Abstract 6672: Unraveling the microbiome: antibiotic impact on CAR T therapy and the synergistic potential of vancomycin in enhancing antitumor immunity

Abstract

Abstract The landscape of treating hematologic malignancies has undergone a revolutionary transformation with the advent of Anti-CD19 chimeric antigen receptor T cell therapy (CART-19). Despite its success, persistent challenges like disease relapse and CAR-mediated toxicities remain. A comprehensive multicenter study involving 228 individuals revealed a significant association between antibiotic administration, particularly piperacillin/tazobactam, meropenem, and imipenem/cilastatin (P-I-M), targeting anaerobes within four weeks preceding CART-19 therapy, and adverse outcomes, including worsened survival and increased neurotoxicity. Intriguingly, another antibiotic, Cefepime, also used for neutropenic fever, displayed a positive trend when compared with P-I-M. This highlights the intricate relationship between the modulation of the intestinal microbiome and outcomes in CART-19 therapy for B cell malignancies. Building on these critical observations, our study delved into the impact of vancomycin-induced gut microbiota dysbiosis on chimeric antigen receptor (CAR) T immunotherapy. Utilizing preclinical models of CD19+ A20 lymphoma and CD19+ B16 melanoma, we discovered that mice receiving vancomycin alongside CART-19 therapy exhibited enhanced tumor control and increased cross-presentation of tumor-associated antigens (TAAs) compared to those receiving CART-19 alone. This effect was further validated through fecal microbiota transplants from healthy human donors to pre-conditioned mice, replicating the favorable findings. Importantly, our study extends to clinical correlates, as B cell acute lymphoblastic leukemia patients treated with CART-19 and oral vancomycin displayed elevated CART-19 peak expansion compared to unexposed patients. These compelling results underscore the profound influence of the gut microbiota on CAR T cell therapy and suggest that vancomycin-induced gut microbiota modulation may emerge as a potent strategy to enhance therapeutic outcomes across various tumor types. Citation Format: Andrea Facciabene, Mireia Uribe-Herranz, Vijay Bhoj. Unraveling the microbiome: antibiotic impact on CAR T therapy and the synergistic potential of vancomycin in enhancing antitumor immunity [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 6672.