Molecular biomarkers for cancer immunotherapy

Patent metadata

Field	Value
Publication number	US-11939637-B2
Application number	US-202117179956-A
Country	US
Kind code	B2
Filing date	Feb 19, 2021
Priority date	Dec 19, 2014
Publication date	Mar 26, 2024
Grant date	Mar 26, 2024

Abstract

In one aspect, provided herein is a method comprising: (a) (i) determining cytolytic activity in a tumor from the subject; and/or (ii) determining genetic alterations associated with cytolytic activity in the tumor; and (b) administering an immunotherapeutic agent to the subject if (i) cytolytic activity is detected in the tumor and/or (ii) a genetic alteration associated with induction of cytolytic activity, tumor resistance to cytolytic activity and/or suppression of cytolytic activity is detected in the tumor.

First claim

What is claimed is:

1. A method of treating cancer in a patient in need thereof, comprising
(a) selecting a patient suffering from cancer for immunotherapy by detecting cytolytic activity in tumor tissue from the patient, wherein detecting cytolytic activity comprises measuring cytolytic activity in tumor tissue from the patient by assaying the expression of granzyme A (GZMA) and perforin (PRF1), wherein the measuring comprises sequencing RNA expressed in the tumor tissue, and comprises (i) calculating the log-average of the transcript levels of granzyme A (GZMA) and perforin (PRF1), and (ii) assigning a cytolytic activity (CYT) score to the tumor based on the log average calculated in (i); and
(b) administering to the patient an agent that stimulates the patient's preexisting immune response if the cytolytic activity detected in the tumor is at least two-fold greater than the median value observed among patients diagnosed with the same histological cancer type.

2. The method according to claim 1 , further comprising:
(a) detecting a genetic alteration in the tumor, wherein the genetic alteration is a mutation in a gene selected from the group consisting of CASP8, B2M, PIK3CA, SMC1A, ARID5B, TET2, ALPK2, COL5A1, TP53, DNER, NCOR1, MORC4, CIC, IRF6, MYOCD, ANKLE1, CNKSR1, NF1, SOS1, ARID2, CUL4B, DDX3X, FUBP1, TCP11L2, HLA-A, B or C, CSNK2A1, MET, ASXL1, PD-L1, PD-L2, IDO1, IDO2, ALOX12B and ALOX15B, or copy number gain, excluding whole-chromosome events, impacting any of the following chromosomal bands: 6q16.1-q21, 6q22.31-q24.1, 6q25.1-q26, 7p11.2-q11.1, 8p23.1, 8p11.23-p11.21, 9p24.2-p23, 10p15.3, 10p15.1-p13, 11p14.1, 12p13.32-p13.2, 17p13.1 and 22q11.1-q11.21; and
(b) administering an agent that stimulates the patient's preexisting immune response if a genetic alteration associated with induction of cytolytic activity, tumor resistance to cytolytic activity and/or suppression of cytolytic activity is detected in the tumor.

3. The method according to claim 2 , wherein the detecting further comprises (a) measuring expression levels of granzyme A (GZMA) and perforin (PRF1) in a sample from the tumor, and (b) assigning a cytolytic activity (CYT) score to the tumor based on the expression levels obtained in (a).

4. The method according to claim 2 , wherein the genetic alteration is detected by sequencing.

5. The method according to claim 1 , wherein the tumor is head and neck cancer, colon cancer, stomach cancer, lung adenocarcinoma, lung squamous cell carcinoma, uterine cancer, glioma, cervical cancer, breast cancer, bladder cancer or colorectal cancer.

6. The method according to claim 2 , wherein
(a) the genetic alteration is a mutation in CASP8, and wherein the tumor is selected from the group consisting of head and neck cancer, colorectal cancer, lung squamous cell carcinoma and uterine cancer;
(b) the genetic alteration is a mutation in PIK3CA, and wherein the tumor is stomach cancer;
(c) the genetic alteration is a mutation in B2M, and wherein the tumor is uterine cancer, breast cancer, colorectal cancer or stomach cancer;
(d) the genetic alteration is a mutation in HLA-A, B or C, and wherein the tumor is colorectal cancer, head and neck cancer, uterine cancer, stomach cancer or cervical cancer; or
(e) the genetic alteration is a mutation in CNKSR1, MET or CSNK2A1.

7. The method according to claim 2 , wherein the genetic alteration is the copy number gain, excluding whole-chromosome events, of any of the following chromosomal bands: 6q16.1-q21, 6q22.31-q24.1, 6q25.1-q26, 7p11.2-q11.1, 8p23.1, 8p11.23-p11.21, 9p24.2-p23 (containing PDL1, PDL2), 10p15.3, 10p15.1-p13, 11p14.1, 12p13.32-p13.2, 17p13.1, and 22q11.1-q11.21,
(a) wherein the genetic alteration is an amplification of a gene selected from PD-L1 and PD-L2, and wherein the tumor is lung squamous cell carcinoma, head and neck cancer, cervical or colorectal cancer; or
(b) wherein the genetic alteration is an amplification of a gene selected from IDO1, IDO2, ALOX12B and ALOX15B, and wherein the tumor is breast cancer or ovarian cancer.

8. The method according to claim 2 , wherein the genetic alteration associated with cytolytic activity comprises a plurality of neoantigen mutations,
wherein at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or 20 neoantigen mutations are present in the tumor; and/or
wherein the tumor is selected from the group consisting of uterine cancer, breast cancer, stomach cancer, cervical cancer, colorectal cancer and lung adenocarcinoma.

9. The method according to claim 2 , wherein induction of cytolytic activity in the tumor is associated with virus infection,
(i) wherein the virus is HPV, and wherein the tumor is cervical cancer, head and neck cancer, bladder cancer, kidney clear cell cancer, colorectal cancer, glioma, lung squamous cell cancer or uterine cancer; or
(ii) wherein the virus is EBV, and wherein the tumor is stomach cancer.

10. The method according to claim 1 , wherein cytolytic activity in the tumor is associated with expression of one or more endogenous retrovirus genes.

11. The method according to claim 1 , wherein the agent comprises a checkpoint inhibitor,
(a) wherein the checkpoint inhibitor is an inhibitor of the programmed death-1 (PD-1) pathway,
wherein the inhibitor of the PD-1 pathway is an anti-PD1 antibody, and wherein the inhibitor of the PD-1 pathway is nivolumab; or
(b) wherein the checkpoint inhibitor is an anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibody, and
wherein the anti-CTLA4 antibody is ipilimumab or tremelimumab.

12. The method according to claim 2 , wherein the genetic alteration is a viral infection of tumor cells,
(a) wherein the virus is one of HPV, EBV, HCV, or HBV; or
(b) wherein viral infection status is detected by quantitative DNA or RNA sequencing of tumor and peripheral blood, where the tumor titer is non-zero and exceeds that observed in the non-tumor peripheral blood of the patient by at least five fold.

Assignees

• Massachusetts Inst Technology
• Massachusetts Gen Hospital

Inventors

• Hacohen Nir
• Rooney Michael S

Classifications

• G01N33/57557

  of other specific parts of the body, e.g. brain · CPC title

• C12Q1/6886 Primary

  for cancer (immunoassay for cancer G01N33/575) · CPC title

• G01N33/57407

  Physics · mapped topic

• C12Q2600/106

  Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism · CPC title

• C12Q2600/156

  Polymorphic or mutational markers · CPC title