolumab for subjects weighing more than 15 kg but not exceeding 40 kg is 400 mg every three weeks (for example, 400 mg ± 10 mg, 400 ± 6 mg, 400 ± 5 mg, 400 ± 3 mg, 400 ± 1 mg, 400 ± 0.5 mg, or 400 mg every three weeks).

[0328] In some cases, the effective dose of tilagolumab is less than 15 kg of body weight (for example, 0.5 kg, 1 kg, 1.5 kg, 2.0 kg, 2.5 kg, 3.0 kg, 3.5 kg, 4.0 kg, 4.5 kg, 5.0 kg, 5.5 kg, 6.0 kg, 6.5 kg, 7.0 kg, 7.5 kg, 8.0 kg, 8.5 kg, 9.0 kg, 9.5 kg, 10.0 kg, 10.5 kg, 11.0 kg, 11.5 kg, 12.0 kg, 12.5 kg, 13.0 kg, 13.5 kg, 14.0 kg, 14.5 kg, and also For subjects weighing 15.0 kg, the dosage is between approximately 10 mg and approximately 1000 mg every three weeks (Q3W) (for example, between approximately 10 mg and approximately 900 mg, between approximately 50 mg and approximately 900 mg, between approximately 100 mg and approximately 750 mg, between approximately 100 mg and approximately 600 mg, between approximately 150 mg and approximately 500 mg, between approximately 200 mg and approximately 400 mg, between approximately 250 mg and approximately 350 mg, between approximately 290 mg and approximately 310 mg, for example, approximately 300 mg). In some cases, the effective dose of tiragolumab for subjects weighing 15 kg or less is approximately 300 mg every three weeks (for example, 300 mg ± 10 mg, 300 ± 6 mg, 300 ± 5 mg, 300 ± 3 mg, 300 ± 1 mg, 300 ± 0.5 mg, or 300 mg every three weeks).In some cases, the effective dose of tilagolumab is less than 15 kg of body weight (for example, 0.5 kg, 1 kg, 1.5 kg, 2.0 kg, 2.5 kg, 3.0 kg, 3.5 kg, 4.0 kg, 4.5 kg, 5.0 kg, 5.5 kg, 6.0 kg, 6.5 kg, 7.0 kg, 7.5 kg, 8.0 kg, 8.5 kg, 9.0 kg, 9.5 kg, 10.0 kg, 10.5 kg, 11.0 kg, 11.5 kg, 12.0 kg, 12.5 kg, 13.0 kg, 13.5 kg, 14.0 kg). For subjects weighing 14.5 kg or 15.0 kg, the dosage is between 10 mg and 1000 mg every three weeks (Q3W) (for example, between 10 mg and 900 mg, between 50 mg and 900 mg, between 100 mg and 750 mg, between 100 mg and 600 mg, between 150 mg and 500 mg, between 200 mg and 400 mg, between 250 mg and 350 mg, between 290 mg and 310 mg, or between 300 mg). In some cases, the effective dose of tiragolumab for subjects weighing 15 kg or less is 300 mg every three weeks (for example, 300 mg ± 10 mg, 300 ± 6 mg, 300 ± 5 mg, 300 ± 3 mg, 300 ± 1 mg, 300 ± 0.5 mg, or 300 mg every three weeks).

[0329] In some cases, the effective dose of tiragolumab to treat patients with cancer is a stepwise dose based on the patient's body surface area. In some cases, the effective dose of tiragolumab is a stepwise dose based on the patient's body surface area, and the patient is (a) 0.5 m 2 (b) 0.5m 2 Over 0.75m 2 For patients with the following body surface area, tiragolumab is administered at doses between approximately 10 mg and 1000 mg every three weeks (e.g., approximately 350 mg every three weeks); (c) 0.75 m 2 Over 1.25m 2Having the following body surface area, tislelizumab is administered at a dose between about 10 mg and about 1000 mg every 3 weeks (e.g., about 450 mg every 3 weeks); or (d) having a body surface area greater than 1.25 m 2 Having a body surface area greater than 1.25 m, tislelizumab is administered at a dose between about 30 mg and about 1200 mg every 3 weeks (e.g., about 600 mg every 3 weeks). In some cases, the effective amount of tislelizumab is a stepwise dose based on the body surface area of the subject, and the subject has (a) a body surface area of 0.5 m 2 or less, and tislelizumab is administered at a dose between about 250 mg and about 350 mg every 3 weeks (e.g., about 300 mg every 3 weeks); (b) having a body surface area greater than 0.5 m 2 and less than 0.75 m 2 Having a body surface area of or less, and tislelizumab is administered at a dose between about 300 mg and about 400 mg every 3 weeks (e.g., about 350 mg every 3 weeks); or (c) having a body surface area greater than 0.75 m 2 and less than 1.25 m 2 Having a body surface area of or less, and tislelizumab is administered at a dose between about 400 mg and about 500 mg every 3 weeks (e.g., about 450 mg every 3 weeks); or (d) having a body surface area greater than 1.25 m 2 Having a body surface area greater than, and tislelizumab is administered at a dose between about 550 mg and about 650 mg every 3 weeks (e.g., about 600 mg every 3 weeks). In some cases, the effective amount of tislelizumab is a stepwise dose based on the body surface area of the subject, and the subject has (a) a body surface area of 0.5 m 2 or less, and tislelizumab is administered at a dose of about 300 mg every 3 weeks; (b) having a body surface area greater than 0.5 m 2 and less than 0.75 m 2 Having a body surface area of or less, and tislelizumab is administered at a dose of about 400 mg every 3 weeks; (c) having a body surface area greater than 0.75 m 2 and less than 1.25 m 2 Having a body surface area of or less, and tislelizumab is administered at 450 mg every 3 weeks; or (d) having a body surface area greater than 1.25 m 2having a body surface area exceeding [value], tislelizumab is administered at approximately 600 mg every three weeks. In some cases, the effective amount of tislelizumab for treating a subject having cancer is a stepped dosage based on the body surface area of the subject. In some cases, the effective amount of tislelizumab is a stepped dosage based on the body surface area of the subject, and the subject has (a) a body surface area of 0.5 m 2 or less, and tislelizumab is administered at a dosage between 10 mg and 1000 mg every three weeks (e.g., 300 mg every three weeks); (b) a body surface area exceeding 0.5 m 2 and up to 0.75 m 2 or less, and tislelizumab is administered at a dosage between 10 mg and 1000 mg every three weeks (e.g., 350 mg every three weeks); (c) a body surface area exceeding 0.75 m 2 and up to 1.25 m 2 or less, and tislelizumab is administered at a dosage between 10 mg and 1000 mg every three weeks (e.g., 450 mg every three weeks); or (d) a body surface area exceeding 1.25 m 2 and tislelizumab is administered at a dosage between 30 mg and 1200 mg every three weeks (e.g., 600 mg every three weeks). In some cases, the effective amount of tislelizumab is a stepped dosage based on the body surface area of the subject, and the subject has (a) a body surface area of 0.5 m 2 or less, and tislelizumab is administered at a dosage between 250 mg and 350 mg every three weeks (e.g., 300 mg every three weeks); (b) a body surface area exceeding 0.5 m 2 and up to 0.75 m 2 or less, and tislelizumab is administered at a dosage between 300 mg and 400 mg every three weeks (e.g., 350 mg every three weeks); or (c) a body surface area exceeding 0.75 m 2 and up to 1.25 m 2 or less, and tislelizumab is administered at a dosage between 400 mg and 500 mg every three weeks (e.g., 450 mg every three weeks); or (d) a body surface area exceeding 1.25 m 2For individuals with a body surface area exceeding (a) 0.5 m², tiragolumab is administered at a dose between 550 mg and 650 mg every three weeks (e.g., 600 mg every three weeks). In some cases, the effective dose of tiragolumab is a stepwise dose based on the subject's body surface area, where the subject is (a) 0.5 m² 2 (b) 0.5m² 2 Over 0.75m 2 Patients with the following body surface area are administered tiragolumab at a dose of 400 mg every 3 weeks; (c) 0.75 m 2 Over 1.25m 2 For those with the following body surface area, tilagolumab is administered at 450 mg every 3 weeks; or (d) 1.25 m² 2 For patients with a body surface area exceeding [a certain value], tiragolumab is administered at a dose of 600 mg every three weeks.

[0330] In some cases, the effective dose of tilagolumab was found to be for a body surface area of ​​1.25 m². 2 exceeding (for example, 1.25m) 2 , 1.35m 2 , 1.45m 2 , 1.50m 2 , 1.55m 2 , 1.60m 2 , 1.65m 2 , 1.70m 2 , 1.75m 2 , 1.80m 2 , 1.85m 2 , 1.90m 2 , 1.95m 2 , 2.0m 2 , 2.1m 2 , 2.2m 2 , 2.3m 2 , 2.4m 2 , 2.5m 2 , 2.6m 2 , 2.7m 2 , 2.8m 2 , 2.9m 2 , 3.0m 2For subjects (or more), every three weeks (Q3W), approximately 30 mg and approximately 1200 mg (for example, between approximately 30 mg and approximately 1100 mg, between approximately 60 mg and approximately 1000 mg, between approximately 100 mg and approximately 900 mg, between approximately 200 mg and approximately 800 mg, between approximately 300 mg and approximately 800 mg, between approximately 400 mg and approximately 800 mg, for example, approximately 4 The effective dose is between 00 mg and approximately 750 mg, for example, between approximately 450 mg and approximately 750 mg, for example, between approximately 500 mg and approximately 700 mg, for example, between approximately 550 mg and approximately 650 mg, for example, 600 mg ± 10 mg, for example, 600 ± 6 mg, for example, 600 ± 5 mg, for example, 600 ± 3 mg, for example, 600 ± 1 mg, for example, 600 ± 0.5 mg, for example, 600 mg). In some cases, the effective dose of tiragolumab is for a body surface area of ​​1.25 m². 2 For subjects exceeding a certain size, the dose is approximately 600 mg every three weeks. In some cases, the effective dose of tiragolumab was found for patients with a body surface area of ​​1.25 m². 2 exceeding (for example, 1.25m) 2 , 1.35m 2 , 1.45m 2 , 1.50m 2 , 1.55m 2 , 1.60m 2 , 1.65m 2 , 1.70m 2 1.75m 2 , 1.80m 2 , 1.85m 2 , 1.90m 2 , 1.95m 2 , 2.0m 2 , 2.1m 2 , 2.2m 2 , 2.3m 2 , 2.4m 2 , 2.5m 2 , 2.6m 2 , 2.7m 2 , 2.8m 2 , 2.9m 2 , 3.0m 2For the subjects mentioned above, the dosage is between 30 mg and 1200 mg every three weeks (Q3W) (for example, between 30 mg and 1100 mg, between 60 mg and 1000 mg, between 100 mg and 900 mg, between 200 mg and 800 mg, between 300 mg and 800 mg, between 400 mg and 800 mg, between 400 mg and 750 mg, between 450 mg and 750 mg, between 500 mg and 700 mg, between 550 mg and 650 mg, between 600 mg ± 10 mg, between 600 ± 6 mg, between 600 ± 5 mg, between 600 ± 3 mg, between 600 ± 1 mg, between 600 ± 0.5 mg, or 600 mg). In some cases, the effective dose of tiragolumab is found for a body surface area of ​​1.25 m². 2 For those exceeding a certain threshold, the dosage is 600 mg every three weeks.

[0331] In some cases, the effective dose of tilagormab was 0.75 mg. 2 Over 1.25m 2 The following (for example, 0.76m) 2 , 0.77m 2 , 0.78m 2 , 0.79m 2 , 0.80m 2 , 0.82m 2 , 0.84m 2 , 0.86m 2 , 0.88m 2 , 0.90m 2 , 0.95m 2 , 1.0m 2 , 1.05m 2 , 1.10m 2 , 1.15m 2 , 1.20m 2 , or 1.25m 2For subjects with a body surface area of ​​0.75 m², the effective dose is between approximately 10 mg and 1000 mg every three weeks (Q3W) (for example, between approximately 20 mg and 1000 mg, between approximately 50 mg and 900 mg, between approximately 100 mg and 850 mg, between approximately 200 mg and 700 mg, between approximately 250 mg and 600 mg, between approximately 300 mg and 500 mg, between approximately 400 mg and 500 mg, between approximately 440 mg and 460 mg, or 450 mg). In some cases, the effective dose of tiragolumab is for subjects with a body surface area of ​​0.75 m². 2 Over 1.25m 2 The dosage for the following subjects is approximately 450 mg every three weeks (for example, 450 mg ± 10 mg, 450 ± 6 mg, 450 ± 5 mg, 450 ± 3 mg, 450 ± 1 mg, 450 ± 0.5 mg, or 450 mg every three weeks).

[0332] In some cases, the effective dose of tilagormab was 0.5 mg. 2 Over 0.75m 2 The following (for example, 0.51m) 2 , 0.52m 2 , 0.53m 2 , 0.54m 2 , 0.55m 2 , 0.56m 2 , 0.57m 2 , 0.58m 2 , 0.59m 2 , 0.60m 2 , 0.61m 2 , 0.62m 2 , 0.63m 2 , 0.64m 2 , 0.65m 2 , 0.66m 2 , 0.67m 2 , 0.68m 2 , 0.69m 2 , 0.70m 2 , 0.71m 2 , 0.72m 2 , 0.73m 2 , 0.74m 2 , or 0.75m 2For subjects with a body surface area of ​​0.5 m², the effective dose is between approximately 10 mg and 1000 mg every three weeks (Q3W) (for example, between approximately 20 mg and 1000 mg, between approximately 50 mg and 900 mg, between approximately 100 mg and 850 mg, between approximately 200 mg and 700 mg, between approximately 250 mg and 600 mg, between approximately 300 mg and 500 mg, between approximately 300 mg and 400 mg, between approximately 340 mg and 360 mg, or 350 mg). In some cases, the effective dose of tiragolumab is found in subjects with a body surface area of ​​0.5 m². 2 Over 0.75m 2 The dosage for the following subjects is approximately 350 mg every three weeks (for example, 350 mg ± 10 mg, 350 ± 6 mg, 350 ± 5 mg, 350 ± 3 mg, 350 ± 1 mg, 350 ± 0.5 mg, or 350 mg every three weeks).

[0333] In some cases, the effective dose of tilagormab was 0.5 mg. 2 (For example, 0.02m) 2 , 0.04m 2 , 0.06m 2 , 0.08m 2 , 0.1m 2 , 0.15m 2 , 0.20m 2 , 0.25m 2 , 0.30m 2 , 0.35m 2 , 0.40m 2 , 0.45m 2 , or 0.50m 2 For subjects with a body surface area of ​​) , the dose is between approximately 10 mg and approximately 1000 mg every three weeks (Q3W) (for example, between approximately 10 mg and approximately 900 mg, between approximately 50 mg and approximately 900 mg, between approximately 100 mg and approximately 750 mg, between approximately 100 mg and approximately 600 mg, between approximately 150 mg and approximately 500 mg, between approximately 200 mg and approximately 400 mg, between approximately 250 mg and approximately 350 mg, between approximately 290 mg and approximately 310 mg, for example, approximately 300 mg). In some cases, the effective dose of tiragolumab is 0.5 m 2For subjects with the following body surface area, the dosage is approximately 300 mg every three weeks (for example, 300 mg ± 10 mg, 300 ± 6 mg, 300 ± 5 mg, 300 ± 3 mg, 300 ± 1 mg, 300 ± 0.5 mg, or 300 mg every three weeks).

[0334] In some cases, the effective dose of tiragolumab is a fixed dose (e.g., between approximately 10 mg and 1000 mg every two weeks (Q2W) (e.g., between approximately 20 mg and 1000 mg, between approximately 50 mg and 900 mg, between approximately 100 mg and 850 mg, between approximately 200 mg and 800 mg, between approximately 300 mg and 600 mg, between approximately 400 mg and 500 mg, between approximately 405 mg and 450 mg, between approximately 410 mg and 430 mg, or 420 mg). In some cases, the effective dose of tiragolumab is approximately 420 mg every two weeks (e.g., 420 mg ± 10 mg, e.g., 420 ± 6 mg, e.g., 420 ± 5 mg, e.g., 420 ± 3 mg, e.g., 420 ± 1 mg, e.g., 420 ± 0.5 mg, e.g., 420 mg every two weeks). In some cases, the method involves administering tiragolumab to the subject or target population at a dose of approximately 300 mg to approximately 600 mg every two weeks. In some cases, the method involves administering tiragolumab to the subject or target population at a dose of 300 mg to 600 mg every two weeks. In some cases, the method involves administering tiragolumab to the subject or target population at a dose of approximately 420 mg every two weeks. In some cases, the method involves administering tiragolumab to the subject or target population at a dose of 420 mg every two weeks. In some cases, the dose of tiragolumab is fixed.

[0335] In some cases, the effective dose of tiragolumab every three weeks (Q3W) is between approximately 30 mg and 1200 mg (for example, between approximately 30 mg and 1100 mg, between approximately 60 mg and 1000 mg, between approximately 100 mg and 900 mg, between approximately 200 mg and 800 mg, between approximately 300 mg and 800 mg, between approximately 400 mg and 800 mg, etc.). The dose (e.g., fixed dose) is between 0 mg and approximately 750 mg, for example, between approximately 450 mg and approximately 750 mg, for example, between approximately 500 mg and approximately 700 mg, for example, between approximately 550 mg and approximately 650 mg, for example, 600 mg ± 10 mg, for example, 600 ± 6 mg, for example, 600 ± 5 mg, for example, 600 ± 3 mg, for example, 600 ± 1 mg, for example, 600 ± 0.5 mg, for example, 600 mg). In some cases, the effective dose of tiragolumab is a dose of approximately 600 mg every three weeks. In some cases, the method involves administering tiragolumab to the subject or target population at a dose of approximately 600 mg every three weeks. In some cases, the method involves administering tiragolumab to the subject or target population at a dose of 600 mg every three weeks. In some cases, the dose of tiragolumab is a fixed dose.

[0336] In some cases, the effective dose of tiragolumab is between approximately 200 mg and 2000 mg every three weeks (Q3W) (for example, between approximately 200 mg and 2000 mg, between approximately 400 mg and 1900 mg, between approximately 500 mg and 1800 mg, between approximately 600 mg and 1700 mg, between approximately 700 mg and 1400 mg, between approximately 800 mg and 1600 mg, between approximately 900 mg and 1500 mg, or between approximately 1000 mg and 1400 mg). For example, doses between approximately 1050 mg and 1350 mg, between approximately 1100 mg and 1300 mg, between approximately 1150 mg and 1250 mg, between approximately 1175 mg and 1225 mg, between approximately 1190 mg and 1210 mg, for example, approximately 1200 mg, for example, 1200 mg ± 10 mg, for example, 1200 ± 6 mg, for example, 1200 ± 5 mg, for example, 1200 ± 3 mg, for example, 1200 ± 1 mg, for example, 1200 ± 0.5 mg, for example, 1200 mg). In some cases, the effective dose of tiragolumab is approximately 600 mg every three weeks. In some cases, the effective dose of tiragolumab is 600 mg every three weeks.

[0337] In some cases, the effective dose of tiragolumab is between approximately 200 mg and 2000 mg every four weeks (Q4W) (for example, between approximately 200 and 300 mg, between approximately 300 and 400 mg, between approximately 400 and 500 mg, between approximately 500 and 600 mg, between approximately 600 and 700 mg, between approximately 700 and 800 mg, between approximately 800 and 900 mg, between approximately 900 and 1000 mg, between approximately 1000 and 1100 mg, between approximately 1100 and 1200 mg, and between approximately 1200 and 130 mg). Between 0 mg, between approximately 1300 and 1400 mg, between approximately 1400 and 1500 mg, between approximately 1500 and 1600 mg, between approximately 1600 and 1700 mg, between approximately 1700 and 1800 mg, between approximately 1800 and 1900 mg, or between approximately 1900 and 2000 mg, for example between approximately 200 mg and approximately 1600 mg, for example between approximately 250 mg and approximately 1600 mg, for example between approximately 300 mg and approximately 1600 mg, for example between approximately 400 mg and approximately 1500 mg, for example approximately Between 500mg and approximately 1400mg, for example between approximately 600mg and approximately 1200mg, for example between approximately 700mg and approximately 1100mg, for example between approximately 800mg and approximately 1000mg, for example between approximately 800mg and approximately 900mg, for example approximately 200, approximately 250, approximately 300, approximately 350, approximately 400, approximately 450, approximately 500, approximately 550, approximately 600, approximately 650, approximately 700, approximately 750, approximately 800, approximately 850, approximately 900, approximately 950, approximately 1000, approximately 1050, approximately 1100, approximately The dosages are approximately 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, or 2000 mg (for example, approximately 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, or 900 mg). In some cases, the effective dose of tiragolumab is approximately 700 mg to 1000 mg every four weeks. In some cases, the effective dose of tiragolumab is approximately 840 mg every four weeks.The 840 mg Q4W dosing regimen is supported by PK modeling and simulation results, as well as exposure-safety analysis results. In short, the mean concentration after the 840 mg Q4W dosing regimen is similar to the mean concentration of the 600 mg dosing regimen every three weeks evaluated in previous studies. The Cmax of the 840 mg Q4W dosing regimen was simulated to be 28% higher at steady state compared to the Cmax of the 600 mg dosing regimen every three weeks, but this is within the range of exposure for the highest dose observed in the clinic (1200 mg every three weeks). A preliminary analysis of the exposure-safety relationship of tilagorumab based on previous observations (tiragolumab doses of 2–1200 mg every three weeks administered as monotherapy or in combination with 1200 mg atezolizumab every three weeks) suggests that tilagorumab exhibits a flat exposure-safety relationship. In summary, given that the predicted exposure falls within the range of observed effective exposures and tiragolumab exhibits a flat exposure-safety relationship, the 840 mg Q4W dosing regimen may offer comparable safety and efficacy to the 600 mg dosing regimen every three weeks.

[0338] In some cases, during the effective dose of tiragolumab, doses were taken every four weeks (Q4W) between approximately 200 mg and approximately 2000 mg (for example, between approximately 200 mg and approximately 2000 mg, between approximately 400 mg and approximately 1900 mg, between approximately 500 mg and approximately 1800 mg, between approximately 600 mg and approximately 1700 mg, between approximately 700 mg and approximately 1400 mg, or between approximately 800 mg and approximately 16 Between 00mg, for example between approximately 900mg and 1500mg, for example between approximately 1000mg and 1400mg, for example between approximately 1050mg and 1350mg, for example between approximately 1100mg and 1300mg, for example between approximately 1150mg and 1250mg, for example between approximately 1175mg and 1225mg, for example between approximately 1190mg and 1210mg (for example between 200mg and 2000mg) The dosages are between (for example, between 400 mg and 1900 mg, between 500 mg and 1800 mg, between 600 mg and 1700 mg, between 700 mg and 1400 mg, between 800 mg and 1600 mg, between 900 mg and 1500 mg, between 1000 mg and 1400 mg, between 1050 mg and 1350 mg, between 1100 mg and 1300 mg, between 1150 mg and 1250 mg, between 1175 mg and 1225 mg, between 1190 mg and 1210 mg), for example, approximately 1200 mg, for example, 1200 mg ± 10 mg, for example, 1200 ± 6 mg, for example, 1200 ± 5 mg, for example, 1200 ± 3 mg, for example, 1200 ± 1 mg, for example, 1200 ± 0.5 mg, for example, 1200 mg). In some cases, the effective dose of tiragolumab is approximately 840 mg every four weeks (e.g., 840 mg ± 10 mg, 840 ± 6 mg, 840 ± 5 mg, 840 ± 3 mg, 840 ± 1 mg, 840 ± 0.5 mg, 840 mg every four weeks). In some cases, the effective dose of tiragolumab is 840 mg every four weeks. In some cases, the dose of tiragolumab is a fixed dose.

[0339] In some cases, the effective dose of tiragolumab is approximately 1200 mg every four weeks.

[0340] In some cases, the dose of tilagorumab administered in combination therapy (e.g., in combination with atezolizumab) may be reduced compared to the standard dose of tilagorumab administered as monotherapy.

[0341] In some cases, tiragolumab is administered intravenously. Alternatively, in some embodiments, tiragolumab is administered subcutaneously. In some cases, tiragolumab is administered intravenously to patients in doses of approximately 420 mg every two weeks, approximately 600 mg every three weeks, or approximately 840 mg every four weeks. In some cases, tiragolumab is administered intravenously to patients in doses of 420 mg every two weeks, 600 mg every three weeks, or 840 mg every four weeks.

[0342] In some cases, the patient receives a total of 1 to 20 doses of tiragolumab, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 doses. In some cases, the patient receives a total of 1 to 50 doses, for example, 1 to 50 doses, 1 to 45 doses, 1 to 40 doses, 1 to 35 doses, 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 50 doses, 2 to 45 doses, 2 to 40 doses, 2 to 35 doses, 2 to 30 doses, 2 to 25 doses, 2 to 20 doses, 2 to 15 doses, 2 to 10 doses, 2 to 5 doses, 3 ~50 doses, 3~45 doses, 3~40 doses, 3~35 doses, 3~30 doses, 3~25 doses, 3~20 doses, 3~15 doses, 3~10 doses, 3~5 doses, 4~50 doses, 4~45 doses, 4~ 40 doses, 4~35 doses, 4~30 doses, 4~25 doses, 4~20 doses, 4~15 doses, 4~10 doses, 4~5 doses, 5~50 doses, 5~45 doses, 5~40 doses, 5~35 doses, 5~3 0 dose, 5~25 dose, 5~20 dose, 5~15 dose, 5~10 dose, 10~50 dose, 10~45 dose, 10~40 dose, 10~35 dose, 10~30 dose, 10~25 dose, 10~2 0 dose, 10~15 dose, 15~50 dose, 15~45 dose, 15~40 dose, 15~35 dose, 15~30 dose, 15~25 dose, 15~20 dose, 20~50 dose, 20~45 dose, Tiragolumab is administered in doses of 20-40, 20-35, 20-30, 20-25, 25-50, 25-45, 25-40, 25-35, 25-30, 30-50, 30-45, 30-40, 30-35, 35-50, 35-45, 35-40, 40-50, 40-45, or 45-50. In certain cases, the dose may be administered intravenously.

