DIAGNOSTIC AND THERAPEUTIC METHODS FOR CANCER
The present invention provides diagnostic methods, therapeutic methods, and compositions for the treatment of cancer (e.g., a bladder cancer (e.g., UC, e.g., mUC), a kidney cancer, a lung cancer, a liver cancer, an ovarian cancer, a pancreatic cancer, a colorectal cancer, or a breast cancer). The invention is based, at least in part, on the discovery that expression levels of one or more biomarkers described herein in a sample from an individual having cancer can be used in methods of identifying an individual having a cancer who may benefit with an anti-cancer therapy that includes an immunotherapy (e.g., a PD-L1 axis binding antagonist such as an anti-PD-L1 antibody (e.g., atezolizumab)) and a suppressive stromal antagonist (e.g., a TGF-β antagonist), methods for selecting a therapy for an individual having cancer, methods of treating an individual having cancer, methods for assessing a response or monitoring the response of an individual to treatment with an anti-cancer therapy that includes an immunotherapy (e.g., a PD-L1 axis binding antagonist such as an anti-PD-L1 antibody (e.g., atezolizumab)) and a suppressive stromal antagonist (e.g., a TGF-β antagonist), and related kits, anti-cancer therapies, and uses.
1 - 139 . (canceled)
140 . A method of identifying and treating an individual having a cancer who may benefit from treatment with an anti-cancer therapy comprising a PD-L1 binding antagonist and a TGF-β antagonist, the method comprising:
(i) determining the expression level of TGFB1 and/or TGFBR2 in a sample from the individual obtained prior to treatment with the PD-L1 binding antagonist and the TGF-β antagonist, wherein the expression level of TGFB1 and/or TGFBR2 in the sample is at or above a reference expression level of TGFB1 and/or TGFBR2, thereby identifying the individual as one who may benefit from treatment with an anti-cancer therapy comprising a PD-L1 binding antagonist and a TGF-β antagonist; and
(ii) administering an effective amount of an anti-cancer therapy comprising a PD-L1 binding antagonist and a TGF-β antagonist to the individual identified in step (i) as being one who may benefit from treatment with an anti-cancer therapy comprising an anti-PD-L1 antibody and a TGF-β antagonist, wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody.
141 . The method of claim 140 , wherein the cancer is urothelial carcinoma (UC), non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), or pancreatic ductal adenocarcinoma (PDAC).
142 . The method of claim 140 , wherein the anti-PD-L1 antibody comprises the following hypervariable regions (HVRs):
(a) an HVR-H1 sequence of
(SEQ ID NO: 63)
GFTFSDSWIH;
(b) an HVR-H2 sequence of
(SEQ ID NO: 64)
AWISPYGGSTYYADSVKG;
(c) an HVR-H3 sequence of
(SEQ ID NO: 65)
RHWPGGFDY;
(d) an HVR-L1 sequence of
(SEQ ID NO: 66)
RASQDVSTAVA;
(e) an HVR-L2 sequence of
(SEQ ID NO: 67)
SASFLYS;
and
(f) an HVR-L3 sequence of
(SEQ ID NO: 68)
QQYLYHPAT
143 . The method of claim 141 , wherein the anti-PD-L1 antibody comprises the following HVRs:
(a) an HVR-H1 sequence of
(SEQ ID NO: 63)
GFTFSDSWIH;
(b) an HVR-H2 sequence of
(SEQ ID NO: 64)
AWISPYGGSTYYADSVKG;
(c) an HVR-H3 sequence of
(SEQ ID NO: 65)
RHWPGGFDY;
(d) an HVR-L1 sequence of
(SEQ ID NO: 66)
RASQDVSTAVA;
(e) an HVR-L2 sequence of
(SEQ ID NO: 67)
SASFLYS;
and
(f) an HVR-L3 sequence of
(SEQ ID NO: 68)
QQYLYHPAT
144 . A method of treating an individual having a cancer, the method comprising administering to the individual an anti-cancer therapy comprising a PD-L1 binding antagonist and a TGF-β antagonist, wherein prior to treatment the expression level of TGFB1 and/or TGFBR2 in a sample obtained from the individual has been determined to be at or above a reference expression level of TGFB1 and/or TGFBR2, wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody.
145 . The method of claim 144 , wherein the cancer is UC, NSCLC, TNBC, or PDAC.
