Project Details
Description
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.
Status | Finished |
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Effective start/end date | 12/7/22 → 11/30/23 |
Funding
- National Institute of Allergy and Infectious Diseases: $306,500.00
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