A novel car-t cell therapy for the one-time treatment of chronic HIV infection in patients who are not art suppressed
Ended Project Grant Awarded Last action
- Award ID
- R42AI167175
- Recipient
-
Marpam Pharma LLC UEI FJN8ZEF912K7
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $4,745,397
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date
- Originally
- Place of performance
- Minnesota, USA
Award details come from USAspending.gov.
Description
- Abstract
- We aim to develop a one-time treatment for durable remission of human immunodeficiency virus (HIV) for patients who are not suppressed by antiretroviral therapy (art), including patients who are art naïve or art non-compliant. Our treatment is an autologous HIV-specific chimeric antigen receptor (car)-t cell therapy that employs the CXCR5 chemokine receptor as a homing device to direct anti-HIV killer t cells into immune- protected "hidden" viral reservoirs in lymphoid b cell follicles, where most virus-producing cells are located during chronic infections. 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 few virus-specific CD8 t cells reside. In fact, we showed that the ratio of in vivo effector virus-specific CD8 t cells to target SIV RNA+ cells is >40-fold lower inside compared to outside of b cell follicles in lymphoid tissues in SIV-infected macaques. Furthermore, the majority of virus-specific CD8 t cells fail to express the follicular homing molecule CXCR5, likely explaining low levels of virus-spcific CD8 t cells localizing to and surveilling b cell follicles. These data suggest that the inability of HIV- and SIV-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 during chronic HIV and SIV infections, we targeted lymphoid cells by autologously infusing anti-viral car (specifically car/CXCR5) t cells into chronically SIV-infected rhesus macaques. The treated animals showed car/CXCR5- t cell localization to b cell follicles and decreased virus replication in the follicles compared to control animals. In addition, this product showed safety and efficacy in a pilot preclinical study of art-suppressed SIV-infected macaques. Based on these findings and the success of our preclinical studies in art-suppressed macaques, we propose to: (phase 1, aim 1) modify our current car/CXCR5 construct by producing and characterizing an optimized (OPT) car/CXCR5 construct that contains a TRI-specific HIV binding domain, an alternate CO-stimulatory domain, and an HIV resistance domain; (phase 2, aim 2) develop a GMP-scalable method to produce car-t cells using the optcar/CXCR5 construct and pbmcs from a) SIV-infected non-art-treated rhesus macaques for use in an IND-enabling preclinical study; and b) HIV-infected non-art treated individuals to prepare for the first-in-human phase 1 clinical trial; and (phase 2, aim 3) assess the safety and efficacy of car-t cells produced with the human optcar/CXCR5 construct in a simian/human HIV (shiv) model of chronic HIV infection. Successful completion of the proposed studies will be IND-enabling, moving the optcar/CXCR5-t cell product from the preclinical stage into clinical development.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $979,050 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $1,000,449 | |
| Amendment | $1,000,449 | |
| Amendment | $1,000,449 | |
| Amendment | $55,000 | |
| Amendment | $55,000 | |
| Amendment | $55,000 | |
| Amendment | $300,000 | |
| Original award | $300,000 |
Show all 12
Quick answers
Who received award R42AI167175?
R42AI167175 was awarded to Marpam Pharma LLC by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on July 5, 2022.
How much is award R42AI167175 worth?
$4,745,397 has been obligated on R42AI167175.
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