146 . The method of claim 144 , wherein the anti-PD-L1 antibody comprises the following HVRs:
(a) an HVR-H1 sequence of
(SEQ ID NO: 63)
GFTFSDSWIH;
(b) an HVR-H2 sequence of
(SEQ ID NO: 64)
AWISPYGGSTYYADSVKG;
(c) an HVR-H3 sequence of
(SEQ ID NO: 65)
RHWPGGFDY;
(d) an HVR-L1 sequence of
(SEQ ID NO: 66)
RASQDVSTAVA;
(e) an HVR-L2 sequence of
(SEQ ID NO: 67)
SASFLYS;
and
(f) an HVR-L3 sequence of
(SEQ ID NO: 68)
QQYLYHPAT
147 . The method of claim 145 , wherein the anti-PD-L1 antibody comprises the following HVRs:
(a) an HVR-H1 sequence of
(SEQ ID NO: 63)
GFTFSDSWIH;
(b) an HVR-H2 sequence of
(SEQ ID NO: 64)
AWISPYGGSTYYADSVKG;
(c) an HVR-H3 sequence of
(SEQ ID NO: 65)
RHWPGGFDY;
(d) an HVR-L1 sequence of
(SEQ ID NO: 66)
RASQDVSTAVA;
(e) an HVR-L2 sequence of
(SEQ ID NO: 67)
SASFLYS;
and
(f) an HVR-L3 sequence of
(SEQ ID NO: 68)
QQYLYHPAT
148 . The method of claim 144 , further comprising:
(i) determining the expression level in the sample of one or more additional genes selected from PD-L1, CD8A, CXCL10, CXCL9, GZMA, GZMB, IFNG, PRF1, and TBX21;
(ii) determining a tumor mutational burden (TMB) score in a tumor sample from the individual; and/or
(iii) administering an additional therapeutic agent to the individual.
149 . The method of claim 148 , wherein the additional therapeutic agent is an immunotherapy agent, a cytotoxic agent, a growth inhibitory agent, a radiation therapy agent, an anti-angiogenic agent, or a combination thereof.
150 . The method of claim 144 , wherein:
(i) a tumor from the individual has an immune excluded phenotype characterized by the localization of CD8+ T-cells in the peri-tumoral stromal compartment;
(ii) the reference expression level is determined from a population of individuals having a cancer;
(iii) the expression level is a nucleic acid expression level;
(iv) the expression level is a protein expression level; and/or
(v) the sample is a tissue sample, a cell sample, a whole blood sample, a plasma sample, a serum sample, or a combination thereof.
151 . The method of claim 150 , wherein the reference expression level is a median expression level or is determined by principal component analysis of Z-score-transformed expression levels.
152 . The method of claim 144 , wherein:
(i) the TGF-β antagonist is a polypeptide, a small molecule, or a nucleic acid; and/or
(ii) the anti-PD-L1 antibody comprises:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 69; and
(b) a VL domain comprising the amino acid sequence of SEQ ID NO: 70.
153 . The method of claim 152 , wherein:
(i) the polypeptide is an anti-TGF-β antibody, a soluble TGF-β receptor, or a peptide; the small molecule is galunisertib (LY2157299), LY2382770, LY3022859, SB-431542, SD208, SM16, tranilast, pirfenidone, TEW-7197, PF-03446962, or pyrrole-imidazole polyamide; or the nucleic acid is trabedersen (AP12009) or belagenpumatucel-L; and/or
(ii) the anti-PD-L1 antibody is atezolizumab.
154 . The method of claim 153 , wherein:
(i) the anti-TGF-β antibody is fresolimumab, metelimumab, lerdelimumab, 1 D11, 2G7, or a derivative thereof; or
(ii) the peptide is disitertide (P144).
155 . The method of claim 141 , wherein the UC is a metastatic UC.
156 . The method of claim 145 , wherein the UC is a metastatic UC.
157 . The method of claim 140 , wherein:
(i) the anti-PD-L1 antibody is atezolizumab; and/or
(ii) the reference expression level is determined from a population of individuals having the cancer.
158 . The method of claim 157 , wherein the reference expression level is a median expression level or is determined by principal component analysis of Z-score-transformed expression levels.
159 . A method of treating an individual having a cancer, the method comprising administering to the individual an anti-cancer therapy comprising a PD-L1 binding antagonist and a TGF-β antagonist, wherein prior to treatment the expression level of TGFB1 and/or TGFBR2 in the individual is at or above a reference expression level of TGFB1 and/or TGFBR2, wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody.