Ifn-gamma gene signature biomarkers of tumor response to pd-1 antagonists

Patent metadata

Field	Value
Publication number	US-2016304969-A1
Application number	US-201415104245-A
Country	US
Kind code	A1
Filing date	Dec 15, 2014
Priority date	Dec 17, 2013
Publication date	Oct 20, 2016
Grant date	—

Abstract

The present disclosure describes IFN-γ gene signature biomarkers that are useful for identifying cancer patients who are most likely to benefit from treatment with a PD-1 antagonist. The disclosure also provides methods and kits for testing tumor samples for the biomarkers, as well as methods for treating subjects with a PD-1 antagonist based on the test results.

First claim

1 . A method for testing a tumor for the presence or absence of a biomarker that predicts response to treatment with a PD-1 antagonist, which comprises:
obtaining a sample from the tumor, measuring the raw RNA expression level in the tumor sample for each gene in a IFN-γ gene signature; normalizing each of the measured raw RNA expression levels; and calculating the arithmetic mean of the normalized RNA expression levels for each of the genes to generate a score for the IFN-γ gene signature; wherein the IFN-γ gene signature comprises at least five of the genes in Table 1 below:

TABLE 1

Gene
Target Transcript

CCL4
NM_002984.2

CCL5
NM_002985.2

CCR5
NM_000579.1

CD2
NM_001767.2

CD86
NM_175862.3

CIITA
NM_000246.3

CXCL10
NM_001565.1

CXCL11
NM_005409.3

CXCL9
NM_002416.1

GZMA
NM_006144

HLA-DRA
NM_019111.3

IDO1
NM_002164.3

IFNG
NM_000619.2

KLRK1
NM_007360.1

PRF1
NM_001083116

STAT1
NM_007315.2

2 . The method of claim 1 , wherein the method further comprises:
comparing the calculated score to a reference score for the IFN-γ gene signature; and classifying the tumor as biomarker positive or biomarker negative; wherein if the calculated score is equal to or greater than the reference score, then the tumor is classified as biomarker positive, and if the calculated IFN-γ gene signature score is less than the reference IFN-γ gene signature score, then the tumor is classified as biomarker negative.

3 . A method for treating a subject having a tumor which comprises:
determining if the tumor is positive or negative for an IFN-γ gene signature biomarker, and administering to the subject a PD-1 antagonist if the tumor is positive for the biomarker; or administering to the subject a cancer treatment that does not include a PD-I antagonist if the tumor is negative for the biomarker; wherein the IFN-γ gene signature comprises at least five of the genes in Table 1

TABLE 1

Gene
Target Transcript

CCL4
NM_002984.2

CCL5
NM_002985.2

CCR5
NM_000579.1

CD2
NM_001767.2

CD86
NM_175862.3

CIITA
NM_000246.3

CXCL10
NM_001565.1

CXCL11
NM_005409.3

CXCL9
NM_002416.1

GZMA
NM_006144

HLA-DRA
NM_019111.3

IDO1
NM_002164.3

IFNG
NM_000619.2

KLRK1
NM_007360.1

PRF1
NM_001083116

STAT1
NM_007315.2

4 . The method of claim 3 , wherein the determining step comprises:
obtaining a sample from the subject's tumor; sending the tumor sample to a laboratory with a request to test the sample for the presence or absence of an IFN-γ gene signature biomarker; and receiving a report from the laboratory that states whether the tumor sample is biomarker positive or biomarker negative.

5 . A method for treating a subject having a tumor which comprises:
obtaining a sample from the tumor; measuring the raw RNA expression level in the tumor sample for each gene in an IFN-γ gene signature; normalizing each of the measured raw RNA expression levels; calculating the arithmetic mean of the normalized RNA expression levels for each of the genes to generate a score for the IFN-γ gene signature; and administering to the subject a PD-1 antagonist if the calculated score is equal to or greater than a reference score for the IFN-γ gene signature; or administering to the subject a cancer therapy that does not include a PD-1 antagonist if the calculated score is less than the reference score; wherein the IFN-γ gene signature comprises at least five of the genes in Table 1.

TABLE 1

Assignees

• Merck Sharp & Dohme

Inventors

• Ayers Mark
• Loboda Andrey
• Lunceford Jared
• Mcclanahan Terrill K
• Murphy Erin
• Nebozhyn Michael
• Pierce Robert H

Classifications

• G06F19/20

  Physics · mapped topic

• C12Q2600/158

  Expression markers · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C12Q2600/106

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

• C07K16/2818

  against CD28 or CD152 · CPC title