Smith Lab

For patients confronting relapsed or refractory hematological malignancies, allogeneic hematopoietic cell transplantation (allo-HCT) represents a promising strategy to potentially achieve a cure. Nevertheless, despite its therapeutic potential, the issues of relapse and graft-versus-host disease (GVHD) – a complication arising when donor T cells recognize host tissue as foreign – continue to contribute significantly to morbidity and mortality. Dr. Smith’s prior investigations have elucidated the safety and feasibility of employing chimeric antigen receptor (CAR) T cells as a post-allo-HCT therapeutic intervention (Ghosh A, Smith M et al., Nature Medicine 2017; Smith M et al., Blood 2018).

In this context, our research endeavors concentrate on integrating CAR T cell therapy within the post-transplant setting. By utilizing genetic engineering techniques to modify T cells and exploring innovative CAR T cell designs, our primary objective is to unravel the intricate mechanisms underlying the safe development of donor-derived cellular therapies. These studies enable us to broaden our understanding of CAR T cell therapy, potentially improving patient outcomes by reducing disease relapse after allo-HCT.

CAR T cell therapy has broadened the treatment landscape for many cancers, particularly for patients with relapsed or refractory B-cell acute lymphoblastic leukemia and non-Hodgkin lymphoma. However, many of these patients may experience disease relapse or treatment-related toxicity. While several investigators are evaluating the impact of the tumor microenvironment or T cell biology as mechanisms of CAR T cell failure, the Smith lab is exploring the role of endogenous factors on CAR T cell activity.

Dr. Smith led a study that found that exposure to antibiotics in the four weeks before CD19 CAR T cell therapy—especially piperacillin/tazobactam, meropenem, and imipenem/cilastatin—is associated with worse overall survival and increased immune effector cell-associated neurotoxicity syndrome (ICANS) (Smith M., et al. Nature Medicine, 2022). She also identified characteristics of the intestinal microbiome and specific bacterial taxa associated with clinical outcomes. Based on these findings, we are now leveraging mouse models, patient cohorts, next-generation sequencing, and computational approaches to investigate the mechanisms by which antibiotics and specific intestinal microbiome taxa regulate CAR T cell anti-tumor activity and toxicity (Xie J and Smith M. Blood 2024; Darwin A, Xie J, and Smith M. Blood Advances 2025).

Amy Scholar Research Program

ASCI / Young Physician-Scientist Awards, 2025