Development of a treatment for durable remission of HIV using transposon engineered CAR-T and NK cells

项目总结

Project Summary MarPam Pharma aims to develop a one-time treatment for achieving durable remission of human immunodeficiency virus (HIV), after which patients will no longer need to take antiretroviral therapy. Our treatment is an autologous HIV-specific chimeric antigen receptor (CAR) immune cell therapy that employs the CXCR5 chemokine receptor as a homing device to direct either anti-HIV T cells or anti-HIV natural killer (NK) cells into immune-protected “hidden” viral reservoirs in lymphoid B cell follicles, where most virus-producing cells are located during chronic infection. Virus-specific CD8 T cells exert potent antiviral activity against HIV-1 and Simian immunodeficiency virus (SIV), an animal model of HIV. Nevertheless, despite abundant CD8 T cell responses in HIV-1-infected humans and SIV-infected macaques, these cells do not fully suppress virus replication, likely because the majority of HIV-1 and SIV replication occurs in CD4+ T cells concentrated within B cell follicles in secondary lymphoid tissues, where surprisingly few virus-specific CD8 T cells reside in infected individuals. In fact, we found 40-fold lower levels of in vivo effector CTL to target viral (v)RNA+ cells (E:T) inside compared to outside of B cell follicles, likely explained by the fact that very few virus-specific CD8 T cells express the follicular homing molecule CXCR5. 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. As the vast majority of virus-producing cells are CD4 T cells located in secondary lymphoid tissue and concentrated in follicles during chronic HIV and SIV infections, we targeted these infected cells by infusing autologous antiviral CAR/CXCR5-T cells in chronically SIV-infected rhesus macaques. The treated animals showed successful homing of CAR/CXCR5-T cells to B cell follicles, evidence of direct contact of the CAR/CXCR5-T cells with vRNA+ infected cells and decreased viral loads in treated animals compared to untreated animals. Our pilot study showed that the treatment was safe and effective. These findings have prompted us to further refine our promising targeted CAR/CXCR5-T cell therapy by enhancing its efficacy and to investigate whether this targeted immune cell therapy could be developed using NK cells. CAR-T and CAR-NK cell therapies are individualized therapies that modify a patient’s own immune cells to fight disease; NK cell therapies also have the potential to function as off-the-shelf treatments using allogenic cells. This proposal seeks to optimize the effectiveness of our CAR/CXCR5 immune cell therapy. In addition, we aim to generate and evaluate optimized Car/CXCR5-T and -NK cells using less expensive production methods. Successful completion of the proposed studies will lead to Phase II IND-enabling primate studies to assess the safety and efficacy of the T cell and NK cell therapies for durable HIV remission.