Boosting the therapeutic potential of engineered T cells through revamped synthetic circuits

Despite showing remarkable clinical responses in certain late-stage hematological malignancies, chimeric antigen receptor (CAR) T cell-based therapy have failed to demonstrate comparable effects for solid tumors.

The goal of this proposal is to enhance the therapeutic potency of CAR T cells by next-generation synthetic circuit designs.First, I will explore the intrinsic value of conditional perturbation T cell-associated transcriptional regulators in synNotch CAR T cells in a syngeneic tumor using a curated shRNA library.

Critical regulators, alone or in combinations, in these engineered T cells will be determined through multi-parameter flow cytometry and deep-sequencing techniques.

Secondly, to follow up on my postdoctoral work, I aim to remodel the cold tumor-microenvironment by local tumor delivery of three distinct extrinsic payloads based on characteristics seen in patients and preclinical models of mesothelioma using sophisticated synNotch CAR T cells. This work, partly done in collaboration with Dr.

Kole Roybal (USCF), will assess the additive effect of these payloads in a highly relevant syngeneic mesothelioma mouse model.

Lastly, I will develop a in vivo system that allows for conditional and permanent tracking of tumor-experienced CAR T cells to advance our understanding of the mechanisms behind a long-lasting therapeutic response.Combined these aims will enable us to understand and improve cell-based therapy for patients currently lacking viable treatment options.