Methods and biomarkers for predicting efficacy and evaluation of an ox40 agonist treatment

Abstract

The present disclosure provides methods for predicting responsiveness of a subject having cancer to an OX40 agonist treatment by measuring the expression level of one or more biomarkers. Also provided are methods for monitoring pharmacodynamic activity of or responsiveness to an OX40 agonist treatment by measuring the expression level of one or more biomarkers. Further provided are methods related thereto for treating or delaying progression of cancer in a subject by administering an effective amount of an OX40 agonist to a subject. Specific biomarkers for all such methods are described herein.

1 . A method for predicting responsiveness of a subject having cancer to an OX40 agonist treatment, comprising:
 (a) measuring the expression level of one or more marker genes in a sample comprising leukocytes obtained from the subject, wherein said one or more marker genes are selected from the group consisting of CD8a, CD8b, H2-d, CTLA4, CD64, CXCL9, IFNg, IDO1, GZMA, GZMB, PRF1, PDCA1, KLRK1, PTPRC, CXCL1, ITGAM, and IL7R; and   (b) classifying the subject as a responsive or non-responsive subject based on the expression level of said one or more marker genes in the sample obtained from the subject, as compared with a reference, wherein an increased expression level of the one or more marker genes as compared with the reference indicates the subject may be responsive to an OX40 agonist treatment.   
     
     
         2 . A method for treating or delaying progression of cancer in a subject, comprising:
 (a) measuring the expression level of one or more marker genes in a sample comprising leukocytes obtained from the subject, wherein said one or more marker genes are selected from the group consisting of CD8a, CD8b, H2-d, CTLA4, CD64, CXCL9, IFNg, IDO1, GZMA, GZMB, PRF1, PDCA1, KLRK1, PTPRC, CXCL1, ITGAM, and IL7R; and   (b) if the expression level of said one or more marker genes in the sample obtained from the subject is higher than a reference, administering to the subject an effective amount of an OX40 agonist.   
     
     
         3 . A method for treating or delaying progression of cancer in a subject, comprising administering to the subject an effective amount of an OX40 agonist, wherein a sample comprising leukocytes obtained from the subject has increased expression of one or more marker genes are selected from the group consisting of CD8a, CD8b, H2-d, CTLA4, CD64, CXCL9, IFNg, IDO1, GZMA, GZMB, PRF1, PDCA1, KLRK1, PTPRC, CXCL1, ITGAM, and IL7R, as compared with a reference. 
     
     
         4 - 6 . (canceled) 
     
     
         7 . A method for predicting responsiveness of a subject having cancer to an OX40 agonist treatment, comprising:
 (a) measuring the expression level of one or more marker genes in a sample comprising leukocytes obtained from the subject, wherein said one or more marker genes are selected from the group consisting of CSF2, CCL22, EPCAM, GATA3, IL13, and VTCN1; and   (b) classifying the subject as a responsive or non-responsive subject based on the expression level of said one or more marker genes in the sample obtained from the subject, as compared with a reference, wherein a decreased expression level of the one or more marker genes as compared with the reference indicates the subject may be responsive to an OX40 agonist treatment.   
     
     
         8 . A method for treating or delaying progression of cancer in a subject, comprising
 (a) measuring the expression level of one or more marker genes in a sample comprising leukocytes obtained from the subject, wherein said one or more marker genes are selected from the group consisting of CSF2, CCL22, EPCAM, GATA3, IL13, and VTCN1; and   (b) if the expression level of said one or more marker genes in the sample obtained from the subject is lower than a reference, administering to the subject an effective amount of an OX40 agonist.   
     
     
         9 . A method for treating or delaying progression of cancer in a subject, comprising administering to the subject an effective amount of an OX40 agonist, wherein a sample comprising leukocytes obtained from the subject has decreased expression of one or more marker genes are selected from the group consisting of CSF2, CCL22, EPCAM, GATA3, IL13, and VTCN1, as compared with a reference. 
     
     
         10 . A method for monitoring pharmacodynamic activity of an OX40 agonist treatment, comprising:
 (a) measuring the expression level of one or more marker genes in a sample comprising leukocytes obtained from the subject, wherein the subject has been treated with an OX40 agonist, and wherein said one or more marker genes are selected from the group consisting of ARG1, CCL2, CCL22, CCL5, CCR5, CD226, CD27, CD274, CD28, CD3E, CD40, CD8A, CD8b, CXCL10, CXCL9, EOMES, FasL, Fcgr1/CD64, FOXP3, GZMA, GZMB, HAVCR2, ICAM1, IDO1, IFNg, IL10, IL12A (TDO2), IL13, IL2, IL7R, ITGAM, KLRK1, LAG3, MAP4K1, MS4A1, PDCD1, PDCD1LG2, PRF1, PTPRC, TNF, TNFRSF14, TNFRSF9, and TNFSF4; and   (b) determining the treatment as demonstrating pharmacodynamic activity based on the expression level of said one or more marker genes in the sample obtained from the subject, as compared with a reference, wherein an increased expression level of the one or more marker genes as compared with the reference indicates pharmacodynamic activity to the OX40 agonist treatment.   
     
     
         11 . (canceled) 
     
     
         12 . A method for monitoring responsiveness of a subject to an OX40 agonist treatment, comprising:
 (a) measuring the expression level of one or more marker genes in a sample comprising leukocytes obtained from the subject, wherein the subject has been treated with an OX40 agonist, and wherein said one or more marker genes are selected from the group consisting of BTLA, CD4, CD69, CD80, CD83, CD86, CSF2, CTLA4, CXCR3, Fcgr2b/CD32, Fcgr3/CD16, H2-aa, H2-d, H2-k, ICOS, IL10, PDCA1, and TNFRSF18; and   (b) classifying the subject as responsive or non-responsive to said treatment based on the expression level of said one or more marker genes in the sample obtained from the subject, as compared with a reference, wherein an increased expression level of the one or more marker genes as compared with the reference indicates a responsive subject.   
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 12 , wherein responsiveness comprises immune activation and/or treatment efficacy. 
     
     
         15 . The method of  claim 2 , wherein the leukocytes are in a tumor sample obtained from the subject. 
     
     
         16 . The method of  claim 2 , wherein the leukocytes are in a peripheral blood sample obtained from the subject. 
     
     
         17 . The method of  claim 2 , wherein the expression level of said one or more marker genes is normalized to the expression level of a reference gene in the sample. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 2 , wherein the expression level of said one or more marker genes is mRNA expression level. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 2 , wherein the expression level of said one or more marker genes is protein expression level. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 2 , wherein the cancer is selected from the group consisting of colorectal cancer, non-small cell lung cancer, renal cell carcinoma, bladder cancer, ovarian cancer, glioblastoma, neuroblastoma, melanoma, triple-negative breast carcinoma, gastric cancer, and hepatocellular carcinoma. 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 2 , wherein the OX40 agonist is an antibody. 
     
     
         26 - 30 . (canceled) 
     
     
         31 . The method of  claim 25 , wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, 8 or 9; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, 10, 11, 12, 13, or 14; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4, 15 or 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:7, 22, 23, 24, 25, 26, 27 or 28. 
     
     
         32 - 34 . (canceled) 
     
     
         35 . The method of  claim 25 , wherein the antibody is MEDI6469 or MEDI0562. 
     
     
         36 . The method of  claim 2 , wherein the OX40 agonist comprises one or more extracellular domains of OX40L. 
     
     
         37 . The method of  claim 2 , wherein the OX40 agonist is MEDI6383.