We hypothesize that interplay between host immune responses and the gut microbiota affect the efficacy and toxicity of immune checkpoint inhibition (ICI) in melanoma patients. Increasing evidence suggests that gut microbiota play important roles in regulating the innate and adaptive immune response to cancer immunotherapy. We and others have provided compelling evidence that the gut microbiome is associated with the efficacy and the toxicity of immunotherapy. We also showed that novel baseline pre-treatment T-cell phenotypes and the levels and suppressive function of T regulatory cells in the peripheral blood were associated with increased relapse-free survival (RFS) after PD-1 blockade in melanoma. Moreover, we found that alterations in serum protein immune pathways were associated with decreased survival with PD-1 blockade, underlining the importance of host immune responses for immunotherapy outcomes. Nonetheless, no definitive, large scale human studies have identified the gut microbial taxa associated with the efficacy and/or toxicity of immunotherapy, nor investigated their relationships with host immune responses. The goal of Project 1 is to identify microbial and host immune biomarkers that predict the efficacy and toxicity of ICI in a randomized phase III adjuvant trial testing combination PD-1/CTLA-4 blockade versus PD-1 alone in patients with high-risk resected stage IIIB/C and IV melanoma. As part of a large, well-controlled randomized and blinded trial (n=2000; a subset of n=1500 available blood/stool samples), we will evaluate gut microbiota in stool and a series of innovative biomarkers in serum and peripheral blood immune cells, and examine the utility of these biomarkers to predict clinical efficacy and toxicity from immunotherapy (Aims 1 and 2). Based on integration of these biomarkers, we will additionally define cohorts of patients who may derive differential benefit from combination versus single-agent checkpoint blockade (Aim 3). This study, based on a large clinical trial with standardized treatments and clinical outcome as well as toxicity assessments, will provide excellent power for biomarker identification with rigorous replications. This research will improve patient care by defining predictive biomarkers and developing a predictive classifier ? using easily obtainable stool, serum, and blood samples ? that can facilitate personalized immunotherapy decisions. Finally, given the modifiable nature of gut bacteria, findings could lead to tailored microbe-targeted interventional approaches to improve the efficacy of, and attenuate the toxicity of, ICI.
PROJECT 1 NARRATIVE The goal of Project 1 is to identify microbial and host immune biomarkers that predict the efficacy and toxicity of immune checkpoint inhibition. This research will improve patient care by defining predictive biomarkers and developing a predictive classifier ? using easily obtainable stool, serum, and blood immune cell samples, ? that can facilitate personalized immunotherapy decisions.
