In vivo killing of primary HIV-infected cells by peripheral-injected early memory–enriched anti-HIV duoCAR T cells
HIV-specific chimeric antigen receptor–T cell (CAR T cell) therapies are candidates to functionally cure HIV infection in people with HIV (PWH) by eliminating reactivated HIV-infected cells derived from latently infected cells within the HIV reservoir. Paramount to translating such therapeutic candi...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2022-11-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.161698 |
| _version_ | 1827767997355261952 |
|---|---|
| author | Kim Anthony-Gonda Alex Ray Hang Su Yuge Wang Ying Xiong Danica Lee Ariele Block Vanessa Chilunda Jessica Weiselberg Lily Zemelko Yen Y. Wang Sarah Kleinsorge-Block Jane S. Reese Marcos de Lima Christina Ochsenbauer John C. Kappes Dimiter S. Dimitrov Rimas Orentas Steven G. Deeks Rachel L. Rutishauser Joan W. Berman Harris Goldstein Boro Dropulić |
| author_facet | Kim Anthony-Gonda Alex Ray Hang Su Yuge Wang Ying Xiong Danica Lee Ariele Block Vanessa Chilunda Jessica Weiselberg Lily Zemelko Yen Y. Wang Sarah Kleinsorge-Block Jane S. Reese Marcos de Lima Christina Ochsenbauer John C. Kappes Dimiter S. Dimitrov Rimas Orentas Steven G. Deeks Rachel L. Rutishauser Joan W. Berman Harris Goldstein Boro Dropulić |
| author_sort | Kim Anthony-Gonda |
| collection | DOAJ |
| description | HIV-specific chimeric antigen receptor–T cell (CAR T cell) therapies are candidates to functionally cure HIV infection in people with HIV (PWH) by eliminating reactivated HIV-infected cells derived from latently infected cells within the HIV reservoir. Paramount to translating such therapeutic candidates successfully into the clinic will require anti-HIV CAR T cells to localize to lymphoid tissues in the body and eliminate reactivated HIV-infected cells such as CD4+ T cells and monocytes/macrophages. Here we show that i.v. injected anti-HIV duoCAR T cells, generated using a clinical-grade anti-HIV duoCAR lentiviral vector, localized to the site of active HIV infection in the spleen of humanized mice and eliminated HIV-infected PBMCs. CyTOF analysis of preinfusion duoCAR T cells revealed an early memory phenotype composed predominantly of CCR7+ stem cell–like/central memory T cells (TSCM/TCM) with expression of some effector-like molecules. In addition, we show that anti-HIV duoCAR T cells effectively sense and kill HIV-infected CD4+ T cells and monocytes/macrophages. Furthermore, we demonstrate efficient genetic modification of T cells from PWH on suppressive ART into anti-HIV duoCAR T cells that subsequently kill autologous PBMCs superinfected with HIV. These studies support the safety and efficacy of anti-HIV duoCAR T cell therapy in our presently open phase I/IIa clinical trial (NCT04648046). |
| first_indexed | 2024-03-11T12:06:16Z |
| format | Article |
| id | doaj.art-07c21215b58f4bf69b7d186bb38fd62e |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:16Z |
| publishDate | 2022-11-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-07c21215b58f4bf69b7d186bb38fd62e2023-11-07T16:24:47ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-11-01721In vivo killing of primary HIV-infected cells by peripheral-injected early memory–enriched anti-HIV duoCAR T cellsKim Anthony-GondaAlex RayHang SuYuge WangYing XiongDanica LeeAriele BlockVanessa ChilundaJessica WeiselbergLily ZemelkoYen Y. WangSarah Kleinsorge-BlockJane S. ReeseMarcos de LimaChristina OchsenbauerJohn C. KappesDimiter S. DimitrovRimas OrentasSteven G. DeeksRachel L. RutishauserJoan W. BermanHarris GoldsteinBoro DropulićHIV-specific chimeric antigen receptor–T cell (CAR T cell) therapies are candidates to functionally cure HIV infection in people with HIV (PWH) by eliminating reactivated HIV-infected cells derived from latently infected cells within the HIV reservoir. Paramount to translating such therapeutic candidates successfully into the clinic will require anti-HIV CAR T cells to localize to lymphoid tissues in the body and eliminate reactivated HIV-infected cells such as CD4+ T cells and monocytes/macrophages. Here we show that i.v. injected anti-HIV duoCAR T cells, generated using a clinical-grade anti-HIV duoCAR lentiviral vector, localized to the site of active HIV infection in the spleen of humanized mice and eliminated HIV-infected PBMCs. CyTOF analysis of preinfusion duoCAR T cells revealed an early memory phenotype composed predominantly of CCR7+ stem cell–like/central memory T cells (TSCM/TCM) with expression of some effector-like molecules. In addition, we show that anti-HIV duoCAR T cells effectively sense and kill HIV-infected CD4+ T cells and monocytes/macrophages. Furthermore, we demonstrate efficient genetic modification of T cells from PWH on suppressive ART into anti-HIV duoCAR T cells that subsequently kill autologous PBMCs superinfected with HIV. These studies support the safety and efficacy of anti-HIV duoCAR T cell therapy in our presently open phase I/IIa clinical trial (NCT04648046).https://doi.org/10.1172/jci.insight.161698AIDS/HIVTherapeutics |
| spellingShingle | Kim Anthony-Gonda Alex Ray Hang Su Yuge Wang Ying Xiong Danica Lee Ariele Block Vanessa Chilunda Jessica Weiselberg Lily Zemelko Yen Y. Wang Sarah Kleinsorge-Block Jane S. Reese Marcos de Lima Christina Ochsenbauer John C. Kappes Dimiter S. Dimitrov Rimas Orentas Steven G. Deeks Rachel L. Rutishauser Joan W. Berman Harris Goldstein Boro Dropulić In vivo killing of primary HIV-infected cells by peripheral-injected early memory–enriched anti-HIV duoCAR T cells JCI Insight AIDS/HIV Therapeutics |
| title | In vivo killing of primary HIV-infected cells by peripheral-injected early memory–enriched anti-HIV duoCAR T cells |
| title_full | In vivo killing of primary HIV-infected cells by peripheral-injected early memory–enriched anti-HIV duoCAR T cells |
| title_fullStr | In vivo killing of primary HIV-infected cells by peripheral-injected early memory–enriched anti-HIV duoCAR T cells |
| title_full_unstemmed | In vivo killing of primary HIV-infected cells by peripheral-injected early memory–enriched anti-HIV duoCAR T cells |
| title_short | In vivo killing of primary HIV-infected cells by peripheral-injected early memory–enriched anti-HIV duoCAR T cells |
| title_sort | in vivo killing of primary hiv infected cells by peripheral injected early memory enriched anti hiv duocar t cells |
| topic | AIDS/HIV Therapeutics |
| url | https://doi.org/10.1172/jci.insight.161698 |
| work_keys_str_mv | AT kimanthonygonda invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT alexray invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT hangsu invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT yugewang invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT yingxiong invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT danicalee invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT arieleblock invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT vanessachilunda invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT jessicaweiselberg invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT lilyzemelko invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT yenywang invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT sarahkleinsorgeblock invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT janesreese invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT marcosdelima invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT christinaochsenbauer invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT johnckappes invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT dimitersdimitrov invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT rimasorentas invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT stevengdeeks invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT rachellrutishauser invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT joanwberman invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT harrisgoldstein invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells AT borodropulic invivokillingofprimaryhivinfectedcellsbyperipheralinjectedearlymemoryenrichedantihivduocartcells |