[0343] ii. Administration of atezolizumab As a general suggestion, the therapeutically effective dose of atezolizumab in humans, whether administered in single or multiple doses, is likely to be in the range of approximately 0.01 to 50 mg / kg (patient's body weight).

[0344] In some exemplary embodiments, atezolizumab is administered in doses of approximately 0.01 to 45 mg / kg, approximately 0.01 to 40 mg / kg, approximately 0.01 to 35 mg / kg, approximately 0.01 to 30 mg / kg, approximately 0.01 to 25 mg / kg, approximately 0.01 to 20 mg / kg, approximately 0.01 to 15 mg / kg, approximately 0.01 to 10 mg / kg, approximately 0.01 to 5 mg / kg, or approximately 0.01 to 1 mg / kg, for example, daily, weekly, every two weeks, every three weeks, or every four weeks. In some exemplary embodiments, atezolizumab is administered in doses of 0.01–45 mg / kg, 0.01–40 mg / kg, 0.01–35 mg / kg, 0.01–30 mg / kg, 0.01–25 mg / kg, 0.01–20 mg / kg, 0.01–15 mg / kg, 0.01–10 mg / kg, 0.01–5 mg / kg, or 0.01–1 mg / kg, for example, daily, weekly, every two weeks, every three weeks, or every four weeks.

[0345] In some cases, atezolizumab is administered around day 1 of the medication cycle (e.g., day -3, day -2, day -1, day 1, day 2, or day 3).

[0346] In some cases, the effective dose of atezolizumab is a fixed dose (e.g., a dose between approximately 20 mg and approximately 1600 mg every two weeks (Q2W) (e.g., between approximately 40 mg and approximately 1500 mg, between approximately 200 mg and approximately 1400 mg, between approximately 300 mg and approximately 1400 mg, between approximately 400 mg and approximately 1400 mg, between approximately 500 mg and approximately 1300 mg, between approximately 600 mg and approximately 1200 mg, between approximately 700 mg and approximately 1100 mg, between approximately 800 mg and approximately 1000 mg, between approximately 800 mg and approximately 900 mg, for example, approximately 800, approximately 810, approximately 820, approximately 830, approximately 840, approximately 850, approximately 860, approximately 870, approximately 880, approximately 890, or approximately 900 mg). In some cases, the effective dose of atezolizumab is a fixed dose (e.g., a fixed dose) between 20 mg and 1600 mg every two weeks (Q2W). (e.g., between 40 mg and 1500 mg, between 200 mg and 1400 mg, between 300 mg and 1400 mg, between 400 mg and 1400 mg, between 500 mg and 1300 mg, between 600 mg and 1200 mg, between 700 mg and 1100 mg, between 800 mg and 1000 mg, between 800 mg and 900 mg, or between 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, or 900 mg.) In some cases, the effective dose of atezolizumab is approximately 840 mg every two weeks (for example, 840 mg ± 10 mg, 840 ± 6 mg, 840 ± 5 mg, 840 ± 3 mg, 840 ± 1 mg, 840 ± 0.5 mg, or 840 mg every two weeks).

[0347] In some cases, the effective dose of atezolizumab is approximately 0.01 mg / kg to 50 mg / kg (body weight of the subject) every two weeks (for example, approximately 0.01 mg / kg to 45 mg / kg, approximately 0.1 mg / kg to 40 mg / kg, approximately 1 mg / kg to 35 mg / kg, approximately 2.5 mg / kg to 30 mg / kg, approximately 5 mg / kg to 25 mg / kg, approximately 5 mg / kg to 15 mg / kg, approximately 7.5 mg / kg to 12.5 mg / kg, approximately 10 ± 2 mg / kg, approximately 10 ± 1 mg / kg, approximately 10 ± 0.5 mg / kg, approximately 10 ± 0.2 mg / kg, or approximately 10 ± 0.1 mg / kg, for example, approximately 10 mg / kg). In some cases, the effective dose of atezolizumab is approximately 0.01 mg / kg to approximately 10 mg / kg (body weight of the subject) every two weeks (for example, approximately 0.1 mg / kg to approximately 10 mg / kg, approximately 0.5 mg / kg to approximately 10 mg / kg, approximately 1 mg / kg to approximately 10 mg / kg, approximately 2.5 mg / kg to approximately 10 mg / kg, approximately 5 mg / kg to approximately 10 mg / kg, approximately 7.5 mg / kg to approximately 10 mg / kg, approximately 8 mg / kg to approximately 10 mg / kg, approximately 9 mg / kg to approximately 10 mg / kg, approximately 9.5 mg / kg to approximately 10 mg / kg, approximately 10 ± 1 mg / kg, approximately 10 ± 0.5 mg / kg, approximately 10 ± 0.2 mg / kg, approximately 10 ± 0.1 mg / kg, and approximately 10 mg / kg). In some cases, the effective dose of atezolizumab is between 0.01 mg / kg and 50 mg / kg (body weight of the subject) every two weeks (for example, between 0.01 mg / kg and 45 mg / kg, between 0.1 mg / kg and 40 mg / kg, between 1 mg / kg and 35 mg / kg, between 2.5 mg / kg and 30 mg / kg, between 5 mg / kg and 25 mg / kg, between 5 mg / kg and 15 mg / kg, between 7.5 mg / kg and 12.5 mg / kg, for example, 10 ± 2 mg / kg, 10 ± 1 mg / kg, 10 ± 0.5 mg / kg, 10 ± 0.2 mg / kg, or 10 ± 0.1 mg / kg, for example, 10 mg / kg).In some cases, the effective dose of atezolizumab is between 0.01 mg / kg and 10 mg / kg (body weight) every two weeks (e.g., between 0.1 mg / kg and 10 mg / kg, between 0.5 mg / kg and 10 mg / kg, between 1 mg / kg and 10 mg / kg, between 2.5 mg / kg and 10 mg / kg, between 5 mg / kg and 10 mg / kg, between 7.5 mg / kg and 10 mg / kg, between 8 mg / kg and 10 mg / kg, between 9 mg / kg and 10 mg / kg, between 9.5 mg / kg and 10 mg / kg, between 10 ± 1 mg / kg, between 10 ± 0.5 mg / kg, between 10 ± 0.2 mg / kg, between 10 ± 0.1 mg / kg, or 10 mg / kg). In some cases, the effective dose of atezolizumab is approximately 10 mg / kg every two weeks. In some cases, the effective dose of atezolizumab is 10 mg / kg every two weeks.

[0348] In some cases, the effective dose of atezolizumab to treat patients with cancer is between approximately 0.01 mg / kg and approximately 50 mg / kg (body weight of the patient) every three weeks (for example, between approximately 0.01 mg / kg and approximately 45 mg / kg, for example between approximately 0.1 mg / kg and approximately 40 mg / kg, for example between approximately 1 mg / kg and approximately 35 mg / kg, for example between approximately 2.5 mg / kg and approximately 30 mg / kg, for example between approximately 5 mg / kg and approximately 25 mg / kg, for example between approximately 10 mg / kg and approximately 20 mg / kg, for example between approximately 12.5 mg / kg and approximately 15 mg / kg, for example between approximately 15 ± 2 mg / kg, approximately 15 ± 1 mg / kg, approximately 15 ± 0.5 mg / kg, approximately 15 ± 0.2 mg / kg, or approximately 15 ± 0.1 mg / kg, for example, approximately 15 mg / kg). In some cases, the effective dose of atezolizumab is between approximately 0.01 mg / kg and approximately 15 mg / kg (body weight) every three weeks (for example, between approximately 0.1 mg / kg and approximately 15 mg / kg, for example, between approximately 0.5 mg / kg and approximately 15 mg / kg, for example, between approximately 1 mg / kg and approximately 15 mg / kg, for example, between approximately 2.5 mg / kg and approximately 15 mg / kg, for example, between approximately 5 mg / kg and approximately 15 mg / kg, for example, For example, the dosage is between approximately 7.5 mg / kg and approximately 15 mg / kg, for example between approximately 10 mg / kg and approximately 15 mg / kg, for example between approximately 12.5 mg / kg and approximately 15 mg / kg, for example between approximately 14 mg / kg and approximately 15 mg / kg, for example between approximately 15 ± 1 mg / kg, for example between approximately 15 ± 0.5 mg / kg, for example between approximately 15 ± 0.2 mg / kg, for example between approximately 15 ± 0.1 mg / kg, for example between approximately 15 mg / kg).In some cases, the effective dose of atezolizumab to treat patients with cancer is between 0.01 mg / kg and 50 mg / kg (body weight of the patient) every three weeks (e.g., between 0.01 mg / kg and 45 mg / kg, between 0.1 mg / kg and 40 mg / kg, between 1 mg / kg and 35 mg / kg, between 2.5 mg / kg and 30 mg / kg, between 5 mg / kg and 25 mg / kg, between 10 mg / kg and 20 mg / kg, between 12.5 mg / kg and 15 mg / kg, for example, 15 ± 2 mg / kg, 15 ± 1 mg / kg, 15 ± 0.5 mg / kg, 15 ± 0.2 mg / kg, or 15 ± 0.1 mg / kg, e.g., 15 mg / kg). In some cases, the effective dose of atezolizumab is between 0.01 mg / kg and 15 mg / kg (body weight of the subject) every three weeks (for example, between 0.1 mg / kg and 15 mg / kg, between 0.5 mg / kg and 15 mg / kg, between 1 mg / kg and 15 mg / kg, between 2.5 mg / kg and 15 mg / kg, between 5 mg / kg and 15 mg / kg, between 7.5 mg / kg and 15 mg / kg, between 10 mg / kg and 15 mg / kg, between 12.5 mg / kg and 15 mg / kg, between 14 mg / kg and 15 mg / kg, between 15 ± 1 mg / kg, between 15 ± 0.5 mg / kg, between 15 ± 0.2 mg / kg, between 15 ± 0.1 mg / kg, or 15 mg / kg). In some cases, the effective dose of atezolizumab is approximately 15 mg / kg administered every three weeks. In other cases, the effective dose of atezolizumab is approximately 15 mg / kg administered every three weeks, with a maximum dose of 1200 mg every three weeks. In some cases, the dose of atezolizumab administered in combination therapy (e.g., in combination with tiragolumab) may be reduced compared to the standard dose of atezolizumab administered as monotherapy. In some embodiments, atezolizumab is administered at a maximum dose of 1200 mg every three weeks.

[0349] In some cases, the effective dose of atezolizumab every three weeks (Q3W) is between approximately 80 mg and 2000 mg (for example, between approximately 100 mg and 1600 mg, between approximately 200 mg and 1600 mg, between approximately 300 mg and 1600 mg, between approximately 400 mg and 1600 mg, between approximately 500 mg and 1600 mg, between approximately 600 mg and 1600 mg, between approximately 700 mg and 1600 mg, between approximately 800 mg and 1600 mg, for example, between approximately 9 The dosage is between 00 mg and approximately 1500 mg, for example, between approximately 1000 mg and approximately 1400 mg, for example, between approximately 1050 mg and approximately 1350 mg, for example, between approximately 1100 mg and approximately 1300 mg, for example, between approximately 1150 mg and approximately 1250 mg, for example, between approximately 1175 mg and approximately 1225 mg, for example, between approximately 1190 mg and approximately 1210 mg, for example, 1200 mg ± 5 mg, for example, 1200 ± 2.5 mg, for example, 1200 ± 1.0 mg, for example, 1200 ± 0.5 mg, for example, 1200 mg). In some cases, the effective dose of atezolizumab is approximately 1200 mg every three weeks (for example, 1200 mg ± 10 mg, 1200 ± 6 mg, 1200 ± 5 mg, 1200 ± 3 mg, 1200 ± 1 mg, 1200 ± 0.5 mg, or 1200 mg every three weeks). In some cases, the effective dose of atezolizumab is 1200 mg every three weeks.

