72P A high-polyphenol dietary intervention to improve response to immune checkpoint blockade for lung cancer via modification of the microbiome

Immune checkpoint blockade has increased survival for lung cancer patients. Unfortunately, many patients' tumors do not respond. Recent evidence suggests that the gut microbiome is critical in response to ICB. The microbiome is malleable; therefore, it holds promise as both a biomarker of response to ICB and a therapeutic target. While several methods of modifying the microbiome are under investigation in clinical trials globally, lifestyle-based interventions are arguably the safest and most patient-empowering strategies. Here, we describe the use of a small dietary intervention designed to increase the abundance of microbes that promote response to ICB. The BEWELL Study (Black raspberry nEctar Working to prEvent Lung cancer NCT04267874) was a randomized, cross-over trial that tested 2x 80 mL black raspberry (BRB) nectar drink boxes per day for 4 weeks versus a taste and texture-matched placebo control. Surveys were collected before the intervention (physical activity, eating patterns), and blood, stool, and urine were collected at four time-points: pre- and post-BRB, and pre- and post-placebo. Plasma cytokines, urine polyphenols, and gut microbes were assessed. Stool from participants before and after the intervention was transferred into tumor-bearing (mc38, CMT167) C57BL/6 mouse models, which were then treated with anti-PD1 (RMP1-14) or control (IgG, clone 2A3), and tumor volumes assessed by caliper. Individual microbes were cultured from stool samples and added to pre-BRB samples at 1e7 CFU to recapitulate the post-BRB response to ICB. Participants in the BEWELL Study showed a significantly greater abundance of several taxa in the family Lachnospiraceae following BRB. Less physically active participants were more likely to experience a significant increase in Lachnospiraceae. In mouse models, a change in Lachnospiraceae was associated with smaller tumor volumes. Further, a Lachnospiraceae isolate promoted smaller tumor volumes when supplemented into a pre-BRB stool gavage. These results suggest that a BRB dietary intervention may alter the human gut microbiome to support improved response to ICB.