My goal is to develop a T cell receptor (TCR) gene therapy program for hematologic diseases at the National Cancer Institute. In contrast to antibody-based approaches and chimeric antigen receptors (CAR) where the target antigen is expressed on the cell surface, TCR has the ability to recognize both extracellular and intracellular antigens. This broadens the scope of potential target antigens and, consequently, the spectra of diseases that can be addressed with T-cell-mediated cytotoxic mechanisms. TCR T cells can also recognize cancer cells that lose antibody epitopes or cell-surface expression of target antigen(s), which are examples of mechanisms by which diseases relapse after treatment with antibodies and CAR-T cell-based therapies. Furthermore, toxicities of currently established cell therapies are often prohibitive for older patients with hematologic malignancies. Therefore, it is of clinical importance to investigate whether cell therapies using the physiologic TCRs, as opposed to synthetic molecules, improve toxicity profiles in the context of hematologic diseases.

Ongoing research studies are structured around three goals that complement each other: 1) identify and describe the landscape of naturally processed and presented MHC class I and II epitopes of target antigens in hematologic malignancies, 2) discover high-avidity TCRs against antigens shared among subgroups of hematologic malignancies, and 3) conduct clinical trials with the TCRs. Based on the preliminary results from goal #1, we were able to discover candidate TCRs (goal #2) for potential clinical translation. We are currently in the process of conducting pre-clinical validations, which will eventually lead to the execution of clinical trials (goal #3). While current efforts are mainly focused on achieving an expeditious bench-to-bedside translation, the vision of the program, as we make progress, is to also provide clinically relevant models and further our mechanistic understanding of how T cell-mediated therapies and the host’s immune environment affect clinical responses and hematologic disease biology.