[0350] In some cases, the effective dose of atezolizumab is between approximately 10 mg and approximately 800 mg every three weeks (Q3W) (for example, between approximately 10 mg and approximately 800 mg, between approximately 20 mg and approximately 700 mg, between approximately 50 mg and approximately 600 mg, between approximately 75 mg and approximately 500 mg, between approximately 100 mg and approximately 400 mg, between approximately 100 mg and approximately 300 mg, between approximately 125 mg and approximately 275 mg, between approximately 150 mg and approximately 250 mg, between approximately 175 mg and approximately 225 mg, between approximately 190 mg and approximately 210 mg, for example, approximately 200 mg ± 10 mg, for example, 200 mg ± 7.5 mg, for example, 200 mg ± 5 mg, for example, 200 ± 2.5 mg, for example, 200 ± 1.0 mg, for example, 200 ± 0.5 mg, for example, 200 mg). In some cases, the effective dose of atezolizumab is approximately 200 mg every three weeks (for example, 200 mg ± 10 mg, 200 ± 6 mg, 200 ± 5 mg, 200 ± 3 mg, 200 ± 1 mg, 200 ± 0.5 mg, or 200 mg every three weeks). In some cases, the effective dose of atezolizumab is approximately 200 mg every three weeks (for example, 200 mg ± 10 mg, 200 ± 6 mg, 200 ± 5 mg, 200 ± 3 mg, 200 ± 1 mg, 200 ± 0.5 mg, or 200 mg every three weeks). In some cases, the effective dose of atezolizumab is between 10 mg and 800 mg every three weeks (Q3W) (e.g., between 10 mg and 800 mg, between 20 mg and 700 mg, between 50 mg and 600 mg, between 75 mg and 500 mg, between 100 mg and 400 mg, between 100 mg and 300 mg, between 125 mg and 275 mg, between 150 mg and 250 mg, between 175 mg and 225 mg, between 190 mg and 210 mg, between 200 mg ± 10 mg, between 200 mg ± 7.5 mg, between 200 mg ± 5 mg, between 200 mg ± 2.5 mg, between 200 mg ± 1.0 mg, between 200 mg ± 0.5 mg, or 200 mg).In some cases, the effective dose of atezolizumab is 200 mg every three weeks (for example, 200 mg ± 10 mg, 200 ± 6 mg, 200 ± 5 mg, 200 ± 3 mg, 200 ± 1 mg, 200 ± 0.5 mg, or 200 mg every three weeks). In some cases, the effective dose of atezolizumab is 200 mg every three weeks (for example, 200 mg ± 10 mg, 200 ± 6 mg, 200 ± 5 mg, 200 ± 3 mg, 200 ± 1 mg, 200 ± 0.5 mg, or 200 mg every three weeks). In some cases, the effective dose of atezolizumab is approximately 200 mg every three weeks. In some cases, the effective dose of atezolizumab is 200 mg every three weeks.

[0351] In some cases, the effective dose of atezolizumab is between approximately 80 mg and 3000 mg every four weeks (Q4W) (for example, between approximately 80 mg and 200 mg, between approximately 200 mg and 400 mg, between approximately 400 mg and 600 mg, between approximately 600 mg and 800 mg, between approximately 800 mg and 1000 mg, between approximately 1000 mg and 1200 mg, between approximately 1200 mg and 1400 mg, between approximately 1400 mg and 1600 mg, between approximately 1600 mg and 1800 mg, and between approximately 1800 mg and 2000 mg). , between approximately 2200 mg and 2400 mg, between approximately 2400 mg and 2600 mg, between approximately 2600 mg and 2800 mg, or between approximately 2800 mg and 3000 mg, for example between approximately 100 mg and 3000 mg, for example between approximately 200 mg and 2900 mg, for example between approximately 500 mg and 2800 mg, for example between approximately 600 mg and 2700 mg, for example between approximately 650 mg and 2600 mg, for example between approximately 700 mg and 2500 mg, for example between approximately 1000 mg and 2400 mg, For example, between approximately 1100mg and 2300mg, between approximately 1200mg and 2200mg, between approximately 1300mg and 2100mg, between approximately 1400mg and 2000mg, between approximately 1500mg and 1900mg, between approximately 1600mg and 1800mg, between approximately 1620mg and 1700mg, between approximately 1640mg and 1690mg, between approximately 1660mg and 1680mg, approximately 1680mg, for example, approximately 80mg, approximately 200mg, The dosages are approximately 400 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, 2400 mg, 2600 mg, 2800 mg, or 3000 mg (for example, approximately 1600 mg, 1610 mg, 1620 mg, 1630 mg, 1640 mg, 1650 mg, 1660 mg, 1670 mg, 1680 mg, 1690 mg, or 1700 mg).In some cases, the effective dose of atezolizumab was between 500 mg and 3000 mg every four weeks (Q4W) (for example, between 500 mg and 2800 mg, between 600 mg and 2700 mg, between 650 mg and 2600 mg, between 700 mg and 2500 mg, between 1000 mg and 2400 mg, between 1100 mg and 2300 mg, between 1200 mg and 2200 mg, between 1300 mg and 2100 mg, for example, 140 mg The dosage is between 0 mg and 2000 mg, for example between 1500 mg and 1900 mg, for example between 1600 mg and 1800 mg, for example between 1620 mg and 1700 mg, for example between 1640 mg and 1690 mg, for example between 1660 mg and 1680 mg, 1680 mg, for example 1600 mg, 1610 mg, 1620 mg, 1630 mg, 1640 mg, 1650 mg, 1660 mg, 1670 mg, 1680 mg, 1690 mg, or 1700 mg. In some cases, the effective dose of atezolizumab is 1680 mg every four weeks (e.g., 1680 mg ± 10 mg, 1680 ± 6 mg, 1680 ± 5 mg, 1680 ± 3 mg, 1680 ± 1 mg, 1680 ± 0.5 mg, or 1680 mg every four weeks). In some cases, the effective dose of atezolizumab is approximately 1680 mg every four weeks. In some cases, the effective dose of atezolizumab is 1680 mg every four weeks.

[0352] In some cases, the effective dose of atezolizumab was between approximately 50 mg and 2000 mg every six weeks (Q6W) (for example, between approximately 50 mg and 100 mg, between approximately 100 mg and 250 mg, between approximately 250 mg and 500 mg, between approximately 500 mg and 750 mg, between approximately 750 mg and 1000 mg, between approximately 1000 mg and 1250 mg, between approximately 1250 mg and 1500 mg, and between approximately 1500 mg and 1750 mg). , or between approximately 1750 mg and 2000 mg, for example between approximately 100 mg and 1000 mg, between approximately 120 mg and 900 mg, between approximately 150 mg and 800 mg, between approximately 200 mg and 700 mg, between approximately 250 mg and 600 mg, between approximately 300 mg and 500 mg, or between approximately 350 mg and 450 mg, for example between approximately 50 mg and 100 mg, between approximately 100 mg and 200 mg, approximately 200 mg Between approximately 300 mg, between approximately 300 mg and approximately 400 mg, between approximately 400 mg and approximately 500 mg, between approximately 500 mg and approximately 600 mg, between approximately 600 mg and approximately 700 mg, between approximately 700 mg and approximately 800 mg, or between approximately 800 mg and approximately 1000 mg, for example, approximately 50 mg, approximately 100 mg, approximately 250 mg, approximately 500 mg, approximately 750 mg, approximately 1000 mg, approximately 1250 mg, approximately 1500 mg, approximately 1750 mg, Alternatively, the dosage may be approximately 2000 mg, for example, approximately 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, or approximately 500 mg (for example, 400 mg).In some cases, the effective dose of atezolizumab is between 50 mg and 2000 mg every six weeks (Q6W) (for example, between 100 mg and 1000 mg, between 120 mg and 900 mg, between 150 mg and 800 mg, between 200 mg and 700 mg, between 250 mg and 600 mg, between 300 mg and 500 mg, or between 350 mg and 450 mg, for example, between 50 mg and 100 mg, between 100 mg and 200 mg, between 200 mg and 300 mg, between 300 mg and 400 mg, or between 400 mg). The dosages are between 500mg and 500mg, between 500mg and 600mg, between 600mg and 700mg, between 700mg and 800mg, or between 800mg and 1000mg, for example, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, or 500mg (for example, 400mg). In some cases, the effective dose of an anti-PD-1 antagonist antibody (e.g., pembrolizumab) is approximately 400 mg every 6 weeks (e.g., 400 mg ± 10 mg, 400 ± 6 mg, 400 ± 5 mg, 400 ± 3 mg, 400 ± 1 mg, 400 ± 0.5 mg, 400 mg every 6 weeks). In some cases, the dose of atezolizumab is fixed. In some cases, the effective dose of atezolizumab is approximately 400 mg every 6 weeks (e.g., fixed dose). In some cases, the effective dose of atezolizumab is 400 mg every 6 weeks (e.g., fixed dose).

[0353] In some cases, atezolizumab is administered intravenously. Alternatively, in some embodiments, atezolizumab is administered subcutaneously. In some cases, atezolizumab is administered intravenously to patients in doses of approximately 840 mg every two weeks, approximately 1200 mg every three weeks, or approximately 1680 mg every four weeks. In some cases, atezolizumab is administered intravenously to patients in doses of 840 mg every two weeks, 1200 mg every three weeks, or 1680 mg every four weeks.

[0354] In some cases, the subjects receive a total of 1 to 20 doses of atezolizumab, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 doses. In some cases, the subjects receive a total of 1 to 50 doses, for example, 1 to 50 doses, 1 to 45 doses, 1 to 40 doses, 1 to 35 doses, 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 50 doses, 2 to 45 doses, 2 to 40 doses, 2 to 35 doses, 2 to 30 doses, 2 to 25 doses, 2 to 20 doses, 2 to 15 doses, 2 to 10 doses, 2 to 5 doses, 3 to 50 doses, 3~45 doses, 3~40 doses, 3~35 doses, 3~30 doses, 3~25 doses, 3~20 doses, 3~15 doses, 3~10 doses, 3~5 doses, 4~50 doses, 4~45 doses, 4~4 0 dose, 4~35 dose, 4~30 dose, 4~25 dose, 4~20 dose, 4~15 dose, 4~10 dose, 4~5 dose, 5~50 dose, 5~45 dose, 5~40 dose, 5~35 dose, 5~30 Doses, 5-25 doses, 5-20 doses, 5-15 doses, 5-10 doses, 10-50 doses, 10-45 doses, 10-40 doses, 10-35 doses, 10-30 doses, 10-25 doses, 10-20 Doses, 10-15 doses, 15-50 doses, 15-45 doses, 15-40 doses, 15-35 doses, 15-30 doses, 15-25 doses, 15-20 doses, 20-50 doses, 20-45 doses, 2 Atezolizumab is administered in doses of 0-40, 20-35, 20-30, 20-25, 25-50, 25-45, 25-40, 25-35, 25-30, 30-50, 30-45, 30-40, 30-35, 35-50, 35-45, 35-40, 40-50, 40-45, or 45-50. In certain cases, the dose may be administered intravenously.

[0355] iii. Dosage cycles for tilagolmab and atezolizumab In any of the methods and uses of the present invention, tiragolumab and / or atezolizumab may be administered in one or more dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more dosing cycles). In some cases, dosing cycles of tiragolumab and / or atezolizumab continue until there is a loss of clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity). In some cases, the length of each medication cycle is approximately 7 to 42 days (for example, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42 days). In some cases, the length of each medication cycle is approximately 14 days. In some cases, the length of each medication cycle is approximately 21 days. In some cases, the length of each medication cycle is approximately 28 days. In some cases, the length of each medication cycle is approximately 42 days. In some cases, the length of each medication cycle is approximately 7 days. In some cases, tiragolumab is administered around day 1 of each dosing cycle (e.g., day 1 ± 3 days). In some cases, tiragolumab is administered around day 15 of each dosing cycle (e.g., day 15 ± 3 days). In some cases, tiragolumab is administered around day 22 of each dosing cycle (e.g., day 22 ± 3 days). In some cases, tiragolumab is administered around day 29 of each dosing cycle (e.g., day 29 ± 3 days). For example, tiragolumab may be administered intravenously at a dose of approximately 600 mg on day 1 of each 21-day cycle (e.g., a fixed dose) (i.e., a dose of approximately 600 mg every 3 weeks).In another example, tiragolumab is administered intravenously at a dose of approximately 600 mg (e.g., a fixed dose) on days 1 and 15 of each 28-day cycle (i.e., a dose of approximately 420 mg every two weeks). For example, tiragolumab may be administered intravenously at a dose of approximately 600 mg (e.g., a fixed dose) on days 1, 15, and 29 of each 42-day cycle (i.e., a dose of approximately 420 mg every two weeks). For example, tiragolumab may be administered intravenously at a dose of approximately 600 mg (e.g., a fixed dose) on days 1 and 22 of each 42-day cycle (i.e., a dose of approximately 600 mg every three weeks). In some cases, atezolizumab is administered at approximately day 1 of each medication cycle (e.g., day 1 ± 3 days). In some cases, atezolizumab is administered around day 15 of each dosing cycle (e.g., day 15 ± 3 days). For example, atezolizumab may be administered intravenously at a dose of approximately 1200 mg on day 1 of each 21-day cycle (i.e., approximately 1200 mg every 3 weeks). For example, atezolizumab may be administered intravenously at a dose of approximately 1200 mg on days 1 and 15 of each 28-day cycle (i.e., approximately 840 mg every 2 weeks). In some cases, tiragolumab is administered intravenously at a dose of 600 mg on day 1 of each 21-day cycle (e.g., a fixed dose) (i.e., 600 mg every 3 weeks). In some cases, atezolizumab is administered on day 1 of each dosing cycle (e.g., day 1 ± 3 days). For example, atezolizumab can be administered intravenously at a dose of 1200 mg on day 1 of each 21-day cycle (i.e., 1200 mg every three weeks).

