Next generations of CAR-T cells - new therapeutic opportunities in hematology?
In recent years, the introduction of chimeric antigen receptor (CAR) T-cell therapies into clinics has been a breakthrough in treating relapsed or refractory malignancies in hematology and oncology. To date, Food and Drug Administration (FDA) has approved six CAR-T therapies for specific non-Hodgkin...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1034707/full |
| _version_ | 1811257640937848832 |
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| author | Jaromir Tomasik Marcin Jasiński Marcin Jasiński Grzegorz W. Basak |
| author_facet | Jaromir Tomasik Marcin Jasiński Marcin Jasiński Grzegorz W. Basak |
| author_sort | Jaromir Tomasik |
| collection | DOAJ |
| description | In recent years, the introduction of chimeric antigen receptor (CAR) T-cell therapies into clinics has been a breakthrough in treating relapsed or refractory malignancies in hematology and oncology. To date, Food and Drug Administration (FDA) has approved six CAR-T therapies for specific non-Hodgkin lymphomas, B-cell acute lymphoblastic leukemia, and multiple myeloma. All registered treatments and most clinical trials are based on so-called 2nd generation CARs, which consist of an extracellular antigen-binding region, one costimulatory domain, and a CD3z signaling domain. Unfortunately, despite remarkable overall treatment outcomes, a relatively high percentage of patients do not benefit from CAR-T therapy (overall response rate varies between 50 and 100%, with following relapse rates as high as 66% due to limited durability of the response). Moreover, it is associated with adverse effects such as cytokine release syndrome and neurotoxicity. Advances in immunology and molecular engineering have facilitated the construction of the next generation of CAR-T cells equipped with various molecular mechanisms. These include additional costimulatory domains (3rd generation), safety switches, immune-checkpoint modulation, cytokine expression, or knockout of therapy-interfering molecules, to name just a few. Implementation of next-generation CAR T-cells may allow overcoming current limitations of CAR-T therapies, decreasing unwanted side effects, and targeting other hematological malignancies. Accordingly, some clinical trials are currently evaluating the safety and efficacy of novel CAR-T therapies. This review describes the CAR-T cell constructs concerning the clinical application, summarizes completed and ongoing clinical trials of next-generation CAR-T therapies, and presents future perspectives. |
| first_indexed | 2024-04-12T18:00:36Z |
| format | Article |
| id | doaj.art-9f2124f6399445e9b37395f12060e5cc |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T18:00:36Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-9f2124f6399445e9b37395f12060e5cc2022-12-22T03:22:11ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-10-011310.3389/fimmu.2022.10347071034707Next generations of CAR-T cells - new therapeutic opportunities in hematology?Jaromir Tomasik0Marcin Jasiński1Marcin Jasiński2Grzegorz W. Basak3Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, PolandDepartment of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, PolandDoctoral School, Medical University of Warsaw, Warsaw, PolandDepartment of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, PolandIn recent years, the introduction of chimeric antigen receptor (CAR) T-cell therapies into clinics has been a breakthrough in treating relapsed or refractory malignancies in hematology and oncology. To date, Food and Drug Administration (FDA) has approved six CAR-T therapies for specific non-Hodgkin lymphomas, B-cell acute lymphoblastic leukemia, and multiple myeloma. All registered treatments and most clinical trials are based on so-called 2nd generation CARs, which consist of an extracellular antigen-binding region, one costimulatory domain, and a CD3z signaling domain. Unfortunately, despite remarkable overall treatment outcomes, a relatively high percentage of patients do not benefit from CAR-T therapy (overall response rate varies between 50 and 100%, with following relapse rates as high as 66% due to limited durability of the response). Moreover, it is associated with adverse effects such as cytokine release syndrome and neurotoxicity. Advances in immunology and molecular engineering have facilitated the construction of the next generation of CAR-T cells equipped with various molecular mechanisms. These include additional costimulatory domains (3rd generation), safety switches, immune-checkpoint modulation, cytokine expression, or knockout of therapy-interfering molecules, to name just a few. Implementation of next-generation CAR T-cells may allow overcoming current limitations of CAR-T therapies, decreasing unwanted side effects, and targeting other hematological malignancies. Accordingly, some clinical trials are currently evaluating the safety and efficacy of novel CAR-T therapies. This review describes the CAR-T cell constructs concerning the clinical application, summarizes completed and ongoing clinical trials of next-generation CAR-T therapies, and presents future perspectives.https://www.frontiersin.org/articles/10.3389/fimmu.2022.1034707/fullCAR-T cellsacute lymphoblastic leukemiaimmunotherapylymphocytecytokine release syndromeCRS |
| spellingShingle | Jaromir Tomasik Marcin Jasiński Marcin Jasiński Grzegorz W. Basak Next generations of CAR-T cells - new therapeutic opportunities in hematology? Frontiers in Immunology CAR-T cells acute lymphoblastic leukemia immunotherapy lymphocyte cytokine release syndrome CRS |
| title | Next generations of CAR-T cells - new therapeutic opportunities in hematology? |
| title_full | Next generations of CAR-T cells - new therapeutic opportunities in hematology? |
| title_fullStr | Next generations of CAR-T cells - new therapeutic opportunities in hematology? |
| title_full_unstemmed | Next generations of CAR-T cells - new therapeutic opportunities in hematology? |
| title_short | Next generations of CAR-T cells - new therapeutic opportunities in hematology? |
| title_sort | next generations of car t cells new therapeutic opportunities in hematology |
| topic | CAR-T cells acute lymphoblastic leukemia immunotherapy lymphocyte cytokine release syndrome CRS |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1034707/full |
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