Targeted enhancement of engineered cellular anti-HIV immunity in vivo using immune modulators

About This Grant

Abstract Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer and show promise in treating HIV-1 infection. Our studies in humanized mice and non-human primates (NHPs) have demonstrated that hematopoietic stem cells (HSPCs) based CAR therapy could provide life-long engraftment and production of functional CAR-T, CAR-NK and CAR-Macrophages (CAR-M), resulting in significantly reduced viral rebound after ART withdrawal. These studies underscore both the feasibility and efficacy of HSPCs-based CAR therapy. However, major challenges remain to achieve sustained viral remission in the absence of ART with current engineered immunity approaches. Mounting evidence has shown that environmental factors, such as metabolic regulation, innate signaling and chronic inflammation greatly impact in vivo function and persistence of engineered immune cells. Here we propose to investigate pharmacological interventions to enhance metabolism of engineered cells, improve effector functions, reduce immune suppression, prevent/restore immune exhaustion, and enhance memory formation of engineered CAR cells in vivo. Building on our extensive work on CAR engineered immunity, innate signaling and immune metabolism, we will 1) improve CAR-MQ, CAR-T and CAR-NK effector function and enhance expansion of CAR T cells by modulate immune metabolism with lactase targeting enzymes; 2) promote CAR-T cell persistence, memory formation and prevent exhaustion by targeting mTOR (mammalian target of rapamycin) pathway; and 3) Optimizing CAR-cell function by temporal integration of metabolic and immunoregulatory modulators. To minimize off-target effects and toxicity, we will leverage our established nonocapsule platform to deliver these pharmacological modulators specifically to CAR-expressing cells. We hypothesize that targeted immune modulation will maximize the in vivo function and persistence of multilineage CAR cells, providing a robust strategy towards a functional HIV cure.