Methods of determining patient populations amenable to immunomodulatory treatment of cancer

Abstract

The disclosure provides methods of determining patient populations amenable or suitable for immunomodulatory treatment of disease such as cancer by measuring the relative or absolute levels of T-cell sub-populations correlated with disease such as cancer.

1 .- 32 . (canceled) 
     
     
         33 . A method of determining whether cancer is amendable to treatment with an anti-CTLA-4 antibody product, the method comprising:
 (a) isolating a population of peripheral blood mononuclear cells (PBMCs) from a subject having cancer and a cancer-free subject;   (b) quantifying the percentages of total CD4+ T cells expressing PD-1, PD-L1, and/or CTLA-4 in each of the populations;   (c) comparing the percentages of total CD4+ T cells expressing PD-1, PD-L1, and/or CTLA-4 in the population of PBMCs from the subject having cancer and the percentages of total CD4+ T cells expressing PD-1, PD-L1, and/or CTLA-4 in the population of PBMCs from the cancer-free subject; and   (d) determining the subject having cancer is amenable to treatment with an anti-CTLA-4 antibody product if:
 (1) the percentage of total CD4+ T cells expressing PD-1 in the population of PBMCs from the subject having cancer is lower than the percentage of total CD4+ T cells expressing PD-1 in the population of PBMCs from the cancer-free subject; or 
 (2) the percentage of total CD4+ T cells expressing PD-L1 in the population of PBMCs from the subject having cancer is lower than the percentage of total CD4+ T cells expressing PD-L1 in the population of PBMCs from the cancer-free subject; or 
 (3) the percentage of total CD4+ T cells expressing CTLA-4 in the population of PBMCs from the subject having cancer is higher than the percentage of total CD4+ T cells expressing CTLA-4 in the population of PBMCs from the cancer-free subject. 
   
     
     
         34 . The method of  claim 33 , wherein the anti-CTLA-4 antibody product is selected from the group consisting of an anti-CTLA-4 antibody or fragment thereof, an anti-CTLA-4 chimeric antibody, an anti-CTLA-4 CDR-grafted antibody, an anti-CTLA-4 single-chain antibody, an anti-CTLA-4 single-chain variable fragment, an anti-CTLA-4 Fab antibody fragment, an anti-CTLA-4 Fab′ antibody fragment, an anti-CTLA-4 F(ab′)2 antibody fragment, an anti-CTLA-4 bi-body, an anti-CTLA-4 tri-body, an anti-CTLA-4 diabody, and an anti-CTLA-4 bispecific antibody. 
     
     
         35 . The method of  claim 34 , wherein the anti-CTLA-4 antibody product comprises the anti-CTLA-4 antibody or fragment thereof. 
     
     
         36 . The method of  claim 35 , wherein the anti-CTLA-4 antibody is ipilimumab. 
     
     
         37 . The method of  claim 33 , wherein the cancer is an adenocarcinoma, a castration-resistant prostate cancer, a melanoma, a head-and-neck cancer, a lung cancer, a kidney cancer, a bladder cancer, a gastric cancer, a colorectal cancer, an ovarian cancer, a hepatocellular cancer, a hepatobiliary cancer, or a breast cancer. 
     
     
         38 . A method of determining whether cancer is amendable to treatment with an anti-CTLA-4 antibody product, the method comprising:
 (a) isolating a population of PBMCs from a subject having cancer and a cancer-free subject;   (b) quantifying the percentages of CD4+ T eff  cells expressing PD-1, PD-L1, and/or CTLA-4 in each of the populations;   (c) comparing the percentages of CD4+ T eff  cells expressing PD-1, PD-L1, and/or CTLA-4 in the population of PBMCs from the subject having cancer and the percentages of CD4+ T eff  cells expressing PD-1, PD-L1, and/or CTLA-4 in the population of PBMCs from the cancer-free subject; and   (d) diagnosing the subject having cancer is amenable to treatment with an anti-CTLA-4 antibody product if:
 (1) the percentage of CD4+ T eff  cells expressing PD-1 in the population of PBMCs from the subject having cancer is lower than the percentage of CD4+ T eff  cells expressing PD-1 in the population of PBMCs from the cancer-free subject; or 
 (2) the percentage of CD4+ T eff  cells expressing PD-L1 in the population of PBMCs from the subject having cancer is lower than the percentage of CD4+ T eff  cells expressing PD-L1 in the population of PBMCs from the cancer-free subject; or 
 (3) the percentage of CD4+ T eff  cells expressing CTLA-4 in the population of PBMCs from the subject having cancer is higher than the percentage of CD4+ T eff  cells expressing CTLA-4 in the population of PBMCs from the cancer-free subject. 
   
