Proof of concept studies for in vivo produced… (R41AI184054) – Project Grant to Marpam Pharma LLC

Abstract: Marpam pharma is developing a chimeric antigen receptor (car)-t cell treatment that targets viral reservoirs for durable remission of HIV without the need for antiretroviral therapies (art). This treatment is an HIV-specific car (specifically, CD4-MBL-car) t cell therapy that employs the CXCR5 chemokine receptor as a homing device to direct anti-HIV killer t cells into "hidden" viral reservoirs in b cell follicles of secondary lymphoid tissue, so that they can kill HIV-producing cells where the majority of viral replication occurs. Using the best in vivo nonhuman primate (NHP) model of HIV, we developed car/CXCR5-t cells that show successful homing to b cell follicles, evidence of direct contact with viral RNA+ infected cells, markedly decreased virus in b cell follicles, and decreased viral loads in car/CXCR5-t cell treated art-suppressed simian immunodeficiency virus- infected nhps compared to controls. Our human car/CXCR5-t cells also show CXCR5-driven migratory and anti-HIV killing characteristics in vitro, showing promise as a treatment for people living with HIV. FDA-approved car-t cell therapies are successful in treating various cancers; however, the processes to produce the car- t cells are complex, involving leukapheresis and EX-vivo manipulation of peripheral blood mononuclear cells prior to reinfusion back to the patient. Thus, recent efforts are focused on developing universal, off-the-shelf in vivo-produced car-t cell therapies, including the use of adeno-associated virus (AAV) gene delivery systems. Since the process to produce an off-the-shelf AAV gene therapy is a fraction of the complexity of EX-vivo production of car-t cells individualized for each patient, the expectation is that AAV gene therapy to produce car/CXCR5-t cells will eventually prove to be less costly than current life-long therapy for HIV, which is estimated at over $500,000. To develop an off-the-shelf in vivo car/CXCR5-t cell product, this proposal seeks to perform the necessary first steps of producing receptor-targeted, AAV-directed car-t cells (second generation [2G] -car/CXCR5-t cells) in vitro and assessing their targeted efficacy against HIV. Using our intellectual property-protected technology to assemble AAV composites for receptor-targeted gene delivery, we propose in vitro proof-of-concept studies to produce receptor-targeted, AAV-directed 2G-car/CXCR5-t cells using AAV composites containing anti-CD5 monoclonal antibody (CD5MAB) and carrying a 2G-car/CXCR5 DNA payload. As t cells specifically express CD5 on their cell surface, AAV-CD5MAB composites carrying 2G- car/CXCR5 DNA payload (AAV-CD5MAB-2G-car/CXCR5) are expected to specifically bind CD5 on t cells and transduce them, thereby producing functional 2G-car/CXCR5-t cells that home to b cell follicles in vivo. Successful completion of the proposed studies will lay the groundwork not only for phase II IND-enabling studies for in vivo HIV 2G-car/CXCR5-t cells, but also for other therapeutic areas that could benefit from off-the-shelf in vivo production of car-t cells.

Action	Obligated	Date
Amendment	$0	Jul 7, 2025
Original award	$302,248	Mar 14, 2024

Proof of concept studies for in vivo produced car-t cells that target b cell follicles as a treatment for HIV

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