DESCRIPTION:

Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment of large B-cell lymphoma and multiple myeloma, yet roughly half of patients relapse within two years and most develop cytokine release syndrome or neurotoxicity. Nearly all efforts to improve these outcomes have focused on engineering the T cell. This talk makes the case for a different target: the gut microbiome. I will present our preliminary work showing that in 295 consecutive adults receiving commercial CAR-T at our center, peri-infusion anaerobe-targeting antibiotic exposure was associated with inferior progression-free survival, fecal alpha-diversity declined progressively from leukapheresis through Day +90 without recovery, and butyrate-producing commensals and butyrate-biosynthesis pathways were enriched in responders. Building from these data, we designed and cGMP-manufactured Con.CART.A, a defined ten-strain oral live biotherapeutic that produces butyrate through complementary cross-feeding routes. I will show that it engrafts and raises intestinal butyrate preclinically, that a fermentable substrate alone cannot reproduce this benefit in the antibiotic-conditioned gut, and that adding the consortium to CD19-directed CAR-T significantly prolongs survival in mice. I will close with the design of MICRO-CART, our FDA-authorized randomized, double-blind, placebo-controlled Phase 1 trial testing this consortium in 32 CAR-T recipients, and what it will tell us about microbiome reconstitution as a new therapeutic class for cellular immunotherapy.

LEARNING OBJECTIVES:

• Describe how antibiotics and chemotherapy damage the gut microbiome in CAR-T patients, and why that matters for outcomes
• Explain how oral bacterial consortium can restore butyrate and improve CAR-T function
• Describe the design of Phase 1 trial testing this approach in CAR-T recipients