[0356] In some cases, tiragolumab and atezolizumab are administered around day 1 of each drug cycle (e.g., day 1 ± 3 days).

[0357] In some cases, tiragolumab is administered intravenously at a dose of approximately 600 mg on day 1 of each 21-day cycle (i.e., approximately 600 mg every three weeks), and atezolizumab is administered intravenously at a dose of approximately 1200 mg on day 1 of each 21-day cycle (i.e., approximately 1200 mg every three weeks). In some cases, tiragolumab is administered intravenously at a dose of 600 mg on day 1 of each 21-day cycle (i.e., 600 mg every three weeks), and atezolizumab is administered intravenously at a dose of 1200 mg on day 1 of each 21-day cycle (i.e., 1200 mg every three weeks).

[0358] In other cases, tiragolumab is administered intravenously at a dose of approximately 420 mg on day 1 of each 14-day cycle (i.e., approximately 420 mg every two weeks), and atezolizumab is administered intravenously at a dose of approximately 840 mg on day 1 of each 14-day cycle (i.e., approximately 840 mg every two weeks). In some cases, tiragolumab is administered intravenously at a dose of 420 mg on day 1 of each 14-day cycle (i.e., approximately 420 mg every two weeks), and atezolizumab is administered intravenously at a dose of 840 mg on day 1 of each 14-day cycle (i.e., 840 mg every two weeks).

[0359] In other cases, tiragolumab is administered intravenously at a dose of approximately 840 mg on day 1 of each 28-day cycle (i.e., approximately 840 mg every four weeks), and atezolizumab is administered intravenously at a dose of approximately 1680 mg on day 1 of each 28-day cycle (i.e., approximately 1680 mg every four weeks). In some cases, tiragolumab is administered intravenously at a dose of 840 mg on day 1 of each 28-day cycle (i.e., 840 mg every four weeks), and atezolizumab is administered intravenously at a dose of 1680 mg on day 1 of each 28-day cycle (i.e., 1680 mg every four weeks).

[0360] In some cases, the dose of tiragolumab administered in combination therapy (e.g., in combination with atezolizumab) may be reduced compared to the standard dose of tiragolumab administered as monotherapy.

[0361] In some cases, the dose of atezolizumab administered in combination therapy (e.g., in combination with tiragolumab) may be reduced compared to the standard dose of atezolizumab administered as monotherapy.

[0362] iv. Intravenous and subcutaneous administration of tiragolumab and atezolizumab In some cases, tiragolumab is administered intravenously. Alternatively, in some embodiments, tiragolumab is administered subcutaneously. In some cases, atezolizumab is administered intravenously. Alternatively, in some embodiments, atezolizumab is administered subcutaneously.

[0363] In some cases, tiragolumab is administered to the target or target population by intravenous infusion over approximately 60 ± 15 minutes (e.g., approximately 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75 minutes). In some cases, tiragolumab is administered to the target or target population by intravenous infusion over approximately 60 ± 10 minutes (e.g., approximately 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 minutes). In some cases, atezolizumab is administered to subjects by intravenous infusion over approximately 60 ± 15 minutes (for example, approximately 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75 minutes).

[0364] In some cases, tiragolumab is administered to subjects by intravenous infusion over approximately 30 ± 10 minutes (for example, approximately 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 minutes). In some cases, atezolizumab is administered to subjects by intravenous infusion over approximately 30 ± 10 minutes (for example, approximately 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 minutes).

[0365] v. Administration order and observation period In some cases where both tiragolumab and atezolizumab are administered to the target population, tiragolumab is administered to the target population before atezolizumab.

[0366] In some cases, for example, after administration of tiragolumab and before administration of atezolizumab, this method includes an intervening first observation period. In some cases, for example, atezolizumab is administered to the subject after administration of tiragolumab. In some cases, tiragolumab is administered to the subject first, and atezolizumab is administered to the subject after administration of tiragolumab.

[0367] In some cases, this method further includes a second observation period after atezolizumab administration.

[0368] In some cases, the method includes both a first observation period after administration of tiragolumab and a second observation period after administration of atezolizumab. In some cases, the first and second observation periods are each approximately 30 to 60 minutes long. In cases where the first and second observation periods are each approximately 60 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) approximately 30 ± 10 minutes after administration of tiragolumab or atezolizumab during the first or second observation period. In cases where the first and second observation periods are each approximately 30 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) approximately 15 ± 10 minutes after administration of tiragolumab or atezolizumab during the first or second observation period.

[0369] In some cases, atezolizumab is administered to the subjects or target population before tilagormab. In some cases, for example, after atezolizumab administration and before tilagormab administration, this method includes an intervening first observation period.

[0370] In some cases, the method further includes a second observation period after administration of tiragolumab.

[0371] In some cases, the method includes both a first observation period after administration of atezolizumab and a second observation period after administration of tiragolumab. In some cases, the first and second observation periods are each approximately 30 to 60 minutes long. In cases where the first and second observation periods are each approximately 60 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) approximately 30 ± 10 minutes after administration of atezolizumab or tiragolumab during the first or second observation period. In cases where the first and second observation periods are each approximately 30 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) approximately 15 ± 10 minutes after administration of atezolizumab or tiragolumab during the first or second observation period.

[0372] vi. Combination therapy with tilagolumab and atezolizumab In some cases, for example, for the treatment of subjects with NSCLC, an effective dose of tiragolumab is administered together with a dose of atezolizumab in combination therapy (e.g., combination therapy with tiragolumab and atezolizumab). In some cases, tiragolumab is administered every two weeks as described in Section III(D)(i) of this specification, and atezolizumab is administered every two weeks as described in Section III(D)(ii) of this specification. In some cases, tiragolumab is administered every two weeks as described in Section III(D)(i) of this specification, and atezolizumab is administered every three weeks as described in Section III(D)(ii) of this specification. In some cases, tiragolumab is administered every two weeks as described in Section III(D)(i) of this specification, and atezolizumab is administered every four weeks as described in Section III(D)(ii) of this specification. In some cases, tiragolumab is administered every two weeks as described in Section III(D)(i) of this specification, and atezolizumab is administered every six weeks as described in Section III(D)(ii) of this specification. In some cases, tiragolumab is administered every three weeks as described in Section III(D)(i) of this specification, and atezolizumab is administered every two weeks as described in Section III(D)(ii) of this specification. In some cases, tiragolumab is administered every three weeks as described in Section III(D)(i) of this specification, and atezolizumab is administered every three weeks as described in Section III(D)(ii) of this specification. In some cases, tiragolumab is administered every three weeks as described in Section III(D)(i) of this specification, and atezolizumab is administered every four weeks as described in Section III(D)(ii) of this specification. In some cases, tiragolumab is administered every three weeks as described in Section III(D)(i) of this specification, and atezolizumab is administered every six weeks as described in Section III(D)(ii) of this specification.In some cases, tiragolumab is administered every four weeks as described in Section III(D)(i) of this specification, and atezolizumab is administered every two weeks as described in Section III(D)(ii) of this specification. In some cases, tiragolumab is administered every four weeks as described in Section III(D)(i) of this specification, and atezolizumab is administered every three weeks as described in Section III(D)(ii) of this specification. In some cases, tiragolumab is administered every four weeks as described in Section III(D)(i) of this specification, and atezolizumab is administered every four weeks as described in Section III(D)(ii) of this specification. In some cases, tiragolumab is administered every four weeks as described in Section III(D)(i) of this specification, and atezolizumab is administered every six weeks as described in Section III(D)(ii) of this specification. In some cases, tiragolumab is administered every two, three, or four weeks as described in Section III(D)(i) herein, and atezolizumab is administered every two, three, four, or six weeks as described in Section III(D)(ii) herein.

[0373] In some cases, the dose of tiragolumab is approximately 600 mg every three weeks. In some cases, the dose of tiragolumab is 600 mg every three weeks. In some cases, tiragolumab is administered in a stepwise dosing regimen (e.g., based on the patient's body weight (BW) or body surface area (BSA)) (e.g., every three weeks), and atezolizumab is administered in doses of approximately 0.01 mg / kg to approximately 50 mg / kg (e.g., approximately 15 mg / kg) up to a maximum of 1200 mg, e.g., every three weeks. In some cases, tiragolumab is administered in a stepwise dosing regimen (e.g., based on the subject's body weight (BW) or body surface area (BSA)) (e.g., every 3 weeks), and atezolizumab is administered in doses of 0.01 mg / kg to 50 mg / kg (e.g., 15 mg / kg) up to a maximum of 1200 mg, e.g., every 3 weeks. Such dosing regimens can be used to treat subjects with relatively low body weight (e.g., ≤40 kg (e.g., 5 kg to 40 kg, 15 kg to 40 kg, or 5 kg to 15 kg)) and have been developed through biosimulation studies based on extrapolation of pharmacokinetic parameters estimated from adult data. In some cases, the dose of tiragolumab is a stepwise dose based on the subject's body weight (e.g., BW > 40 kg: 600 mg, BW > 15 kg and ≤ 40 kg: 400 mg, BW ≤ 15 kg: 300 mg). In some cases, the dose of atezolizumab is based on the patient's body weight (e.g., 15 mg / kg). In other cases, the dose of atezolizumab is based on the patient's body surface area (e.g., body surface area (BSA) > 1.25 m²). 2 : 600mg, BSA > 0.75mg 2 and ≤ 1.25m 2 : 450mg, BSA > 0.5mg 2 and ≤0.75m 2 : 350 mg, and BSA ≤ 0.5 m 2The dosage is based on the subject's body weight (e.g., 300 mg). In some cases, the tilagolumab dose (e.g., approximately 600 mg) is administered every three weeks in combination with the subject's body weight-based atezolizumab dose (e.g., 15 mg / kg). In some cases, a stepwise dose of tilagolumab (e.g., body weight (BW) > 40 kg: 600 mg, BW > 15 kg and ≤ 40 kg: 400 mg, BW ≤ 15 kg: 300 mg) is administered every three weeks in combination with the subject's body weight-based atezolizumab dose (e.g., 15 mg / kg). In some cases, a stepwise dose of tilagolumab (e.g., body weight (BW) > 40 kg: 600 mg, BW > 15 kg and ≤ 40 kg: 400 mg, BW ≤ 15 kg: 300 mg) is administered every three weeks in combination with the subject's body surface area-based atezolizumab dose (e.g., BSA > 1.25 m²). 2 : 600mg, BSA > 0.75mg 2 and ≤ 1.25m 2 : 450mg, BSA > 0.5mg 2 and ≤0.75m 2 : 350mg, BSA ≤ 0.5m 2 It is administered in combination with 300 mg. In some embodiments, atezolizumab is administered at a maximum dose of 1200 mg every three weeks. In some cases, combination therapy is administered with one or more chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and / or non-platinum-based chemotherapeutic agents (e.g., antimetabolites (e.g., pemetrexed or gemcitabine)).

[0374] In some cases, the effective dose of tilagolumab to treat a patient with cancer is a stepwise dose based on the patient's weight, such that (a) if the patient weighs 15 kg or less, tilagolumab is administered in doses between approximately 10 mg and approximately 1000 mg every three weeks (e.g., approximately 300 mg every three weeks); (b) if the patient weighs more than 15 kg but 40 kg or less, tilagolumab is administered in doses between approximately 10 mg and approximately 1000 mg every three weeks (e.g., approximately 400 mg every three weeks); or (c) if the patient weighs more than 40 kg, tilagolumab is administered in doses between approximately 30 mg and approximately 1200 mg every three weeks (e.g., approximately 600 mg every three weeks). In some cases, the effective dose of tiragolumab is a stepwise dose based on the patient's body weight, where (a) if the patient weighs 15 kg or less, tiragolumab is administered in doses between approximately 250 mg and approximately 350 mg every three weeks (e.g., approximately 300 mg every three weeks); (b) if the patient weighs more than 15 kg but 40 kg or less, tiragolumab is administered in doses between approximately 350 mg and approximately 450 mg every three weeks (e.g., approximately 400 mg every three weeks); or (c) if the patient weighs more than 40 kg, tiragolumab is administered in doses between approximately 550 mg and approximately 650 mg every three weeks (e.g., approximately 600 mg every three weeks). In some cases, the effective dose of tiragolumab is a graded dose based on the patient's body weight, such as (a) if the patient weighs 15 kg or less, tiragolumab is administered at a dose of approximately 300 mg every three weeks; (b) if the patient weighs between 15 kg and 40 kg, tiragolumab is administered at a dose of approximately 400 mg every three weeks; or (c) if the patient weighs more than 40 kg, tiragolumab is administered at a dose of approximately 600 mg every three weeks.In some cases, the values ​​were between approximately 0.01 mg / kg and approximately 50 mg / kg (body weight of the subject) (for example, between approximately 0.01 mg / kg and approximately 45 mg / kg, between approximately 0.1 mg / kg and approximately 40 mg / kg, between approximately 1 mg / kg and approximately 35 mg / kg, between approximately 2.5 mg / kg and approximately 30 mg / kg, between approximately 5 mg / kg and approximately 25 mg / kg, between approximately 10 mg / kg and approximately 20 mg / kg, between approximately 12.5 mg / kg and approximately 15 mg / kg, for example, between approximately 15 ± 2 mg / kg, approximately 15 ± 1 mg / kg, approximately 15 ± 0.5 mg / kg, approximately 15 ± 0.2 mg / kg or approximately 15 ± 0.1 mg / kg, for example, approximately 15 m Atezolizumab at a dose of g / ...

