Grant: Project Grant

Cellular immunotherapies of cancer have been under intense development for the past decades. One such therapy is called chimeric antigen receptor (CAR)-T cell therapy where the patient's T cells are removed from the blood, modified in the laboratory to recognize and attack tumor cells, and then given back to the patient. Despite the success of CAR-T cell therapy for treatment of some blood cancers, nearly half of patients either do not respond to the treatment or relapse. To date, research in the CAR-T cell therapy field mostly focuses on how researchers can improve performance of the cells by modifying the genetic component of the CAR receptor to be more efficient. In contrast, we aim to investigate how the patient's microbiome (and small molecules produced by the microbiome) alter the function of the CAR-T cells. The gut microbiome and microbial metabolites have been found to modulate and improve the anti-cancer function of T cells in another type of cancer immunotherapy, called immune checkpoint blockade therapy. Similarly, differences in the patient's microbiome composition may be one of the key extrinsic underlying factors determining responsiveness to CAR-T cell therapy. We have recently identified microbes which aid in immune checkpoint blockade therapy of solid cancers and our preliminary data suggests that the same bacterial species can also aid CAR-T cell function in preclinical animal models of B cell acute lymphoblastic leukemia. In this research project we will further identify the mechanisms involved in this process and confirm the findings in patients undergoing CAR-T cell therapy. Our study will serve as a basis to develop microbial based therapeutics to promote the efficacy of CAR-T cells to ultimately transform non-responding patients into responding patients.