Robust CAR-T memory formation and function via hematopoietic stem cell delivery.
Due to the durability and persistence of reservoirs of HIV-1-infected cells, combination antiretroviral therapy (ART) is insufficient in eradicating infection. Achieving HIV-1 cure or sustained remission without ART treatment will require the enhanced and persistent effective antiviral immune respon...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Jezik: | English |
| Izdano: |
Public Library of Science (PLoS)
2021-04-01
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| Serija: | PLoS Pathogens |
| Online dostop: | https://doi.org/10.1371/journal.ppat.1009404 |
| _version_ | 1830176360004321280 |
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| author | Anjie Zhen Mayra A Carrillo Wenli Mu Valerie Rezek Heather Martin Philip Hamid Irvin S Y Chen Otto O Yang Jerome A Zack Scott G Kitchen |
| author_facet | Anjie Zhen Mayra A Carrillo Wenli Mu Valerie Rezek Heather Martin Philip Hamid Irvin S Y Chen Otto O Yang Jerome A Zack Scott G Kitchen |
| author_sort | Anjie Zhen |
| collection | DOAJ |
| description | Due to the durability and persistence of reservoirs of HIV-1-infected cells, combination antiretroviral therapy (ART) is insufficient in eradicating infection. Achieving HIV-1 cure or sustained remission without ART treatment will require the enhanced and persistent effective antiviral immune responses. Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy and show promise in treating HIV-1 infection. Persistence, trafficking, and maintenance of function remain to be a challenge in many of these approaches, which are based on peripheral T cell modification. To overcome many of these issues, we have previously demonstrated successful long-term engraftment and production of anti-HIV CAR T cells in modified hematopoietic stem cells (HSCs) in vivo. Here we report the development and in vivo testing of second generation CD4-based CARs (CD4CAR) against HIV-1 infection using a HSCs-based approach. We found that a modified, truncated CD4-based CAR (D1D2CAR) allows better CAR-T cell differentiation from gene modified HSCs, and maintains similar CTL activity as compared to the full length CD4-based CAR. In addition, D1D2CAR does not mediate HIV infection or stimulation mediated by IL-16, suggesting lower risk of off-target effects. Interestingly, stimulatory domains of 4-1BB but not CD28 allowed successful hematopoietic differentiation and improved anti-viral function of CAR T cells from CAR modified HSCs. Addition of 4-1BB to CD4 based CARs led to faster suppression of viremia during early untreated HIV-1 infection. D1D2CAR 4-1BB mice had faster viral suppression in combination with ART and better persistence of CAR T cells during ART. In summary, our data indicate that the D1D2CAR-41BB is a superior CAR, showing better HSC differentiation, viral suppression and persistence, and less deleterious functions compared to the original CD4CAR, and should continue to be pursued as a candidate for clinical study. |
| first_indexed | 2024-12-17T19:05:32Z |
| format | Article |
| id | doaj.art-faeeeee9e47a4f8c816035cdbb51a600 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-17T19:05:32Z |
| publishDate | 2021-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-faeeeee9e47a4f8c816035cdbb51a6002022-12-21T21:36:00ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742021-04-01174e100940410.1371/journal.ppat.1009404Robust CAR-T memory formation and function via hematopoietic stem cell delivery.Anjie ZhenMayra A CarrilloWenli MuValerie RezekHeather MartinPhilip HamidIrvin S Y ChenOtto O YangJerome A ZackScott G KitchenDue to the durability and persistence of reservoirs of HIV-1-infected cells, combination antiretroviral therapy (ART) is insufficient in eradicating infection. Achieving HIV-1 cure or sustained remission without ART treatment will require the enhanced and persistent effective antiviral immune responses. Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy and show promise in treating HIV-1 infection. Persistence, trafficking, and maintenance of function remain to be a challenge in many of these approaches, which are based on peripheral T cell modification. To overcome many of these issues, we have previously demonstrated successful long-term engraftment and production of anti-HIV CAR T cells in modified hematopoietic stem cells (HSCs) in vivo. Here we report the development and in vivo testing of second generation CD4-based CARs (CD4CAR) against HIV-1 infection using a HSCs-based approach. We found that a modified, truncated CD4-based CAR (D1D2CAR) allows better CAR-T cell differentiation from gene modified HSCs, and maintains similar CTL activity as compared to the full length CD4-based CAR. In addition, D1D2CAR does not mediate HIV infection or stimulation mediated by IL-16, suggesting lower risk of off-target effects. Interestingly, stimulatory domains of 4-1BB but not CD28 allowed successful hematopoietic differentiation and improved anti-viral function of CAR T cells from CAR modified HSCs. Addition of 4-1BB to CD4 based CARs led to faster suppression of viremia during early untreated HIV-1 infection. D1D2CAR 4-1BB mice had faster viral suppression in combination with ART and better persistence of CAR T cells during ART. In summary, our data indicate that the D1D2CAR-41BB is a superior CAR, showing better HSC differentiation, viral suppression and persistence, and less deleterious functions compared to the original CD4CAR, and should continue to be pursued as a candidate for clinical study.https://doi.org/10.1371/journal.ppat.1009404 |
| spellingShingle | Anjie Zhen Mayra A Carrillo Wenli Mu Valerie Rezek Heather Martin Philip Hamid Irvin S Y Chen Otto O Yang Jerome A Zack Scott G Kitchen Robust CAR-T memory formation and function via hematopoietic stem cell delivery. PLoS Pathogens |
| title | Robust CAR-T memory formation and function via hematopoietic stem cell delivery. |
| title_full | Robust CAR-T memory formation and function via hematopoietic stem cell delivery. |
| title_fullStr | Robust CAR-T memory formation and function via hematopoietic stem cell delivery. |
| title_full_unstemmed | Robust CAR-T memory formation and function via hematopoietic stem cell delivery. |
| title_short | Robust CAR-T memory formation and function via hematopoietic stem cell delivery. |
| title_sort | robust car t memory formation and function via hematopoietic stem cell delivery |
| url | https://doi.org/10.1371/journal.ppat.1009404 |
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