Intestinal Microbiome Analyses Identify Biomarkers for Patient Response to CAR T Cell Therapy (2019)

Cellular therapy with chimeric antigen receptor (CAR) T cells has fundamentally changed the treatment of many cancers. Unfortunately, not all patients who receive this therapy have a favorable response. Additionally, patients may develop toxicity due to cytokine release syndrome (CRS) or neurotoxicity. We hypothesized that the composition of the intestinal microbiota prior to CAR T cell infusion is correlated with efficacy and toxicity.We collected fecal samples from recipients of CAR T cells at Memorial Sloan Kettering Cancer Center (MSKCC) pre-CAR T cell infusion. Microbiota composition was profiled by 16S sequencing. Shotgun metagenomic sequencing was performed on a subset of the samples. Clinical response to assess efficacy was classified as complete response (CR) or no CR. Toxicity was defined as CRS or neurotoxicity of Grade 1 to 4. Linear discriminant analysis effect size (LEfSe) identified differentially abundant bacteria between groups with a linear discriminant analysis (LDA) score threshold >2.5.We analyzed baseline samples from 25 patients treated at MSKCC. The patients were adult recipients of CAR T cells who varied in regard to conditioning regimen, CAR construct and underlying diagnosis, which included hematologic and solid malignancies. LEfSe revealed increased representation of bacterial taxa in the microbiome of CR versus no CR, with Oscilliospiraceae, Ruminococcacaeae and Lachnospiraceae enriched in CR and Peptostreptococcaceae more abundant in no CR (A). A higher abundance of Lachnospiraceae was found in those who experienced toxicity, while Peptostreptococcaceae was more abundant in patients who did not have toxicity (B). We explored shotgun metagenomic sequences from 19 of 25 samples that were functionally annotated using the shortBRED pipeline. We inspected abundances of genes assigned to three pathways that we hypothesized may be immunologically relevant: B vitamin synthesis, bile acid biosynthesis, and short-chain fatty acid production. We observed increased abundance of genes associated with B vitamin biosynthesis in patients who had no CR (C) or toxicity (D).We observe differential abundance of microbiota in patients who achieved a CR or experienced toxicity as compared to those who did not achieve a CR or experience toxicity. We observe that increased B vitamin gene abundance is associated with no CR or toxicity. Overall, this data indicates that features of the microbiota may correlate with outcomes to CAR T cell therapy. Cellular therapy with chimeric antigen receptor (CAR) T cells has fundamentally changed the treatment of many cancers. Unfortunately, not all patients who receive this therapy have a favorable response. Additionally, patients may develop toxicity due to cytokine release syndrome (CRS) or neurotoxicity. We hypothesized that the composition of the intestinal microbiota prior to CAR T cell infusion is correlated with efficacy and toxicity. We collected fecal samples from recipients of CAR T cells at Memorial Sloan Kettering Cancer Center (MSKCC) pre-CAR T cell infusion. Microbiota composition was profiled by 16S sequencing. Shotgun metagenomic sequencing was performed on a subset of the samples. Clinical response to assess efficacy was classified as complete response (CR) or no CR. Toxicity was defined as CRS or neurotoxicity of Grade 1 to 4. Linear discriminant analysis effect size (LEfSe) identified differentially abundant bacteria between groups with a linear discriminant analysis (LDA) score threshold >2.5. We analyzed baseline samples from 25 patients treated at MSKCC. The patients were adult recipients of CAR T cells who varied in regard to conditioning regimen, CAR construct and underlying diagnosis, which included hematologic and solid malignancies. LEfSe revealed increased representation of bacterial taxa in the microbiome of CR versus no CR, with Oscilliospiraceae, Ruminococcacaeae and Lachnospiraceae enriched in CR and Peptostreptococcaceae more abundant in no CR (A). A higher abundance of Lachnospiraceae was found in those who experienced toxicity, while Peptostreptococcaceae was more abundant in patients who did not have toxicity (B). We explored shotgun metagenomic sequences from 19 of 25 samples that were functionally annotated using the shortBRED pipeline. We inspected abundances of genes assigned to three pathways that we hypothesized may be immunologically relevant: B vitamin synthesis, bile acid biosynthesis, and short-chain fatty acid production. We observed increased abundance of genes associated with B vitamin biosynthesis in patients who had no CR (C) or toxicity (D). We observe differential abundance of microbiota in patients who achieved a CR or experienced toxicity as compared to those who did not achieve a CR or experience toxicity. We observe that increased B vitamin gene abundance is associated with no CR or toxicity. Overall, this data indicates that features of the microbiota may correlate with outcomes to CAR T cell therapy. Figure 1.