Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy.

Abstract

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60% of patients still experience disease relapse and up to 80% of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. We investigated the role of the intestinal microbiome on these outcomes in a multicenter study of patients with B cell lymphoma and leukemia. We found in a retrospective cohort (n = 228) that exposure to antibiotics, in particular piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M), in the 4 weeks before therapy was associated with worse survival and increased neurotoxicity. In stool samples from a prospective cohort of CAR T cell recipients (n = 48), the fecal microbiome was altered at baseline compared to healthy controls. Stool sample profiling by 16S ribosomal RNA and metagenomic shotgun sequencing revealed that clinical outcomes were associated with differences in specific bacterial taxa and metabolic pathways. Through both untargeted and hypothesis-driven analysis of 16S sequencing data, we identified species within the class Clostridia that were associated with day 100 complete response. We concluded that changes in the intestinal microbiome are associated with clinical outcomes after anti-CD19 CAR T cell therapy in patients with B cell malignancies.

• Authors: Melody Smith, Anqi Dai, Guido Ghilardi, Kimberly V Amelsberg, Sean M Devlin, Raymone Pajarillo, John B Slingerland, Silvia Beghi, Pamela S Herrera, Paul Giardina, Annelie Clurman, Emmanuel Dwomoh, Gabriel Armijo, Antonio L C Gomes, Eric R Littmann, Jonas Schluter, Emily Fontana, Ying Taur, Jae H Park, Maria Lia Palomba, Elizabeth Halton, Josel Ruiz, Tania Jain, Martina Pennisi, Aishat Olaide Afuye, Miguel-Angel Perales, Craig W Freyer, Alfred Garfall, Shannon Gier, Sunita Nasta, Daniel Landsburg, James Gerson, Jakub Svoboda, Justin Cross, Elise A Chong, Sergio Giralt, Saar I Gill, Isabelle Riviere, David L Porter, Stephen J Schuster, Michel Sadelain, Noelle Frey, Renier J Brentjens, Carl H June, Eric G Pamer, Jonathan U Peled, Andrea Facciabene, Marcel R M van den Brink, Marco Ruella
• Journal: Nature medicine (Nat Med) Vol. 28 Issue 4 Pg. 713-723 (04 2022) ISSN: 1546-170X [Electronic] United States
• PMID: 35288695 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Chemical References

• Antigens, CD19
• Receptors, Chimeric Antigen

Topics

• Antigens, CD19
• Gastrointestinal Microbiome
• Humans
• Immunotherapy, Adoptive (adverse effects)
• Neurotoxicity Syndromes (etiology)
• Prospective Studies
• Receptors, Chimeric Antigen
• Retrospective Studies