Precision Control of Universal CAR Activity by Small Molecule Adaptors

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

SUMMARY Chimeric antigen receptor (CAR) T cell therapy has revolutionized blood cancer treatment and shows potential for solid tumors, autoimmune diseases, and viral infections. We have developed a highly programmable universal CAR called SNAP-CAR, which can target any cell surface antigen by associating with a chemically modified adaptor antibody. However, CAR T therapy faces challenges such as limited specificity, susceptibility to immune inactivation, and complex manufacturing for multi-antigen targeting. To overcome these hurdles, we propose to develop small molecule adaptors for covalent reprogramming of SNAP-CAR. Small molecule drugs offer distinct advantages over antibodies, such as oral availability, cell permeability, chemical synthesis and modification, and lower production cost. We are capitalizing on these advantages and the utilization of covalent and caging chemistries in proposing the following specific aims: 1) Develop small molecule adaptors, and combinations thereof, for targeting of universal CARs to multiple antigens including simultaneous targeting of tumor cells and neighboring immunosuppressive cells. 2) Enhance universal CAR targeting specificity through chemical switches that respond to unique intracellular enzyme characteristics in disease tissue, in particular solid tumors. 3) Expand the antigen targeting breadth of SNAP CAR T cells to neoepitopes on tumor cell surfaces generated through covalent modification and major histocompatibility complex (MHC) display of intracellular oncogene products. The MPIs' expertise in chemical synthesis and immunology will synergistically contribute to the success of this project. The long-term goal is to improve accessibility to treatment and patient outcomes by enhancing both the specificity and breadth of targeting through conditional and combinatorial control of the CAR therapy. The strategies developed will be applicable to other universal receptor technologies and open up new therapeutic possibilities across different disease indications.