Abstract 5566: Discovery and functional validation of a rationally selected, orally administered, live biotherapeutic consortium of commensal bacteria for the treatment of solid tumors

Abstract

Abstract Recent evidence supports the role of gut commensal microbes in mediating patient response to immune checkpoint inhibitor therapies (ICT) and chemotherapy. Fecal transplants from ICT responder or non-responder patients into mice modulate syngeneic tumor growth and response to checkpoint antibody treatment, recapitulating the response patterns seen in the human donors. These and other data support the conclusion that certain gut commensal bacteria can promote a systemic immune response to tumors distant from the gut mucosa. We hypothesize that a well-defined consortium of bacteria, rationally selected based on disease-relevant immunological mechanisms, could provide meaningful clinical benefit upon oral administration and delivery to the intestine of cancer patients. To this end, we have identified candidate live biotherapeutic microbes from a library of commensal bacteria isolated from well-curated healthy human stool samples. Identities of purified bacterial strains were established by 16s and whole genome sequencing. Phenotypic parameters, including C- and N- source utilization and antibiotic resistance were determined. Individual strains were characterized based on function by co-incubating live bacteria with human cells in a panel of validated in vitro assays with endpoints measuring disease-relevant, immune-stimulatory mechanisms for a cancer therapeutic. Bacterial strains that exhibited reproducible immune-stimulatory functions in vitro, such as induction of pro-inflammatory cytokines from dendritic cells or PBMCs, T-cell activation and/or M1 macrophage shift, were selected for in vivo testing by oral administration in CT26 and B16F10 syngeneic mouse tumor models. Results of in vivo testing demonstrated reproducible anti-tumor activities by several bacterial strains, as measured by reduced tumor volume over time compared to vehicle control. Bacteria promoting an anti-tumor response also induced hallmarks of immune activation, such as increased inflammatory cytokines in the tumors and changes in immune cell subsets. Further syngeneic tumor studies are underway to test efficacious bacterial strains in combination with each other as consortia as well as with checkpoint antibodies to ultimately select the best candidate therapeutic consortia for clinical development. Using well-defined robust GMP processes, candidate therapeutic consortia will be prepared as lyophilized formulations confirmed to retain viability and function in the preclinical assays and models, then encapsulated for oral administration and evaluation in human subjects. Citation Format: Linh Nguyen, Peyman Akbari, Jason Hudak, Jun Ma, Kiran Dhami, Karin Ku, Ali Akin, Zuelay Rosario, Jackie Papkoff. Discovery and functional validation of a rationally selected, orally administered, live biotherapeutic consortium of commensal bacteria for the treatment of solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5566.