Hematopoietic Stem/Progenitor Cell-Based Chimeric Antigen Receptor Gene Therapy for HIV Infection

Project Summary More than 4 decades into the pandemic, HIV disease remains a considerable public health concern without a practicable cure. Drug-based therapy can control HIV but is costly, has severe side effects, and is not curative. Stem-cell based therapies have provided the only known cures for HIV infection, with three individuals functionally cured to date. However, replicating these successes has been challenging due to the high toxicities of treatment, need for transplant antigen matching, and requiring extensive myeloablation. However, these “cures” strongly suggest that immune system modification involving hematopoietic stem/progenitor cell (HSPC) transplantation can play a strong role allowing HIV clearance from the body. Gene therapeutic modification of autologous HSPCs to allow resistance of engrafted cells to infection along with the production of cells that are capable of targeting and eliminating HIV infected cells represents a more targeted approach to a HIV cure for all. Through systematic development, we have established an approach to direct cells to target HIV infection in vivo using a novel and optimized HIV-specific chimeric antigen receptor (CAR). This optimized HIV-specific CAR contains a truncated version of the HIV-binding region on the CD4 molecule (the D1D2 regions) with the CD3 zeta TCR signaling domain along with a 4-1BB costimulatory molecule signaling domain (termed D1D2CAR41BB). Extensive preclinical studies in humanized mice have determined that the D1D2CAR was superior in comparison to other CAR candidates in allowing the modification of HSPCs, producing lifelong safe engraftment, enabling development into mature CAR-expressing cells, and resulting in antiviral suppression of HIV. With this strong preclinical data suggesting the safety and feasibility of this approach, we seek to work towards investigational new drug (IND) development and clinical implementation of this approach. In this proposal, we plan to 1) Develop a comprehensive product development strategy for IND submission, 2) Formulate a strategic plan for clinical development, and 3) Establish a comprehensive plan for a regulatory strategy. By address these aims, we seek to develop a comprehensive IND-directed product development strategy to facilitate phase I clinical trials with this approach to attempt to functionally cure HIV infection.