Engineering Metabolically Weaponized T Cell Therapies for Solid Tumor Translation

Chimeric Antigen Receptors (CAR) T cell therapies are revolutionizing treatment of cancer in hematological malignancies, eclipsing 50-90% response rates for refractory, or previously non-responding cancers. If we could recapitulate even a fraction of this efficacy for solid tumor indications, it would provide enormous hope for patients who have no recourse. However, the translation of CAR T cells to the solid tumor has come with several stumbling blocks, broadly in the realm of safety and efficacy due to the immunosuppressive tumor microenvironment. The metabolite adenosine accumulates in tumors at 1000x concentrations compared to healthy tissue and inhibits most essential T cell antitumor functions (tumor killing, proliferation, and cytokine release). Fortunately, using CAR T cells as shuttles, or “living drugs” to unload immunostimulatory proteins to tumors has begun to move the needle on efficacy. Additionally, many researchers have developed sophisticated ways to synthesize cellular logic in CAR T cell therapies to augment their safety profiles. This thesis details two technologies that address both efficacy and safety considerations of CAR T cells (Figure 1). To improve CAR T cell function in solid tumors, we developed a novel ADA2 enzyme that can slow tumor growth when delivered from murine CAR T cells in syngeneic mouse models of triple negative breast cancer. In the realm of safety, we developed and characterized adenosine-activated synthetic gene switches that can provide local activity when expressed by murine CAR T cells in tumor environments. The following introduction explains the current challenge of adenosine in tumor microenvironments as well as developments in therapeutic T cell engineering, providing context for our technological advancements.

Date

2024-07-26

Resource Type

Text

Resource Subtype

Dissertation

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