Synthetic metabolism to armor and enhance a new class of cell therapies

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Project Summary/Abstract Tumors inhibit immune responses through many routes, and it has become widely accepted that preventing multiple immunosuppressive mechanisms is necessary to fully unleash the nascent anti-tumor response. Altered metabolic function is a hallmark of cancer, and the metabolic alterations that enhance cancer cell proliferation also suppress the immune system by starving, shutting down, or killing T cells. Cancers employ two key mechanisms to suppress T cell function via metabolic alterations in tumors: (1) nutrient depletion and (2) accumulation of immunosuppressive metabolic byproducts. These metabolic alterations are recognized as important mechanisms employed by solid tumors to limit the efficacy of autologous T cells therapies and checkpoint inhibitor antibodies, and no therapies exist to allow the immune system to fight back against this immunosuppressive metabolic environment. Therefore, this proposal seeks to develop innovative solutions to resist and actively remediate metabolic mechanisms of immunosuppression, via the first-ever efforts to enhance T cell function with synthetic metabolism. This project will apply the concepts of metabolic engineering and synthetic biology to enhance the ability of T cells to compete with tumoral cells for limited nutrients, to allow T cells to directly degrade immunosuppressive metabolic byproducts, and to enable the direct activation of synthetic T cell genetic programs by the solid tumor environment. These efforts will represent the first attempt to control tumoral metabolism with engineered immune cells, and such innovative approaches to reprogram the metabolic capacity of human cells could easily be applied to other disease states characterized by dysregulated metabolism. The research proposed here is significant because altered metabolic function and the resulting immunosuppressive environment of tumors are hallmarks of cancer, for which adequate therapies are lacking. Therefore, developing suitable approaches to allow T cells to resist or to otherwise fix this altered metabolism is of the utmost importance. The techniques described here will also have broad impact by helping combat key mechanisms of resistance to antibody checkpoint therapeutics, and the synthetic constructs and new approaches developed here will be translatable to human studies to improve the efficacy of CAR-T and other autologous T cell therapies against solid tumors.