Development of a treatment for the durable remission of HIV using autologous human CAR T cells that target B cell follicles

ABSTRACT MarPam Pharma is developing a one-time treatment for durable remission of human immunodeficiency virus (HIV) for patients treated with antiretroviral therapy (ART). This treatment is an autologous HIV-specific chimeric antigen receptor (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 located in lymphoid follicles1,2. B cell follicles are an immune protected site where the majority of viral replication can occur relatively unabated in CD4+ T cells3-7, likely due to a markedly lower presence of virus-specific CD8 T cells inside compared to outside of B cell follicles in lymphoid tissue8-11. In fact, few virus-specific CD8 T cells express the follicular homing molecule CXCR510, possibly explaining the 40-fold lower in vivo effector CTL to target vRNA+ cell levels inside compared to outside of B cell follicles10. These findings suggest that the inability of HIV-specific CD8 T cells to fully suppress virus replication may be due to a deficiency of virus-specific CD8 T cells in B cell follicles. Importantly, pilot studies of this CAR-T cell treatment showed safety in animals and also successful homing of CAR-T cells to B cell follicles, evidence of direct contact of the CAR-T cells with viral RNA+ infected cells, and decreased viral loads in ART-suppressed rhesus macaques infected with simian immunodeficiency virus (SIV), a model of HIV. Here, we propose to conduct an IND-enabling preclinical study to assess the safety and efficacy of autologous CAR-T cells transduced with the human CAR construct in a study statistically powered to demonstrate efficacy in a rhesus macaque simian-human immunodeficiency virus (SHIV) model of HIV. In our recent STTR Phase 1 studies, we successfully produced human CAR-T cells using a small-scale research method. Here, we propose to develop a scalable method for GMP production of gammaretrovirus and CAR/CXR5-T cells. These proposed studies will move our product from the current preclinical stage of development into clinical development.