Methods and compositions for identifying and treating subjects at risk for checkpoint blockade therapy associated colitis

Abstract

The present invention relates to methods and compositions for identifying subjects treated with or considered for treatment with checkpoint blockade therapeutic agents that are at higher or lower risk for developing checkpoint therapy associated colitis, by analyzing the intestinal microbiome of those subjects. It is based, at least in part, on the discovery that the abundance of certain intestinal microbiota of the phyla Bacteroidetes, including the bacteria in the families Bacteroidaceae, Rikenellaceae, and Barnesisllaceae, and/or an increase or decrease in microbial genetic pathways involved in polyamine transport and/or B vitamin biosynthesis (e.g., (riboflavin (B2), pantothenate (B5) and thiamine (B1)) are associated with the likelihood of developing checkpoint therapy associated colitis.

1 . A method of identifying a subject as having a higher or lower risk of developing checkpoint blockade therapy associated colitis or as likely to experience more or less severe checkpoint blockade therapy associated colitis, the method comprising:
 (i) determining the level of one or more bacteria or spores thereof of the Bacteriodetes phylum or one or more bacteria or spores thereof comprising at least one bacterial genetic module for polyamine transport or B vitamin biosynthesis in the intestinal microbiome of the subject;   (ii) comparing the level of the one or more bacteria or spores in the intestinal microbiome of the subject with at least one reference bacteria level, wherein the at least one reference bacteria level is a level of the one or more bacteria or spores thereof in a patient that does not develop checkpoint blockade therapy associated colitis;   (iii) identifying the subject as having a higher risk of developing checkpoint blockade therapy associated colitis or likely to experience more severe checkpoint blockade therapy associated colitis if the level of the one or more bacteria or spores thereof is lower than the level of the at least one reference bacteria level; and   (iv) identifying the subject as having a lower risk of developing checkpoint blockade therapy associated colitis or likely to experience less severe checkpoint blockade therapy associated colitis if the level of the one or more bacteria or spores thereof is greater than the level of the at least one reference bacteria level.   
     
     
         2 . The method of  claim 1 , wherein the one or more bacteria or spores thereof in the Bacteriodetes phylum comprises one or more bacteria or spores thereof selected from the group consisting of the Bacteroidaceae family, Rikenellaceae family, the Barnesiellaceae family and a combination thereof. 
     
     
         3 . The method of  claim 1 , wherein the at least one bacterial genetic module for B vitamin biosynthesis comprises a bacterial genetic module selected from the group consisting of a bacterial genetic module for riboflavin biosynthesis, a bacterial genetic module for pantothenate biosynthesis, a bacterial genetic module for thiamine biosynthesis and a combination thereof. 
     
     
         4 . The method of  claim 1 , wherein determining the level of one or more bacteria or spores thereof of the Bacteriodetes phylum or one or more bacteria or spores thereof comprising at least one bacterial genetic module for polyamine transport or B vitamin biosynthesis in the intestinal microbiome of a subject comprises determining the level of the one or more bacteria in a fecal sample of the subject. 
     
     
         5 . The method of  claim 1 , wherein determining the level of one or more bacteria or spores thereof of the Bacteriodetes phylum or one or more bacteria or spores thereof comprising at least one bacterial genetic module for polyamine transport or B vitamin biosynthesis in the intestinal microbiome of a subject comprises conducting metagenomic sequencing to identify biomarkers associated with the bacteria or spores thereof. 
     
     
         6 . The method of  claim 1 , wherein the at least one reference bacteria level is based on relative abundance of the bacteria or spores thereof as compared to other bacteria in the intestinal microbiome. 
     
     
         7 . The method of  claim 1 , comprising determining the level of two or more bacteria or spores thereof of the Bacteriodetes phylum or two or more bacteria or spores thereof comprising at least one bacterial genetic module for polyamine transport or B vitamin biosynthesis in the intestinal microbiome of a subject and comparing the levels to two reference bacterial levels for the respective bacteria or spores. 
     
     
         8 . A method of treating a subject with or at risk of developing checkpoint blockade therapy associated colitis comprising administering to the subject a pharmaceutical composition comprising (a) (i) one or more isolated bacteria or spores thereof of the Bacteriodetes phylum, (ii) one or more isolated bacteria or spores thereof comprising at least one bacterial genetic module for polyamine transport or B vitamin biosynthesis or (iii) a combination thereof; and (b) a biocompatible pharmaceutical carrier. 
     
     
         9 . The method of  claim 8 , wherein the one or more bacteria or spores thereof of the Bacteriodetes phylum comprises one or more bacteria or spores thereof in the Bacteroidaceae family. 
     
     
         10 . The method of  claim 8 , wherein the one or more bacteria or spores thereof of the Bacteriodetes phylum comprises one or more bacteria or spores thereof in the Rikenellaceae family. 
     
     
         11 . The method of  claim 8 , wherein the one or more bacteria or spores thereof of the Bacteriodetes phylum comprises one or more bacteria or spores thereof in the Barnesiellaceae family. 
     
     
         12 . The method of  claim 8 , wherein the one or more isolated bacteria or spores thereof comprises a recombinant cell. 
     
     
         13 . The method of  claim 8 , wherein the one or more isolated bacteria or spores thereof is present in a cluster. 
     
     
         14 . The method of  claim 8 , wherein the pharmaceutical composition is formulated for oral, nasogastric or rectal administration. 
     
     
         15 . The method of  claim 8 , wherein the pharmaceutical composition is a liquid, suspension, dried powder, tablet, capsule or food product. 
     
     
         16 . The method of  claim 8 , wherein the pharmaceutical composition further comprises a probiotic bacteria, probiotic yeast or a combination thereof; a prebiotic; a postbiotic; an antibiotic; or a combination thereof. 
     
     
         17 . The method of  claim 8 , wherein the one or more isolated bacteria or spores thereof are present in an amount that can reduce the risk or severity of checkpoint blockade therapy associated colitis in the subject administered the pharmaceutical composition. 
     
     
         18 . The method of  claim 8 , wherein the checkpoint blockade therapy comprises a therapy selected from the group consisting of a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a CpG-oligonucleotide immunotherapeutic agent, cyclophosphamide and a combination thereof. 
     
     
         19 . The method of  claim 8 , wherein (a) the subject has cancer and is concurrently or sequentially administered an additional agent with anti-cancer activity and/or (b) the subject has an infectious disease and is concurrently or sequentially administered an additional agent with anti-infection activity. 
     
     
         20 . The method of  claim 8  further comprising determining that the subject has a higher risk of developing checkpoint blockade therapy associated colitis or is likely to experience more severe checkpoint blockade therapy associated colitis.