     
     
         39 . The method of  claim 38 , wherein
 (1) the percentage of CD4+ T eff  cells expressing PD-1 in the population of PBMCs from the subject having cancer is no greater than about 21%; or   (2) the percentage of CD4+ T eff  cells expressing PD-L1 in the population of PBMCs from the subject having cancer is no greater than about 23.5%; or   (3) the percentage of CD4+ T eff  cells expressing CTLA-4 in the population of PBMCs from the subject having cancer is at least about 15.6%.   
     
     
         40 . The method of  claim 38 , wherein the anti-CTLA-4 antibody product is selected from the group consisting of an anti-CTLA-4 antibody or fragment thereof, an anti-CTLA-4 chimeric antibody, an anti-CTLA-4 CDR-grafted antibody, an anti-CTLA-4 single-chain antibody, an anti-CTLA-4 single-chain variable fragment, an anti-CTLA-4 Fab antibody fragment, an anti-CTLA-4 Fab′ antibody fragment, an anti-CTLA-4 F(ab′)2 antibody fragment, an anti-CTLA-4 bi-body, an anti-CTLA-4 tri-body, an anti-CTLA-4 diabody, and an anti-CTLA-4 bispecific antibody. 
     
     
         41 . The method of  claim 39 , wherein the anti-CTLA-4 antibody product comprises the anti-CTLA-4 antibody or fragment thereof. 
     
     
         42 . The method of  claim 41 , wherein the anti-CTLA-4 antibody is ipilimumab. 
     
     
         43 . The method of  claim 38 , wherein the cancer is an adenocarcinoma, a castration-resistant prostate cancer, a melanoma, a head-and-neck cancer, a lung cancer, a kidney cancer, a bladder cancer, a gastric cancer, a colorectal cancer, an ovarian cancer, a hepatocellular cancer, a hepatobiliary cancer, or a breast cancer. 
     
     
         44 . A method of determining whether cancer is amendable to treatment with an anti-CTLA-4 antibody product, the method comprising:
 (a) isolating a population of PBMCs from a subject suspected of having cancer;   (b) determining the percentages of CD4+ T eff  cells expressing PD-1, PD-L1, and/or CTLA-4 the population of PBMCs; and   (c) determining the subject's cancer is amendable to treatment with the anti-CTLA-4 antibody product if:
 the percentage of CD4+ T eff  cells expressing PD-1 in the population of PBMCs from the subject having cancer is no greater than about 21%, or 
 the percentage of CD4+ T eff  cells expressing PD-L1 in the population of PBMCs from the subject having cancer is no greater than about 23.5%, or 
 the percentage of CD4+ T eff  cells expressing CTLA-4 in the population of PBMCs from the subject having cancer is at least about 15.6%; or 
   determining the subject's cancer is not amenable to treatment with the anti-CTLA-4 antibody product if:
 the percentage of CD4+ T eff  cells expressing PD-1 in the population of PBMCs from the subject having cancer is greater than about 21%, or 
 the percentage of CD4+ T eff  cells expressing PD-L1 in the population of PBMCs from the subject having cancer is greater than about 23.5%, or 
 the percentage of CD4+ T eff  cells expressing CTLA-4 in the population of PBMCs from the subject having cancer is less than about 15.6%. 
   
     
     
         45 . The method of  claim 44 , wherein the anti-CTLA-4 antibody product is selected from the group consisting of an anti-CTLA-4 antibody or fragment thereof, an anti-CTLA-4 chimeric antibody, an anti-CTLA-4 CDR-grafted antibody, an anti-CTLA-4 single-chain antibody, an anti-CTLA-4 single-chain variable fragment, an anti-CTLA-4 Fab antibody fragment, an anti-CTLA-4 Fab′ antibody fragment, an anti-CTLA-4 F(ab′)2 antibody fragment, an anti-CTLA-4 bi-body, an anti-CTLA-4 tri-body, an anti-CTLA-4 diabody, and an anti-CTLA-4 bispecific antibody. 
     
     
         46 . The method of  claim 45 , wherein the anti-CTLA-4 antibody product comprises the anti-CTLA-4 antibody or fragment thereof. 
     
     
         47 . The method of  claim 46 , wherein the anti-CTLA-4 antibody is ipilimumab. 
     
     
         48 . The method of  claim 44 , wherein the cancer is an adenocarcinoma, a castration-resistant prostate cancer, a melanoma, a head-and-neck cancer, a lung cancer, a kidney cancer, a bladder cancer, a gastric cancer, a colorectal cancer, an ovarian cancer, a hepatocellular cancer, a hepatobiliary cancer, or a breast cancer.