Abstract 6676: Microbiome modification impacts PSCA directed chimeric antigen receptor (CAR) T cell therapy for prostate cancer
Authors: Murad John Paul , Christian Lea , Yamaguchi Yukiko , Lopez Lupita , Ouyang Ching , Sato Hirokazu , Jarman Bryce , Stromberg Sean , Forman Stephen J. , Van Dien Stephen , Culler Stephanie , Priceman Saul J. 
Published: March 2024

Background: There is growing evidence that responsiveness to immunotherapy is influenced by the composition of a patient’s gut microbiota. Recent analysis identified strong correlations between abundance of gut microbial species and positive response to immune based therapies in cancer patients. Further, enrichment of commensal microbes can promote immunostimulatory effects, immune based anti-tumor responses, and increased cytotoxic T cell abundance within the TME. Conversely, the presence of gut microbes known to cause inflammatory states in gut tissues may be correlated to negative immunotherapy outcomes or toxicities. To this end, we aimed to evaluate the impact of microbiome manipulation on gut microbe diversity, systemic immunity, local TME, and PSCA-targeted chimeric antigen receptor (CAR) T cell therapy in our established syngeneic prostate cancer mouse model.

Methods: In an immune competent mouse model of PSCA+ prostate cancer developed in our lab, we sequentially modified the gut microbiome using antibiotic clearance followed by distinct human derived fecal matter transfers (CPI-FMT, HD-FMT, or No-FMT). Simultaneously, we treated microbiome modified tumor bearing mice with PSCA-targeting CAR T cells and measured differences in anti-tumor efficacy and survival. To provide mechanistic insight, we performed longitudinal whole genome sequencing (WGS) of fecal matter microbes and RNA sequencing on spleen and tissues following FMT administration.

Results: In our model, a unique checkpoint inhibitor (CPI) treated patient derived human FMT (CPI-FMT) improved PSCA-CAR anti-tumor responses relative to healthy donor (HD-FMT) or No-FMT treatment controls. CPI-FMT administration also significantly improved overall survival in CAR T cell and non-targeting T cell control treated mice. Temporal analysis of microbes present in the gut following CPI-FMT and HD-FMT treatment show CPI-FMT treated mice exhibit favorable maintenance of gut microbe species richness and significant increase in microbiota diversity. We identify CPI-FMT provides an enrichment of specific microbes associated with preservation of gut homeostasis and improved immune response. RNA sequencing analysis on tumor tissues show differential transcription of immune related pathways following FMT which may influence immune and CAR T cell function.

Conclusions: We show that our mouse prostate cancer model is sensitive microbiome modulation and can significantly impact PSCA-CAR T cell directed anti-tumor responses. Temporal WGS analysis of gut fecal matter reveal enrichment suggest specific species abundances which may promote gut homeostasis over dysbiosis or inflammatory states and may account for improved CAR T cell response. We aim to further develop this model to interrogate candidate targeted microbiome modifiers which may impact mechanisms which promote CAR T cell and immune function.

Citation Format: John Paul Murad, Lea Christian, Yukiko Yamaguchi, Lupita Lopez, Ching Ouyang, Hirokazu Sato, Bryce Jarman, Sean Stromberg, Stephen J. Forman, Stephen Van Dien, Stephanie Culler, Saul J. Priceman. Microbiome modification impacts PSCA directed chimeric antigen receptor (CAR) T cell therapy for prostate cancer [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 6676.