T CELL THERAPEUTICS
Adoptive T cell Therapy is a rapidly growing field and its recent clinical successes have significantly shaped the current field of immune-oncology. Several modalities have been explored, including expansion and re-infusion of tumor-infiltrating T cells, expansion of tumor antigen-specific T cells from peripheral blood, and infusion of genetically modified T cells (e.g. chimeric antigen receptor (CAR) T cells, transgenic TCR). These approaches have shown remarkable efficacy in hematologic malignancies including B-ALL and more recently Multiple Myeloma, but have been with limited success in solid tumors.
The major limitations hindering efficacy in the solid tumor setting include limited function and persistence of the adoptively transferred T cells by activation of negative regulators and induction of T cell exhaustion through the hostile tumor-microenvironment.
The Kean lab is now addressing these limitations by interrogation of different complementary strategies. Using CRIPSR Cas9 technology we are deleting negative regulators of T cell activation and persistence to increase function and long-term survival of T cells after adoptive transfer. We have established a multitude of in vitro and in vivo tumor targeting T cell models, to validate our strategies and are additionally using single cell transcriptomic and epigenetic assays to explore underlying mechanisms. We are also utilizing our established non-human primate CD20 CAR T cell model to further assess function, persistence and toxicity of our genetically modified T-cells and provide the rationale for future clinical translation.