Claims

1. A method for identifying an individual having non-small cell lung cancer (NSCLC) that may benefit from treatment including atezolizumab and tilagorumab, comprising detecting the expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in a sample from the individual, wherein the expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 that is equal to or greater than the reference expression level of CCL5, CXCR3, CCR7, or CXCR6 identifies the individual as one that may benefit from treatment including atezolizumab and tilagorumab.

2. A method for selecting a treatment for an individual having NSCLC, comprising detecting the expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in a sample from the individual, wherein the expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 being equal to or greater than the reference expression level of CCL5, CXCR3, CCR7, or CXCR6 identifies the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

3. The method according to claim 1 or 2, wherein the individual has an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in the sample that is equal to or greater than the reference expression level of CCL5, CXCR3, CCR7, or CXCR6, and the method further comprises administering an effective amount of atezolizumab and tilagolumab to the individual.

4. A method for treating individuals with NSCLC, (a) detecting the expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in a sample from the individual, wherein the expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 is equal to or greater than the reference expression level of CCL5, CXCR3, CCR7, or CXCR6, thereby identifying and detecting the individual as one that may benefit from treatment including atezolizumab and tilagolumab. (b) Administer an effective dose of atezolizumab and tilagorumab to the individual, Methods that include...

5. A method for treating an individual having NSCLC, comprising administering atezolizumab and tilagorumab to the individual, wherein it is determined that the individual has an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 that is equal to or greater than the reference expression level of CCL5, CXCR3, CCR7, or CXCR6, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

6. The method according to any one of claims 1 to 5, wherein the aforementioned benefit is a clinical response.

7. The method according to claim 6, wherein the clinical response is a complete response (CR) or a partial response (PR).

8. The method according to any one of claims 1 to 7, wherein the individual has an expression level of one or more of CCL5, CXCR3, and CCR7 in the sample that is equal to or greater than the reference expression level of CCL5, CXCR3, or CCR7, and the benefit is an increase in the overall survival (OS) hazard ratio (HR).

9. The method according to any one of claims 1 to 7, wherein the individual has an expression level of one or more of CCL5, CXCR3, and CXCR6 in the sample that is equal to or greater than the reference expression level of CCL5, CXCR3, or CXCR6, and the benefit is an increase in overall survival (OS).

10. The method according to any one of claims 1 to 9, wherein the reference expression level of CCL5, CXCR3, or CXCR6 is a pre-assigned expression level.

11. The method according to any one of claims 1 to 10, wherein the reference expression level of CCL5, CXCR3, or CXCR6 is the expression level in a reference population.

12. The method according to claim 11, wherein the expression level in the reference population is the median expression level of CCL5, CXCR3, or CXCR6 in the reference population.

13. The method according to claim 11 or 12, wherein the reference population is a population of individuals having the NSCLC.

14. A method for identifying an individual having NSCLC that may benefit from treatment including atezolizumab and tilagorumab, comprising detecting the expression levels of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score equal to or greater than a reference gene signature score identifies the individual as one that may benefit from treatment including atezolizumab and tilagorumab.

15. A method for selecting a treatment for an individual having NSCLC, comprising detecting the expression levels of CCL5, CXCR3, and CXCR6 in a sample from the individual, and determining a gene signature score therefrom, wherein a gene signature score equal to or greater than a reference gene signature score identifies the individual as one that may benefit from treatment comprising atezolizumab and tilagolumab.

16. The method according to claim 14 or 15, wherein the individual has a gene signature score in the sample that is equal to or greater than the reference gene signature score, and the method further comprises administering an effective amount of atezolizumab and tilagolumab to the individual.

17. A method for treating individuals with NSCLC, (a) Determining a gene signature score such that the gene signature score is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab; (b) Administer an effective dose of atezolizumab and tilagorumab to the individual, Methods that include...

18. A method for treating an individual having NSCLC, comprising administering atezolizumab and tilagorumab to the individual, wherein the individual has been determined to have a gene signature score equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab, wherein the gene signature score is based on the respective expression levels of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.

19. The method according to any one of claims 14 to 18, wherein the gene signature score is the average of the expression levels of CCL5, CXCR3, and CXCR6 in the sample from the individual.

20. The method according to any one of claims 14 to 17, further comprising detecting the expression level of CCR7 in the sample from the individual.

21. The method according to claim 20, wherein the gene signature score is the average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.

22. The method according to claim 18, wherein the expression level of CCR7 is detected in the sample from the individual.

23. The method according to claim 22, wherein the gene signature score is the average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.

24. The method according to any one of claims 14 to 23, wherein the aforementioned benefit is a clinical response.

25. The method according to claim 24, wherein the clinical response is CR or PR.

26. The method according to any one of claims 14 to 25, wherein the aforementioned benefit is an increase in OS HR.

27. The method according to any one of claims 14 to 26, wherein the aforementioned benefit is an increase in OS.

28. The method according to any one of claims 14 to 27, wherein the reference gene signature score is a pre-assigned gene signature score.

29. The method according to any one of claims 14 to 28, wherein the reference gene signature score is the gene signature score in a reference population.

30. The method according to claim 29, wherein the gene signature score in the reference population is the median of the gene signature scores based on the respective expression levels of CCL5, CXCR3, and CXCR6 in the reference population.

31. The method according to claim 29 or 30, wherein the reference population is a population of individuals having the NSCLC.

32. A method for identifying individuals with NSCLC who may benefit from treatment including atezolizumab and tilagormab, (a) Detect the expression levels of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X in the sample from the individual, and determine the Ccr7.2 gene signature score from there. (b) Detect the expression levels of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZnRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB in ​​the sample from the individual, and determine the Ccr7.3 gene signature score from there. (c) Detect the expression levels of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7 in the sample from the individual, and determine the Cxcr3 gene signature score from there. (d) Detect the expression levels of CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3 in the sample from the individual, and determine the Ccl5.1 gene signature score from there. (e) Detect the expression levels of ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1 in the sample from the individual, and determine the Ifit gene signature score from there. (f) Detect the expression levels of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL in the sample from the individual, and determine the Mitotic gene signature score from there. (g) Detect the expression levels of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT in a sample from the individual, and determine the Cytotox. 2 gene signature score from there, or (h) Detect the expression levels of S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2 in the sample from the individual, and determine the Cytotox. 4 gene signature score from there. Includes, (i) A Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit or Mitotic gene signature score greater than or equal to the reference gene signature score identifies the individual as one that may benefit from treatment including atezolizumab and tilagorumab, (ii) A method for identifying an individual as potentially benefiting from treatment including atezolizumab and tilagorumab, wherein a Cytotox. 2 or Cytotox. 4 gene signature score lower than a reference gene signature score.

33. A method for selecting a treatment for an individual having NSCLC, (a) Detect the expression levels of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X in the sample from the individual, and determine the Ccr7.2 gene signature score from there. (b) Detect the expression levels of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZnRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB in ​​the sample from the individual, and determine the Ccr7.3 gene signature score from there. (c) Detect the expression levels of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7 in the sample from the individual, and determine the Cxcr3 gene signature score from there. (d) Detect the expression levels of CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3 in the sample from the individual, and determine the Ccl5.1 gene signature score from there. (e) Detect the expression levels of ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1 in the sample from the individual, and determine the Ifit gene signature score from there. (f) Detect the expression levels of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL in the sample from the individual, and determine the Mitotic gene signature score from there. (g) Detect the expression levels of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT in a sample from the individual, and determine the Cytotox. 2 gene signature score from there, or (h) Detect the expression levels of S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2 in the sample from the individual, and determine the Cytotox. 4 gene signature score from there. Includes, (i) A Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit or Mitotic gene signature score greater than or equal to the reference gene signature score identifies the individual as one that may benefit from treatment including atezolizumab and tilagorumab, (ii) A method for identifying an individual as potentially benefiting from treatment including atezolizumab and tilagorumab, wherein a Cytotox. 2 or Cytotox. 4 gene signature score lower than a reference gene signature score.

34. The method according to claim 32 or 33, wherein the individual has (i) a Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, or Mitotic gene signature score in the sample equal to or greater than the reference gene signature score, or (ii) a Cytotox. 2 or Cytotox. 4 gene signature score lower than the reference gene signature score, and the method further comprises administering an effective amount of atezolizumab and tilagolumab to the individual.

35. A method for treating individuals with NSCLC, (i) (a) Determining a gene signature score from which the expression levels of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X are detected in a sample from the individual, and a Ccr7.2 gene signature score is determined, wherein the gene signature score is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab. (b) Determining a gene signature score from which the expression levels of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZnRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB are detected, and a Ccr7.3 gene signature score is determined, wherein the gene signature score is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab. (c) Determining a gene signature score from which the expression levels of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7 are detected in a sample from the individual, and a Cxcr3 gene signature score is determined therefrom, wherein the gene signature score is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab. (d) Determining a gene signature score from which the expression levels of CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and HYPEL3 are detected in a sample from the individual, and a Ccl5.1 gene signature score is determined, wherein the gene signature score is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab. (e) Determining an Ifit gene signature score therefrom, wherein the gene signature score is greater than or equal to the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagorumab. (f) Determining a gene signature score from which the expression levels of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL are detected, and a Mitotic gene signature score is determined therefrom, wherein the gene signature score is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab. (g) Determining a gene signature score from which the expression levels of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT are detected in a sample from the individual, and a Cytotox. 2 gene signature score is determined such that the gene signature score is lower than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, or (h) Determining a gene signature score from which the expression levels of S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2 are detected in a sample from the individual, and a Cytotox. 4 gene signature score is determined, wherein the gene signature score is lower than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab. (ii) Administering an effective amount of atezolizumab and tilagolumab to the individual, Methods that include...

36. A method for treating an individual having NSCLC, comprising administering atezolizumab and tilagolumab to the individual, wherein the individual is: (a) Ccr7.2 gene signature score based on the expression levels of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X in a sample from the individual whose Ccr7.2 gene signature score is equal to or greater than the reference Ccr7.2 gene signature score, (b) Ccr7.3 gene signatures based on the expression levels of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZnRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB in ​​a sample from the individual whose Ccr7.3 gene signature score is equal to or greater than the reference Ccr7.3 gene signature score. (c) Cxcr3 gene signature score based on the expression levels of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7 in a sample from the individual whose Cxcr3 gene signature score is equal to or greater than the reference Cxcr3 gene signature score. (d) Ccl5.1 gene signature score based on the expression levels of each of the following in a sample from the individual whose reference Ccl5.1 gene signature score is equal to or greater than that of the individual: Ccl5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and YPEL3, (e) Ifit gene signature scores based on the expression levels of ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1 in a sample from the individual, which are equal to or greater than the reference Ifit gene signature score. (f) Mitotic gene signature scores based on the expression levels of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL in a sample from the individual whose score is equal to or greater than the reference Mitotic gene signature score. (g) A Cytotox. 2 gene signature score based on the expression levels of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT in a sample from the said individual, which is lower than the reference Cytotox. 2 gene signature score, or (h) Cytotox. 4 gene signature scores based on the expression levels of S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2 in samples from the aforementioned individuals, which are lower than the reference Cytotox. 4 gene signature scores. It has been determined that it has A method for identifying the individual as one that may benefit from treatment including atezolizumab and tilagormab.

37. The method according to any one of claims 32 to 36, wherein the gene signature score is the average of the expression levels of the members of the gene signature in the sample from the individual.

38. The method according to any one of claims 32 to 37, wherein the individual has a Ccr7.3, Cxcr3, or Ccl5.1 gene signature score in the sample that is equal to or greater than the reference gene signature score, and the benefit is a clinical response.

39. The method according to claim 38, wherein the clinical response is CR or PR.

40. The method according to any one of claims 32 to 37, wherein the individual has (i) a Ccr7.2, Cxcr3, Ifit, or Mitotic gene signature score in the sample equal to or greater than the reference gene signature score, or (ii) a Cytotox. 2 or Cytotox. 4 gene signature score lower than the reference gene signature score, and the benefit is an increase in OSHR.

