At the AACR Annual Meeting, I was most excited to attend the major symposium entitled “The Microbiome as an Orchestrator of Immunity and Cancer Immunotherapy,” which featured three highly informative talks. First, Gregory Sonnenberg from Weill Cornell Medicine gave an overview of how the microbiome contributes to immune homeostasis in the intestine. Second, Carrie Daniel-MacDougall of MD Anderson Cancer Center talked about how diet and lifestyle affect the microbiome. The third and most exciting presentation, in my opinion, was given by Giorgio Trinchieri from the NCI, who talked about the microbiome in cancer therapy.
In Dr. Trinchieri’s presentation, he talked about how the progression of cancer is affected by the microbiome due to its major role in inflammation and immunity. However, the question he has set out to answer is how the composition of the gut microbiome can affect the efficacy of treatment. His findings indicate that the microbiome appears to affect therapy outcomes by “training” the myeloid and innate immune components at distant tumor sites; possibly priming myeloid cells to produce cytokines that may improve therapeutic responses.
Three separate clinical studies were recently published1-3 which indicate that the composition of the gut microbiome modulates the effects of anti-PD1 therapy. All three studies found that patients can be stratified into responders and nonresponders to immunotherapy based on the composition of their gut microbiomes. Interestingly, these studies, which were performed in different cities (Houston, Chicago, and Paris) using different cancer types, came up with different species of bacteria that were most correlated with response to immunotherapy. Why the discordant results? Dr. Trinchieri hypothesized that because environment dominates over host genetics in shaping the gut microbiome, perhaps the discordance was due to the populations being studied in various geographic locations.
Dr. Trinchieri posed that the goal of future research should be to precisely identify the bacteria species that favor anti-PD1 therapy response and characterize their molecular mechanisms. He noted that machine learning can be used for predicting patients’ anti-PD1 therapy response with 70-80% accuracy within one cohort, but when used to train for predicting outcomes for a different cohort, the accuracy is no better than flipping a coin. This means we need to discover microbiome biomarkers for prediction of response across geographies, which is currently lacking. Despite the infancy of our understanding of microbiome biomarkers, modulation of the microbiome can still have beneficial effects. Dr. Trinchieri told of a small pilot study at the University of Pittsburgh in which patients resistant to anti-PD1 therapy underwent fecal transplant from responders and then additional immune checkpoint therapy. So far, two out of three patients are showing some response to this treatment (stable disease or regression).
This talk, and the others in the session, indicated to me how the microbiome has catapulted into a central role in understanding immuno-oncology. As we’re developing and implementing cancer genotyping assays to predict response to I-O therapies (and corresponding reference standards), we need to consider these non-genomic factors that play a critical, but not-yet fully understood function. I can’t wait to hear what progress will be made in the coming year.
Have you seen our AACR 2019 posters? You can download our featured presentations on reference standards for TMB, liquid biopsy, NTRK, fusion RNA, and more by clicking here.
- Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Gopalakrishnan V. et al. Science. 2018 Jan 5;359(6371):97-103.
- Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Routy B. et al. Science. 2018 Jan 5;359(6371):91-97.
- The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Matson V. et al. Science. 2018 Jan 5;359(6371):104-108