Checkpoint Blockade and Microsatellite Instability

Abstract

Blockade of immune checkpoints such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) shows promise in patients with cancer. Inhibitory antibodies directed at these receptors have been shown to break immune tolerance and promote anti-tumor immunity. These agents work particularly well in patients with a certain category of tumor. Such tumors may be particularly susceptible to treatment because of the multitude of neoantigens which they produce.

We claim: 
     
         1 . A method of treating a cancer patient comprising:
 administering to a cancer patient an immune checkpoint inhibitory antibody, wherein the cancer patient has a microsatellite instable cancer (MSI).   
     
     
         2 . The method of  claim 1  wherein the cancer is selected from the group consisting of:
 colon, gastric, endometrial, cholangiocarcinoma, pancreatic, and prostate cancers. 
 
     
     
         3 . The method of  claim 1  wherein the antibody is an anti-PD-1 antibody. 
     
     
         4 . The method of  claim 1  wherein the antibody is an anti-IDO antibody. 
     
     
         5 . The method of  claim 1  wherein the antibody is an anti-CTLA-4 antibody. 
     
     
         6 . The method of  claim 1  wherein the antibody is an anti-PD-L1 antibody. 
     
     
         7 . The method of  claim 1  wherein the antibody is an anti-LAG-3 antibody. 
     
     
         8 . The method of  claim 1  wherein a sample from the MSI cancer patient is tested to evaluate stability of one or more microsatellite markers prior to the step of administering. 
     
     
         9 . The method of  claim 1  wherein the antibody is a humanized monoclonal antibody. 
     
     
         10 . The method of  claim 1  wherein the antibody is MK-3475. 
     
     
         11 . The method of  claim 1  wherein the antibody is an IgG4 antibody. 
     
     
         12 . The method of  claim 8  wherein a plurality of microsatellite markers is tested. 
     
     
         13 . The method of  claim 8  wherein the one or more microsatellite markers is selected from the group consisting of BAT-25, BAT-26, MON0-27, NR-21, NR-24, Penta C, and Penta D. 
     
     
         14 . The method of  claim 12  wherein the plurality of microsatellite markers comprises BAT-25, BAT-26, MON0-27, NR-21, NR-24, Penta C, and Penta D. 
     
     
         15 . A method of treating a cancer patient comprising:
 testing a sample from a cancer patient and determining instability of one or more microsatellite markers selected from the group consisting of BAT-25, BAT-26, MON0-27, NR-21, NR-24, Penta C, and Penta D; and   administering to the cancer patient an anti-PD-1 antibody, wherein the cancer is selected from the group consisting of: colon, gastric, endometrial, cholangiocarcinoma, pancreatic, and prostate cancers.   
     
     
         16 . A method of categorizing a tumor of a human, comprising:
 testing a sample from the human to evaluate stability of one or more microsatellite markers;   determining microsatellite instability in the sample;   identifying the tumor as a good candidate for treatment with an immune checkpoint inhibitory antibody.   
     
     
         17 . The method of  claim 16  further comprising the step of:
 prescribing an immune checkpoint inhibitory antibody for the human. 
 
     
     
         18 . The method of  claim 16  wherein the one or more microsatellite markers is selected from the group consisting of BAT-25, BAT-26, MON0-27, NR-21, NR-24, Penta C, and Penta D. 
     
     
         19 . The method of  claim 16  wherein the one or more microsatellite markers is selected from the group consisting of BAT-25, BAT-26, MON0-27, NR-21, NR-24, Penta C, and Penta D. 
     
     
         20 . A method of categorizing a tumor of a human, comprising:
 testing a sample from the human to evaluate stability of one or more microsatellite markers;   determining microsatellite stability in the sample;   identifying the tumor as a bad candidate for treatment with an immune checkpoint inhibitory antibody.   
     
     
         21 . The method of  claim 20  wherein the human is being treated with an immune checkpoint inhibitory antibody, and further comprising the step of ceasing treatment with an immune checkpoint inhibitory antibody. 
     
     
         22 . The method of  claim 20  wherein the one or more microsatellite markers is selected from the group consisting of BAT-25, BAT-26, MON0-27, NR-21, NR-24, Penta C, and Penta D. 
     
     
         23 . The method of  claim 20  wherein the one or more microsatellite markers is selected from the group consisting of BAT-25, BAT-26, MON0-27, NR-21, NR-24, Penta C, and Penta D. 
     
     
         24 . A method of treating a cancer patient comprising:
 administering to a cancer patient an immune checkpoint inhibitory antibody, wherein the cancer patient has a mutational burden of at least 100 somatic mutations per tumor.   
     
     
         25 . The method of  claim 24  wherein the antibody is an anti-PD-1 antibody. 
     
     
         26 . The method of  claim 24  wherein the antibody is an anti-IDO antibody. 
     
     
         27 . The method of  claim 24  wherein the antibody is an anti-CTLA-4 antibody. 
     
     
         28 . The method of  claim 24  wherein the antibody is an anti-PD-L1 antibody. 
     
     
         29 . The method of  claim 24  wherein the antibody is an anti-LAG-3 antibody. 
     
     
         30 . The method of  claim 24  further comprising determining a high mutational burden in the tumor prior to the step of administering.