Wednesday, April 2, 2025
4/2/2025
Learning features of optimal CAR T cells for LBCL from patient data - PROJECT SUMMARY/ABSTRACT Chimeric antigen receptor (CAR) T cells have emerged as breakthrough treatments for patients with hematologic malignancies, earning 12 approvals from the U.S. Food and Drug Administration (FDA) since 2017. Experimental CAR T cell therapies have also demonstrated complete remissions in solid tumors, and the FDA is projecting to grant 10-15 approvals per year by 2025, highlighting the potential of these ‘living therapies’. Despite this, current CAR T cell designs have not yet mediated sustained efficacy in solid tumors, and only 30-50% of B cell leukemia and lymphoma patients experience long-term disease control. To develop safe and potent next-generation CAR T cell therapies, it is critical to understand why existing CAR T cells succeed or fail in patients. As a scientist trained in both experimental and computational immuno-oncology, I have chosen to focus my career on using a systems biology approach to uncover the molecular mechanisms governing efficacy of engineered T cell immunotherapies. This proposal outlines a structured 2-year training plan and a comprehensive 5-year career development program to complete my training and launch an independent research career. My specific research goals are: (1) to define the most therapeutically relevant CAR T cell subsets in patients with large B cell lymphoma (LBCL), and (2) to overcome an immune suppression mechanism of resistance to CAR T cell therapy for LBCL. First, I will follow individual CAR T cell clones through time in patients treated for LBCL using matched single-cell sequencing of transcriptome, a panel of surface proteins, and endogenous T cell receptors (Aim 1). This approach, termed reverse fate mapping, will pinpoint T cell clones in the pre-manufacture apheresis and infusion products with sought-after properties, including abilities to expand, persist, and home to the tumor. In Aim 2, I will apply reverse fate mapping and methylation analyses to identify the origin of circulating CAR T regulatory (Treg) cells that I recently linked to limited CAR T cell efficacy in LBCL. In Aim 3, I will mechanistically dissect the interplay between Treg and non-Treg CAR T cells to design a potent ‘Treg-free’ CAR T cell therapy for clinical evaluation. My work will generate a comprehensive CAR T cell atlas and insights, leading to promising avenues for engineering the next-generation CAR T cell therapies. The results of my proposed research will positively impact public health, as they will gather sufficient preliminary data for testing a ‘Treg-free’ CD19-CAR T cell therapy for LBCL in a clinical trial and will deliver fundamental insights into CAR Treg biology that may generalize to other diseases, including solid tumors, where engineered T cell therapies have not manifested similarly potent effects as in LBCL. To build upon my skills, I have assembled a mentorship team, including my primary mentor, Dr. Crystal Mackall, a pioneer in CAR T cell immunotherapies; co-mentor, Dr. Sylvia Plevritis, a leader in cancer systems biology; and an advisory committee with extensive expertise relevant to all aspects of this proposal. The completion of this K99/R00 program will prepare me to compete for R01 funding and to launch an independent research career focused on improving immunotherapies for patient with cancer.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).