Prebiotic diet intervention to enhance the microbiome and immunotherapy response in melanoma

Treatment with immune checkpoint inhibitors (ICI) has been revolutionary in melanoma and other cancers. However, only a subset of patients will have durable responses to first-line therapy and immune-related toxicities remain a significant challenge. Given the critical, unmet need for safe, effective and broadly applicable strategies in this setting, we will conduct a prebiotic food-enriched diet (PreFED) intervention combined with standard-of-care ICI in metastatic melanoma patients. This study seeks to intervene on insights from our own work and others demonstrating that (1) gut microbiome profiles and dietary habits predict response to ICI in melanoma; (2) well-characterized gut commensals consistently implicated in ICI response are highly responsive to prebiotic dietary interventions; and (3) the gut microbiome is a therapeutic target in ICI-induced toxicities. With the overarching goal to test rationally-designed, microbiome-targeted dietary interventions that cancer patients undergoing active therapy can practically implement and sustain throughout treatment, PreFED is a scalable approach focused on providing multiple key microbiota-accessible nutrients through provision of prebiotic foods and nutritional counseling to selectively stimulate beneficial gut microbes that enhance and sustain the overall gut ecosystem. Nutrient and microbiota-derived metabolites from these interactions support the central mechanisms underlying a favorable immune response to ICI (e.g., balancing inflammation and effector T-cell function). Thus to further interrogate mechanism and test whether PreFEDmanipulation of the microbial community could be effective as an adjunctive therapy to ICI, we will transplant paired patients’ fecal samples into germ-free mice to examine the impact of post vs. pre-diet microbiome on melanoma growth and ICI response, as well as mucosal and anti-tumor immunity. Through these studies, we will evaluate the effect of the PreFED on the gut microbiome, host metabolome, and the mucosal, systemic and antitumor immune response to ICI. Integrative analyses of both human and mouse studies will provide significant insights on diet-induced changes in the microbiome and microbiota-mediated changes in the metabolome that influence the immune response to ICI – and highlight avenues whereby patients’ diets may influence the success of other microbiome-targeted strategies being developed in this setting. Notably, to progress to future multicenter trials with robust translational and clinical endpoints, we will define the safety and efficacy profile of PreFED as an adjunct to current ICI regimens (anti-PD1 monotherapy, anti-PD1+LAG3, antiPD1+CTLA4). Though our studies will focus on metastatic melanoma, dietary approaches to enhance the gut microbiome, anti-tumor immunity and ICI response are relevant and applicable to other stages and cancer types. Accessible, appropriately refined and successful dietary interventions offer a cost-effective and safe adjunct that could be implemented across practice settings and geographies, addressing significant healthcare disparities and ultimately offering the potential to improve care for many patients.