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 for treating cancer, the method comprising:
 testing one or more microsatellite markers in a tumor sample from a patient;   determining microsatellite instability (MSI) for the tumor based on the testing; and   identifying the patient as a candidate for treatment with an immune checkpoint inhibitor when the tumor exhibits an MSI phenotype.   
     
     
         2 . The method of  claim 1 , further comprising administering the immune checkpoint inhibitor to the patient. 
     
     
         3 . The method of  claim 1 , wherein the immune checkpoint inhibitor comprises an antibody. 
     
     
         4 . The method of  claim 3 , wherein the antibody is selected from the group consisting of: an anti-PD-1 antibody; an anti-IDO antibody; anti-CTLA-4 antibody; an anti-PD-L1 antibody; and an anti-LAG-3 antibody. 
     
     
         5 . The method of  claim 1 , wherein the one or more microsatellite markers are selected from the group consisting of BAT-25, BAT-26, MONO-27, NR-21, NR-24, Penta C, and Penta D. 
     
     
         6 . The method of  claim 1 , wherein the tumor is determined to display the MSI phenotype when the testing indicates at least 100 mutations in a genome of the tumor relative to normal tissue of the patient. 
     
     
         7 . The method of  claim 1 , wherein the cancer is selected from the group consisting of: colon, gastric, endometrial, cholangiocarcinoma, pancreatic, and prostate cancer. 
     
     
         8 . The method of  claim 1 , wherein the immune checkpoint inhibitor comprises an antibody selected from the group consisting of: a humanized monoclonal antibody; sMK-3475; and an IgG4 antibody. 
     
     
         9 . The method of  claim 1 , wherein a plurality of microsatellite markers is tested. 
     
     
         10 . The method of  claim 9 , wherein the plurality of microsatellite markers is each selected from the group consisting of BAT-25, BAT-26, MONO-27, NR-21, NR-24, Penta C, and Penta D. 
     
     
         11 . The method of  claim 9 , wherein the plurality of microsatellite markers comprises BAT-25, BAT-26, MONO-27, NR-21, NR-24, Penta C, and Penta D. 
     
     
         12 . The method of  claim 1 , wherein testing the one or more microsatellite markers includes one technique selected from the group consisting of an immunohistochemistry (IHC) assay, a PCR test, and next generation sequencing.