Abstract 6691: Engraftment as a determinant of response in fecal microbiome transplantation interventions for immunotherapy in melanoma

Abstract Background: Distinct gut microbiome signatures are associated with response, resistance, and toxicity to immune checkpoint blockade (ICB). Fecal microbiome transplants (FMT) have validated the importance of the gut microbiome in enhancing response and overcoming resistance to immunotherapy. However, donor selection remains a key challenge for FMT. Heterogenous responses using Healthy Donors (HD) and ICB Complete Responders (CR) as FMT donors suggest donor characteristics alone do not determine response. Here, we posit that donor-recipient relationships are critical in determining clinical responses to FMT. Methods: We studied a cohort of ICB-refractory, metastatic melanoma patients treated with combined FMT and ICB (10 recipients, 2 donors). Patient gut microbiomes were profiled using whole metagenomic sequencing (WMS) of longitudinal stool collections (baseline, day 7, day 31, and day 65 post-FMT). Immune infiltration of on-treatment tumor and colon biopsies was quantified with immunohistochemistry. mTraCX, an Earth Mover’s Distance-based algorithm, was used to evaluate taxonomic engraftment between donors and recipients. Bray-Curtis distance was used to measure functional similarities between donor and recipient gut microbiome. Clinical findings were validated in pre-clinical FMT experiments performed on BrafV600EPten−/− melanoma-bearing mice. Results: One-third of recipients (3/10) developed an objective response (R) to ICB following FMT. mTraCX demonstrated an association between clinical response to FMT and durable engraftment of donor microbiota at day 65 post-FMT (p=0.025). Taxonomic engraftment (mTraCX) correlated positively with functional engraftment (Bray-Curtis distance) (r=0.89, p<0.0001). Enhanced engraftment was associated with increased CD4 (r = -0.87, p=0.0045) and CD8 (r = -0.6, p=0.09) T-cell infiltration in the colon, and a trend towards increased CD8 T-cell infiltration (r = -0.5, p=0.2) in the tumor following treatment with FMT+ICB. Pre-clinical models paralleled our clinical findings as responding mice showed better donor engraftment than non-responding mice (p<0.0001 on day 4 and day 24 following FMT). Conclusions: Our data shows that donor engraftment is a favorable prognostic factor for ICB treatments combined with FMT. Future investigations will aim to develop donor-recipient matching criteria to enhance the feasibility and integration of FMTs into clinical practice. Citation Format: Manoj Chelvanambi, Ashish V. Damania, Sarah B. Johnson, Golnaz Morad, Rossana N. Lazcano, Beth A. Helmink, Lon W. Fong, Khalida Wani, Y David Seo, Elizabeth M. Park, Reed I. Ayabe, Bhavana Singh, Matthew C. Wong, Davis R. Ingram, Michael G. White, Alexander J. Lazar, Aditya K. Mishra, Nadim J. Ajami, Erez N. Baruch, Jennifer A. Wargo. Engraftment as a determinant of response in fecal microbiome transplantation interventions for immunotherapy in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6691.