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

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.

Grant Number: 4DP2CA280622-02
NIH Institute/Center: NIH
Principal Investigator: John Blazeck