41. The method according to any one of claims 32 to 37, wherein the individual has a Ccr7.2, Ccr7.3, or Cxcr3 gene signature score in the sample that is equal to or greater than the reference gene signature score, and the benefit is an increase in OS.

42. The method according to any one of claims 32 to 41, wherein the reference gene signature score is a pre-assigned gene signature score.

43. The method according to any one of claims 32 to 42, wherein the reference gene signature score is the gene signature score in a reference population.

44. The method according to claim 43, wherein the gene signature score in the reference population is the median of the gene signature scores for Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox. 2, or Cytotox. 4 in the reference population.

45. The method according to claim 43 or 44, wherein the reference population is a population of individuals having the NSCLC.

46. A method for identifying an individual having NSCLC that may benefit from treatment containing atezolizumab, comprising detecting the expression levels of CCL5, CXCR3, and CXCR6 in a sample from the individual, and determining a gene signature score therefrom, wherein a gene signature score equal to or greater than a reference gene signature score identifies the individual as one that may benefit from treatment containing atezolizumab.

47. A method for selecting a treatment for an individual having NSCLC, comprising detecting the expression levels of CCL5, CXCR3, and CXCR6 in a sample from the individual, and determining a gene signature score therefrom, wherein a gene signature score equal to or greater than a reference gene signature score identifies the individual as one that may benefit from treatment including atezolizumab.

48. The method according to claim 46 or 47, wherein the individual has a gene signature score in the sample that is equal to or greater than the reference gene signature score, and the method further comprises administering an effective amount of atezolizumab to the individual.

49. A method for treating individuals with NSCLC, (a) Determining a gene signature score such that the gene signature score is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab; (b) Administer an effective dose of atezolizumab to the individual, Methods that include...

50. A method for treating an individual having NSCLC, comprising administering atezolizumab to the individual, wherein the individual has been determined to have a gene signature score equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab, and the gene signature score is based on the respective expression levels of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.

51. The method according to any one of claims 46 to 50, wherein the gene signature score is the average of the expression levels of CCL5, CXCR3, and CXCR6 in the sample from the individual.

52. The method according to any one of claims 46 to 49, further comprising detecting the expression level of CCR7 in the sample from the individual.

53. The method according to claim 52, wherein the gene signature score is the average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.

54. The method according to claim 50, wherein the expression level of CCR7 is detected in the sample from the individual.

55. The method according to claim 54, wherein the gene signature score is the average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.

56. The method according to any one of claims 46 to 55, wherein the benefit is an increase in progression-free survival (PFS) or overall survival (OS).

57. The method according to any one of claims 46 to 56, wherein the reference gene signature score is a pre-assigned gene signature score.

58. The method according to any one of claims 46 to 57, wherein the reference gene signature score is the gene signature score in a reference population.

59. The method according to claim 58, wherein the gene signature score in the reference population is the median of the gene signature scores based on the respective expression levels of CCL5, CXCR3, and CXCR6 in the reference population.

60. The method according to claim 58 or 59, wherein the reference population is a population of individuals having the NSCLC.

61. The method according to any one of claims 46 to 60, wherein the treatment comprising atezolizumab is atezolizumab monotherapy.

62. The method according to any one of claims 1 to 61, wherein the expression level is a nucleic acid expression level or a protein expression level.

63. The method according to claim 62, wherein the expression level is a nucleic acid expression level.

64. The method according to claim 63, wherein the nucleic acid expression level is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof.

65. The method according to claim 63 or 64, wherein the nucleic acid expression level is the mRNA expression level.

66. The method according to claim 65, wherein the mRNA expression level is determined by RNA-seq.

67. The method according to claim 62, wherein the expression level is a protein expression level.

68. The method according to claim 67, wherein the protein expression level is determined by mass spectrometry.

69. The method according to any one of claims 1 to 68, wherein the sample is obtained from the individual before treatment with atezolizumab and / or tilagorumab.

70. The method according to any one of claims 1 to 69, wherein the sample is a tissue sample, a tumor sample, a blood sample, a plasma sample, a serum sample, or a combination thereof.

71. The method according to claim 70, wherein the sample is a tissue sample.

72. The method according to claim 71, wherein the tissue sample is a tumor tissue sample.

73. The method according to claim 72, wherein the tumor tissue sample is a biopsy material.

74. The method according to claim 71, wherein the tissue sample is a tumor drainage lymph node (dLN) sample.

75. The method according to claim 70, wherein the sample is a blood sample.

76. The method according to any one of claims 70 to 75, wherein the sample is a stored sample, a fresh sample, or a frozen sample.

77. The method according to any one of claims 1 to 76, wherein the individual has PD-L1 positive NSCLC.

78. The method according to claim 77, wherein the PD-L1-positive NSCLC is determined to have a PD-L1-positive tumor cell fraction by immunohistochemistry (IHC) assay.

79. The method according to claim 78, wherein the PD-L1-positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, and the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8.

80. The method according to any one of claims 1 to 79, wherein the individual is a human.

81. The method according to any one of claims 1 to 80, wherein the individual has not been previously treated for NSCLC.

82. Use of atezolizumab and / or tilagorumab in the manufacture of a pharmaceutical product for treating an individual having NSCLC, wherein the individual is determined to have an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in a sample from the individual which is equal to or greater than the reference expression level of CCL5, CXCR3, CCR7, or CXCR6, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

83. The use according to claim 82, wherein the aforementioned benefit is a clinical response.

84. The use according to claim 83, wherein the clinical response is a complete response (CR) or a partial response (PR).

85. The use according to any one of claims 82 to 84, wherein the individual is determined to have an expression level of one or more of CCL5, CXCR3, and CCR7 in the sample that is equal to or greater than the reference expression level of CCL5, CXCR3, or CCR7, and the benefit is an increase in the overall survival (OS) hazard ratio (HR).

86. The use according to any one of claims 82 to 85, wherein the individual is determined to have an expression level of one or more of CCL5, CXCR3, and CXCR6 in the sample that is equal to or greater than the reference expression level of CCL5, CXCR3, or CXCR6, and the benefit is an increase in overall survival (OS).

87. The use according to any one of claims 82 to 86, wherein the reference expression level of CCL5, CXCR3, or CXCR6 is a pre-assigned expression level.

88. The use according to any one of claims 82 to 87, wherein the reference expression level of CCL5, CXCR3, or CXCR6 is the expression level in a reference population.

89. The use according to claim 88, wherein the expression level in the reference population is the median expression level of CCL5, CXCR3, or CXCR6 in the reference population.

90. The use according to claim 88 or 89, wherein the reference group is a group of individuals having the NSCLC.

91. The use of atezolizumab and / or tilagorumab in the manufacture of a pharmaceutical product for treating an individual having NSCLC, wherein the individual has been determined to have a gene signature score equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab, the gene signature score being based on the respective expression levels of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.

92. The use according to claim 91, wherein the gene signature score is the average of the expression levels of CCL5, CXCR3, and CXCR6 in the sample from the individual.

93. The use according to claim 91 or 92, wherein the expression level of CCR7 is detected in the sample from the individual.

94. The use according to claim 93, wherein the gene signature score is the average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.

95. The use according to any one of claims 91 to 94, wherein the aforementioned benefit is a clinical response.

96. The use according to claim 95, wherein the clinical response is CR or PR.

97. The use according to any one of claims 91 to 96, wherein the aforementioned benefit is an increase in OS HR.

98. The use according to any one of claims 91 to 97, wherein the aforementioned benefit is an increase in OS.

99. The use according to any one of claims 91 to 98, wherein the reference gene signature score is a pre-assigned gene signature score.

100. The use according to any one of claims 91 to 99, wherein the reference gene signature score is the gene signature score in the reference population.

101. The use according to claim 100, wherein the gene signature score in the reference population is the median of the gene signature scores based on the respective expression levels of CCL5, CXCR3, and CXCR6 in the reference population.

102. The use according to claim 100 or 101, wherein the reference population is a population of individuals having the NSCLC.

103. The use of atezolizumab and / or tilagolumab in the manufacture of a pharmaceutical product for treating an individual having NSCLC, wherein the individual is: (i) (a) A Ccr7.2 gene signature score that is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the respective expression levels of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X detected in a sample from the individual, (b) A Ccr7.3 gene signature score that is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the respective expression levels of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZnRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB detected in a sample from the individual, (c) A Cxcr3 gene signature score that is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the respective expression levels of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7 detected in a sample from the individual, (d) A Ccl5.1 gene signature score that is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the respective expression levels of CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and HYPEL3 detected in a sample from the individual, (e) An Ifit gene signature score that is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the respective expression levels of ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1 detected in a sample from the individual, (f) A Mitotic gene signature score that is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the respective expression levels of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL detected in a sample from the individual. (g) A Cytotox. 2 gene signature score lower than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, wherein the gene signature score is based on the respective expression levels of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT detected in a sample from the individual, or (h) A Cytotox.4 gene signature score lower than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, wherein the gene signature score is based on the respective expression levels of S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2 detected in a sample from the individual. It has been decided that it will have use.

104. The use according to claim 103, wherein the gene signature score is the average of the expression levels of the members of the gene signature in the sample from the individual.

105. The use according to claim 103 or 104, wherein the individual is determined to have a Ccr7.3, Cxcr3, or Ccl5.1 gene signature score in the sample that is equal to or greater than the reference gene signature score, and the benefit is a clinical response.

106. The use according to claim 105, wherein the clinical response is CR or PR.

107. The use according to claim 103 or 104, wherein the individual is determined to have (i) a Ccr7.2, Cxcr3, Ifit, or Mitotic gene signature score in the sample equal to or greater than the reference gene signature score, or (ii) a Cytotox. 2 or Cytotox. 4 gene signature score lower than the reference gene signature score, and the benefit is an increase in OSHR.

108. The use according to claim 103 or 104, wherein the individual is determined to have a Ccr7.2, Ccr7.3, or Cxcr3 gene signature score in the sample that is equal to or greater than the reference gene signature score, and the benefit is an increase in OS.

109. The use according to any one of claims 103 to 108, wherein the reference gene signature score is a pre-assigned gene signature score.

110. The use according to any one of claims 103 to 109, wherein the reference gene signature score is the gene signature score in the reference population.

111. The use according to claim 110, wherein the gene signature score in the reference population is the median of the gene signature scores for Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox. 2, or Cytotox. 4 in the reference population.

112. The use according to claim 110 or 111, wherein the reference group is a group of individuals having the NSCLC.

113. The use of atezolizumab in the manufacture of a pharmaceutical product for treating an individual having NSCLC, wherein the individual has been determined to have a gene signature score equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab, and the gene signature score is based on the respective expression levels of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.

114. The use according to claim 113, wherein the gene signature score is the average of the expression levels of CCL5, CXCR3, and CXCR6 in the sample from the individual.

115. The use according to claim 113 or 114, wherein the expression level of CCR7 is detected in the sample from the individual.

116. The use according to claim 115, wherein the gene signature score is the average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.

117. The use according to any one of claims 113 to 116, wherein the benefit is an increase in progression-free survival (PFS) or overall survival (OS).

118. The use according to any one of claims 113 to 117, wherein the reference gene signature score is a pre-assigned gene signature score.

119. The use according to any one of claims 113 to 118, wherein the reference gene signature score is the gene signature score in the reference population.

120. The use according to claim 119, wherein the gene signature score in the reference population is the median of the gene signature scores based on the respective expression levels of CCL5, CXCR3, and CXCR6 in the reference population.

121. The use according to claim 119 or 120, wherein the reference population is a population of individuals having the NSCLC.

122. The use according to any one of claims 113 to 121, wherein the treatment comprising atezolizumab is atezolizumab monotherapy.

123. The use according to any one of claims 82 to 122, wherein the expression level is a nucleic acid expression level or a protein expression level.

124. The use according to claim 123, wherein the expression level is a nucleic acid expression level.

125. The use according to claim 124, wherein the nucleic acid expression level is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof.

126. The use according to claim 124 or 125, wherein the nucleic acid expression level is the mRNA expression level.

127. The use according to claim 126, wherein the mRNA expression level is determined by RNA-seq.

128. The use according to claim 123, wherein the expression level is a protein expression level.

129. The use according to claim 128, wherein the protein expression level is determined by mass spectrometry.

130. The use according to any one of claims 82 to 129, wherein the sample is obtained from the individual before treatment with atezolizumab and / or tilagorumab.

131. The use according to any one of claims 82 to 130, wherein the sample is a tissue sample, a tumor sample, a blood sample, a plasma sample, a serum sample, or a combination thereof.

