Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Cancer Using PD-L1 Isoforms

Patent metadata

Field	Value
Publication number	US-2016122829-A1
Application number	US-201414895551-A
Country	US
Kind code	A1
Filing date	Jun 2, 2014
Priority date	Jun 6, 2013
Publication date	May 5, 2016
Grant date	—

Abstract

The present invention relates to methods for identifying, assessing, preventing, and treating cancer (e.g., head, neck, and/or lung cancers in humans). A variety of PD-L1 isoforni biomarkers are provided, wherein alterations in the copy number of one or more of the biomarkers and/or alterations in the amount, structure, and/or activity of one or more of the biomarkers is associated with cancer status and indicates amenability to treatment or prevention by modulating PD-1 and/or PD-L! levels.

First claim

What is claimed:

1 . A method of determining whether a subject is afflicted with a head, neck, or lung cancer or at risk for developing a head, neck, or lung cancer, the method comprising:
a) obtaining a biological sample from the subject; b) determining the copy number, level of expression, or level of activity of one or more biomarkers listed in Table 1 or a fragment thereof in the subject sample; c) determining the copy number, level of expression, or level of activity of the one or more biomarkers in a control; and d) comparing the copy number, level of expression, or level of activity of said one or more biomarkers detected in steps b) and c); wherein a significant increase in the copy number, level of expression, or level of activity of the one or more biomarkers in the subject sample relative to the control copy number, level of expression, or level of activity of the one or more biomarkers indicates that the subject is afflicted with the head, neck, or lung cancer or is at risk for developing the head, neck, or lung cancer.

2 . A method of determining whether a subject afflicted with a head, neck, or lung cancer or at risk for developing a head, neck, or lung cancer would benefit from modulating PD-1 and/or PD-L1 levels, the method comprising:
a) obtaining a biological sample from the subject; b) determining the copy number, level of expression, or level of activity of one or more biomarkers listed in Table 1 or a fragment thereof in the subject sample; c) determining the copy number, level of expression, or level of activity of the one or more biomarkers in a control; and d) comparing the copy number, level of expression, or level of activity of said one or more biomarkers detected in steps b) and c); wherein a significant increase in the copy number, level of expression, or level of activity of the one or more biomarkers in the subject sample relative to the control copy number, level of expression, or level of activity of the one or more biomarkers indicates that the subject afflicted with the head, neck, or lung cancer or at risk for developing the head, neck, or lung cancer would benefit from modulating PD-L1 and/or PD-L1 levels.

3 . A method for monitoring the progression of a head, neck, or lung cancer in a subject, the method comprising:
a) detecting in a subject sample at a first point in time the copy number, level of expression, or level of activity of one or more biomarkers listed in Table 1 or a fragment thereof; b) repeating step a) at a subsequent point in time; and c) comparing the copy number, level of expression, or level of activity of said one or more biomarkers detected in steps a) and b) to monitor the progression of the head, neck, or lung cancer.

4 . The method of any one of claims 1 - 3 , wherein the one or more biomarkers comprises soluble PD-L1, optionally wherein the soluble PD-L1 a) comprises an amino acid sequence of SEQ ID NO: 13 or 15 or an amino acid sequence that is at least 80% identical to SEQ ID NO: 13 or 15; or b) comprises a nucleic acid molecule comprising a nucleic acid sequence encoding an amino acid sequence of SEQ ID NO: 13 or 15 or an amino acid sequence that is at least 80% identical to SEQ ID NO: 13 or 15.

5 . The method of claim 3 , wherein an at least twenty percent increase or an at least twenty percent decrease between the copy number, level of expression, or level of activity of the one or more biomarkers in the subject sample at a first point in time relative to the copy number, level of expression, or level of activity of the one or more biomarkers in the subject sample at a subsequent point in time indicates progression of the head, neck, or lung cancer; or wherein less than a twenty percent increase or less than a twenty percent decrease between the copy number, level of expression, or level of activity of the one or more biomarkers in the subject sample at a first point in time relative to the copy number, level of expression, or level of activity of the one or more biomarkers in the subject sample at a subsequent point in time indicates a lack of significant progression of the head, neck, or lung cancer.

6 . The method of claim 3 , wherein between the first point in time and the subsequent point in time, the subject has undergone treatment to modulate PD-1 and/or PD-L1 levels.

7 . A method for stratifying subjects afflicted with a head, neck, or lung cancer according to predicted clinical outcome of treatment with one or more modulators of PD-1 and/or PD-L1 levels, the method comprising:
a) determining the copy number, level of expression, or level of activity of one or more biomarkers listed in Table 1 or a fragment thereof in a subject sample; b) determining the copy number, level of expression, or level of activity of the one or more biomarkers in a control sample; and c) comparing the copy number, level of expression, or level of activity of said one or more biomarkers detected in steps a) and b); wherein a significant modulation in the copy number, level of expression, or level of activity of the one or more biomarkers in the subject sample relative to the normal copy number, level of expression, or level of activity of the one or more biomarkers in the control sample predicts the clinical outcome of the patient to treatment with one or more modulators of PD-1 and/or PD-L1 levels.

8 . The method of claim 7 , wherein the predicted clinical outcome is (a) cellular growth, (b) cellular proliferation, or (c) survival time resulting from treatment with one or more modulators of PD-1 and/or PD-L1 levels.

9 . The method of claim 7 , wherein the one or more biomarkers comprises soluble PD-L1, optionally wherein the soluble PD-L1 a) comprises an amino acid sequence of SEQ ID NO: 13 or 15 or an amino acid sequence that is at least 80% identical to SEQ ID NO: 13 or 15; or b) comprises a nucleic acid molecule comprising a nucleic acid sequence encoding an amino acid sequence of SEQ ID NO: 13 or 15 or an amino acid sequence that is at least 80% identical to SEQ ID NO: 1.

10 . The method of claim 7 , wherein an at least twenty percent increase or an at least twenty percent decrease between the copy number, level of expression, or level of activity of the one or more biomarkers in the subject sample compared to the control sample predicts that the subject has a poor clinical outcome; or wherein less than a twenty percent increase or less than a twenty percent decrease between the copy number, level of expression, or level of activity of the one or more biomarkers in the subject sample compared to the control sample predicts that the subject has a favorable clinical outcome.

11 . The method of claim 7 , further comprising treating the subject with a therapeutic agent that specifically modulates the copy number, level of expression, or level of activity of the one or more biomarkers.

12 . The method of claim 7 , further comprising treating the subject with one or more modulators of PD-1 and/or PD-L1 levels.

13 . A method of determining the efficacy of a test compound for inhibiting a head, neck, or lung cancer in a subject, the method comprising:
a) determining the copy number, level of expression, or level of activity of one or more biomarkers listed in Table 1 or a fragment thereof in a first sample obtained from the subject and exposed to the test compound; b) determining the copy number, level of expression, or level of activity of the one or more biomarkers in a second sample obtained from the subject, wherein the second sample is not exposed to the test compound, and c) comparing the copy number, level of expression, or level of activity of the one or more biomarke

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Hammerman Peter

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• G01N33/57557

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

• G01N33/5759

  involving compounds localised on the membrane of tumour or cancer cells · CPC title

• G01N33/5752

  of the lungs · CPC title

• G01N2333/4703

  Regulators; Modulating activity · CPC title