In recent years, chimeric antigen receptor (CAR) T cell therapy has proven to be transformative for the treatment of B cell malignancies. Many challenges remain, however, including the loss of long-term antitumor efficacy, the occurrence of severe adverse events, and, notably, a lack of biomarkers for predicting therapy outcomes. There is an urgent need to improve our ability to predict which patients will respond to immunotherapy, and to improve durability and safety. Growing evidence suggests that the gut microbiome can strongly influence how a patient will respond to immunotherapy by modulating the host immune system. Restoring normal gut microbiota through transplantation, for example, can help mitigate toxicity of checkpoint inhibitor therapy. However, the complexity and dynamic nature of the microbiome make it challenging to study, and our understanding of the interplay between the microbiome and various cancer therapies remains in its infancy.
This multi-national Endeavor team brings together investigators from three top research institutions in Germany and the United States to address these challenges with a translational research strategy aimed at dissecting the impact of the intestinal microbiome on CAR T cell immunotherapy. The investigators will leverage their large bank of longitudinal samples collected from patients receiving CAR T cell treatment to examine changes in the microbiome composition over time, and look for associations with clinical outcome. To complement this metagenomic analysis, they will perform large scale identification of metabolites linked to the microbiome in patient blood and stool, and study the effects of these microbial metabolites on CAR T cell function. They will validate the patient microbiome profiles and associated effectors by humanizing mice with patient-derived microbial ecologies and studying the effects of CAR T cell immune phenotypes and toxicity profiles.
The power of this project lies in the international nature of a team spanning two countries and six different hospitals. The multi-center trial will greatly increase the robustness of the results. Characterizing the functional role of the commensal microbiome and its products in CAR T cell immunotherapy harbors enormous potential to improve current and future T cell transfer therapies for cancer patients.
Ratiner K, Fachler-Sharp T, Elinav E. Small Intestinal Microbiota Oscillations, Host Effects and Regulation-A Zoom into Three Key Effector Molecules. Biology (Basel). 2023.
Stein-Thoeringer CK, Saini NY, Zamir E, Blumenberg V, Schubert ML, Mor U, Fante MA, Schmidt S, Hayase E, Hayase T, Rohrbach R, Chang CC, McDaniel L, Flores I, Gaiser R, Edinger M, Wolff D, Heidenreich M, Strati P, Nair R, Chihara D, Fayad LE, Ahmed S, Iyer SP, Steiner RE, Jain P, Nastoupil LJ, Westin J, Arora R, Wang ML, Turner J, Menges M, Hidalgo-Vargas M, Reid K, Dreger P, Schmitt A, Müller-Tidow C, Locke FL, Davila ML, Champlin RE, Flowers CR, Shpall EJ, Poeck H, Neelapu SS, Schmitt M, Subklewe M, Jain MD, Jenq RR, Elinav E. A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy. Nat Med. 2023.