132. The use according to claim 131, wherein the sample is a tissue sample.

133. The use according to claim 132, wherein the tissue sample is a tumor tissue sample.

134. The use according to claim 133, wherein the tumor tissue sample is a biopsy material.

135. The use according to claim 132, wherein the tissue sample is a tumor drainage lymph node (dLN) sample.

136. The use according to claim 131, wherein the sample is a blood sample.

137. The use according to any one of claims 131 to 136, wherein the sample is a stored sample, a fresh sample, or a frozen sample.

138. The use according to any one of claims 82 to 137, wherein the individual has PD-L1 positive NSCLC.

139. The use according to claim 138, wherein the PD-L1-positive NSCLC is determined to have a PD-L1-positive tumor cell fraction by immunohistochemistry (IHC) assay.

140. The use according to claim 139, wherein the PD-L1-positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, and the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8.

141. The use according to any one of claims 82 to 140, wherein the individual is a human.

142. The use according to any one of claims 82 to 141, wherein the individual has not been previously treated for NSCLC.

143. Atezolizumab and / or tilagorumab for use in treating individuals having NSCLC, wherein the individual has been determined to have an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in a sample from the individual that is equal to or above a reference expression level of CCL5, CXCR3, CCR7, or CXCR6, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab.

144. Atezolizumab and / or tilagolmab for use according to claim 143, wherein the aforementioned benefit is a clinical response.

145. Atezolizumab and / or tilagolumab for use according to claim 144, wherein the clinical response is a complete response (CR) or a partial response (PR).

146. Atezolizumab and / or tilagolumab for use according to any one of claims 143 to 145, wherein the individual is determined to have an expression level of one or more of CCL5, CXCR3, and CCR7 in the sample that is equal to or greater than the reference expression level of CCL5, CXCR3, or CCR7, and the benefit is an increase in the overall survival (OS) hazard ratio (HR).

147. Atezolizumab and / or tilagorumab for use according to any one of claims 143 to 146, wherein the individual is determined to have an expression level of one or more of CCL5, CXCR3, and CXCR6 in the sample that is equal to or greater than the reference expression level of CCL5, CXCR3, or CXCR6, and the benefit is an increase in overall survival (OS).

148. Atezolizumab and / or tilagolumab for use according to any one of claims 143 to 147, wherein the reference expression level of CCL5, CXCR3, or CXCR6 is a pre-assigned expression level.

149. Atezolizumab and / or tilagolumab for use according to any one of claims 143 to 148, wherein the reference expression level of CCL5, CXCR3, or CXCR6 is the expression level in a reference population.

150. Atezolizumab and / or tilagolumab for use according to claim 149, wherein the expression level in the reference population is the median expression level of CCL5, CXCR3, or CXCR6 in the reference population.

151. Atezolizumab and / or tilagormab for use according to claim 149 or 150, wherein the reference population is a population of individuals having the NSCLC.

152. Atezolizumab and / or tilagorumab for use in treating an individual having NSCLC, wherein the individual has been determined to have a gene signature score equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment comprising atezolizumab and tilagorumab, wherein the gene signature score is based on the expression levels of CCL5, CXCR3, and CXCR6, respectively, detected in a sample from the individual.

153. Atezolizumab and / or tilagolumab for use according to claim 152, wherein the gene signature score is the average of the expression levels of CCL5, CXCR3, and CXCR6 in the sample from the individual.

154. The expression level of CCR7 is detected in the sample from the individual, atezolizumab and / or tilagolumab for use according to claim 152 or 153.

155. Atezolizumab and / or tilagolumab for use according to claim 154, wherein the gene signature score is the average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.

156. Atezolizumab and / or tilagolmab for use according to any one of claims 152 to 155, wherein the aforementioned benefit is a clinical response.

157. Atezolizumab and / or tilagolumab for use according to claim 156, wherein the clinical response is CR or PR.

158. Atezolizumab and / or tilagolumab for use according to any one of claims 152 to 157, wherein the aforementioned benefit is an increase in OSHR.

159. Atezolizumab and / or tilagolumab for use according to any one of claims 152 to 158, wherein the aforementioned benefit is an increase in OS.

160. Atezolizumab and / or tilagolumab for use according to any one of claims 152 to 159, wherein the reference gene signature score is a pre-assigned gene signature score.

161. Atezolizumab and / or tilagolumab for use according to any one of claims 152 to 160, wherein the reference gene signature score is a gene signature score in a reference population.

162. Atezolizumab and / or tilagolumab for use according to claim 161, wherein the gene signature score in the reference population is the median of the gene signature scores based on the respective expression levels of CCL5, CXCR3, and CXCR6 in the reference population.

163. Atezolizumab and / or tilagormab for use according to claim 161 or 162, wherein the reference population is a population of individuals having the NSCLC.

164. Atezolizumab and / or tilagorumab for use in the treatment of individuals having NSCLC, wherein the individual is: (i) (a) A Ccr7.2 gene signature score that is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the respective expression levels of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X detected in a sample from the individual, (b) A Ccr7.3 gene signature score that is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the respective expression levels of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZnRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB detected in a sample from the individual, (c) A Cxcr3 gene signature score that is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the respective expression levels of CXCR6, CKB, GIMAP5, ID2, LTB, FGL2, RAMP1, LYST, ASB2, IL2RB, CXCR3, SERINC3, INPP4B, ANXA1, XCL2, SOCS2, CD82, CD4, and GIMAP7 detected in a sample from the individual, (d) A Ccl5.1 gene signature score that is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the respective expression levels of CCL5, ITGB1, BTG1, GZMK, LTB, IL7R, ZFP36L2, ITGA4, TXNIP, SLAMF6, HCST, ETS1, CXCR3, MS4A4A, DGKA, and HYPEL3 detected in a sample from the individual, (e) An Ifit gene signature score that is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the respective expression levels of ISG15, IFIT1B, IFIT3, ISG20, IFI27L2, SAMHD1, ZBP1, SLFN5, IRF7, RTP4, USP18, PHF11, LGALS3BP, BST2, GBP2, IFITM3, STAT1, IFI16, and IFIH1 detected in a sample from the individual, (f) A Mitotic gene signature score that is equal to or greater than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, and the gene signature score is based on the respective expression levels of HSP90AB1, PTMA, XCL2, ODC1, TNFRSF9, ITM2A, MYC, YBX3, HSPA5, GPX1, RPS12, TUBA1B, MCM6, TUBB, MCM3, TPI1, MCM5, DUT, and FTL detected in a sample from the individual. (g) A Cytotox. 2 gene signature score lower than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, wherein the gene signature score is based on the respective expression levels of HMGB2, TOP2A, MKI67, RRM2, PCLAF, TUBB, BIRC5, LMNB1, UBE2C, PTMA, STMN1, HMGN2, TUBA1B, LY6E, and DUT detected in a sample from the individual, or (h) A Cytotox.4 gene signature score lower than the reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab and tilagolumab, wherein the gene signature score is based on the respective expression levels of S100A6, NRN1, CXCR6, KLRC1, PDCD1, LGALS1, LAG3, ITGB1, ID2, LGALS3, NRGN, CST7, NKG7, S100A10, TNFRSF9, CD52, VIM, and IFITM2 detected in a sample from the individual. Atezolizumab and / or tiragolumab for use, which have been determined to have the following properties.

165. Atezolizumab and / or tilagolumab for use according to claim 164, wherein the gene signature score is the average of the expression levels of the members of the gene signature in the sample from the individual.

166. Atezolizumab and / or tilagolumab for use according to claim 164 or 165, wherein the individual is determined to have a Ccr7.3, Cxcr3, or Ccl5.1 gene signature score in the sample that is equal to or greater than the reference gene signature score, and the benefit is a clinical response.

167. Atezolizumab and / or tilagolumab for use according to claim 166, wherein the clinical response is CR or PR.

168. Atezolizumab and / or tilagolumab for use according to claim 164 or 165, wherein the individual is determined to have (i) a Ccr7.2, Cxcr3, Ifit, or Mitotic gene signature score in the sample equal to or greater than the reference gene signature score, or (ii) a Cytotox. 2 or Cytotox. 4 gene signature score lower than the reference gene signature score, and the benefit is an increase in OSHR.

169. Atezolizumab and / or tilagolumab for use according to claim 164 or 165, wherein the individual is determined to have a Ccr7.2, Ccr7.3, or Cxcr3 gene signature score in the sample that is equal to or greater than the reference gene signature score, and the benefit is an increase in OS.

170. Atezolizumab and / or tilagolumab for use according to any one of claims 164 to 169, wherein the reference gene signature score is a pre-assigned gene signature score.

171. Atezolizumab and / or tilagolumab for use according to any one of claims 164 to 170, wherein the reference gene signature score is a gene signature score in a reference population.

172. Atezolizumab and / or tilagolumab for use according to claim 171, wherein the gene signature score in the reference population is the median of the gene signature scores for Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox. 2, or Cytotox. 4 in the reference population.

173. The atezolizumab and / or tilagormab for use according to claim 171 or 172, wherein the reference population is a population of individuals having the NSCLC.

174. Atezolizumab for use in the treatment of individuals having NSCLC, wherein the individual has been determined to have a gene signature score equal to or greater than a reference gene signature score, thereby identifying the individual as one that may benefit from treatment including atezolizumab, and the gene signature score is based on the respective expression levels of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.

175. Atezolizumab for use according to claim 174, wherein the gene signature score is the average of the expression levels of CCL5, CXCR3, and CXCR6 in the sample from the individual.

176. Atezolizumab for use according to claim 174 or 175, wherein the expression level of CCR7 is detected in the sample from the individual.

177. Atezolizumab for use according to claim 176, wherein the gene signature score is the average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.

178. Atezolizumab for use according to any one of claims 174 to 177, wherein the benefit is an increase in progression-free survival (PFS) or overall survival (OS).

179. Atezolizumab for use according to any one of claims 174 to 178, wherein the reference gene signature score is a pre-assigned gene signature score.

180. Atezolizumab for use according to any one of claims 174 to 179, wherein the reference gene signature score is a gene signature score in a reference population.

181. Atezolizumab for use according to claim 180, wherein the gene signature score in the reference population is the median of the gene signature scores based on the respective expression levels of CCL5, CXCR3, and CXCR6 in the reference population.

182. Atezolizumab for use according to claim 180 or 181, wherein the reference population is a population of individuals having the NSCLC.

183. Atezolizumab for use according to any one of claims 174 to 182, wherein the treatment comprising atezolizumab is atezolizumab monotherapy.

184. Atezolizumab and / or tilagolumab for use according to any one of claims 143 to 183, wherein the expression level is a nucleic acid expression level or a protein expression level.

185. The atezolizumab and / or tilagolumab for use according to claim 184, wherein the expression level is a nucleic acid expression level.

186. Atezolizumab and / or tilagolumab for use according to claim 185, wherein the nucleic acid expression level is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof.

187. The atezolizumab and / or tilagolumab for use according to claim 185 or 186, wherein the nucleic acid expression level is an mRNA expression level.

188. Atezolizumab and / or tilagolumab for use according to claim 187, wherein the mRNA expression level is determined by RNA-seq.

189. The atezolizumab and / or tilagolumab for use according to claim 184, wherein the expression level is a protein expression level.

190. Atezolizumab and / or tilagolumab for use according to claim 189, wherein the protein expression level is determined by mass spectrometry.

191. Atezolizumab and / or tilagorumab for use according to any one of claims 143 to 190, wherein the sample is obtained from the individual before treatment with atezolizumab and / or tilagorumab.

192. Atezolizumab and / or tilagolumab for use according to any one of claims 143 to 191, wherein the sample is a tissue sample, a tumor sample, a blood sample, a plasma sample, a serum sample, or a combination thereof.

193. The atezolizumab and / or tilagolumab for use according to claim 192, wherein the sample is a tissue sample.

194. The atezolizumab and / or tilagolumab for use according to claim 193, wherein the tissue sample is a tumor tissue sample.

195. The atezolizumab and / or tilagolumab for use according to claim 194, wherein the tumor tissue sample is biopsy material.

196. The atezolizumab and / or tilagolumab for use according to claim 193, wherein the tissue sample is a tumor drainage lymph node (dLN) sample.

197. The atezolizumab and / or tilagolumab for use according to claim 192, wherein the sample is a blood sample.

198. Atezolizumab and / or tilagolumab for use according to any one of claims 192 to 197, wherein the sample is a stored sample, a fresh sample, or a frozen sample.

199. Atezolizumab and / or tilagormab for use according to any one of claims 143 to 198, wherein the individual has PD-L1 positive NSCLC.

200. Atezolizumab and / or tilagolumab for use according to claim 199, wherein the PD-L1-positive NSCLC is determined to have a PD-L1-positive tumor cell fraction by immunohistochemistry (IHC) assay.

201. Atezolizumab and / or tilagolumab for use according to claim 200, wherein the PD-L1-positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, and the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8.

202. Atezolizumab and / or tilagolumab for use according to any one of claims 143 to 201, wherein the individual is human.

203. Atezolizumab and / or tilagormab for use according to any one of claims 143 to 202, wherein the individual has not been previously treated for NSCLC.

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