Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future
γδ T-cells directly recognize and kill transformed cells independently of HLA-antigen presentation, which makes them a highly promising effector cell compartment for cancer immunotherapy. Novel γδ T-cell-based immunotherapies, primarily focusing on the two major γδ T-cell subtypes that infiltrate tu...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.915837/full |
| _version_ | 1818552447025545216 |
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| author | José Saura-Esteller Milon de Jong Lisa A. King Erik Ensing Benjamin Winograd Tanja D. de Gruijl Paul W. H. I. Parren Paul W. H. I. Parren Hans J. van der Vliet Hans J. van der Vliet |
| author_facet | José Saura-Esteller Milon de Jong Lisa A. King Erik Ensing Benjamin Winograd Tanja D. de Gruijl Paul W. H. I. Parren Paul W. H. I. Parren Hans J. van der Vliet Hans J. van der Vliet |
| author_sort | José Saura-Esteller |
| collection | DOAJ |
| description | γδ T-cells directly recognize and kill transformed cells independently of HLA-antigen presentation, which makes them a highly promising effector cell compartment for cancer immunotherapy. Novel γδ T-cell-based immunotherapies, primarily focusing on the two major γδ T-cell subtypes that infiltrate tumors (i.e. Vδ1 and Vδ2), are being developed. The Vδ1 T-cell subset is enriched in tissues and contains both effector T-cells as well as regulatory T-cells with tumor-promoting potential. Vδ2 T-cells, in contrast, are enriched in circulation and consist of a large, relatively homogeneous, pro-inflammatory effector T-cell subset. Healthy individuals typically harbor in the order of 50-500 million Vγ9Vδ2 T-cells in the peripheral blood alone (1-10% of the total CD3+ T-cell population), which can rapidly expand upon stimulation. The Vγ9Vδ2 T-cell receptor senses intracellular phosphorylated metabolites, which accumulate in cancer cells as a result of mevalonate pathway dysregulation or upon pharmaceutical intervention. Early clinical studies investigating the therapeutic potential of Vγ9Vδ2 T-cells were based on either ex vivo expansion and adoptive transfer or their systemic activation with aminobisphosphonates or synthetic phosphoantigens, either alone or combined with low dose IL-2. Immune-related adverse events (irAE) were generally \mild, but the clinical efficacy of these approaches provided overall limited benefit. In recent years, critical advances have renewed the excitement for the potential of Vγ9Vδ2 T-cells in cancer immunotherapy. Here, we review γδ T-cell-based therapeutic strategies and discuss the prospects of those currently evaluated in clinical studies in cancer patients as well as future therapies that might arise from current promising pre-clinical results. |
| first_indexed | 2024-12-12T09:13:19Z |
| format | Article |
| id | doaj.art-57a7fb13f9c9431cbab1118c84862f44 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T09:13:19Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-57a7fb13f9c9431cbab1118c84862f442022-12-22T00:29:27ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-06-011310.3389/fimmu.2022.915837915837Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-FutureJosé Saura-Esteller0Milon de Jong1Lisa A. King2Erik Ensing3Benjamin Winograd4Tanja D. de Gruijl5Paul W. H. I. Parren6Paul W. H. I. Parren7Hans J. van der Vliet8Hans J. van der Vliet9Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, NetherlandsDepartment of Medical Oncology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, NetherlandsDepartment of Medical Oncology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, NetherlandsLAVA Therapeutics, Utrecht, NetherlandsLAVA Therapeutics, Philadelphia, PA, United StatesDepartment of Medical Oncology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, NetherlandsLAVA Therapeutics, Utrecht, NetherlandsDepartment of Immunology, Leiden University Medical Center, Leiden, NetherlandsDepartment of Medical Oncology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, NetherlandsLAVA Therapeutics, Utrecht, Netherlandsγδ T-cells directly recognize and kill transformed cells independently of HLA-antigen presentation, which makes them a highly promising effector cell compartment for cancer immunotherapy. Novel γδ T-cell-based immunotherapies, primarily focusing on the two major γδ T-cell subtypes that infiltrate tumors (i.e. Vδ1 and Vδ2), are being developed. The Vδ1 T-cell subset is enriched in tissues and contains both effector T-cells as well as regulatory T-cells with tumor-promoting potential. Vδ2 T-cells, in contrast, are enriched in circulation and consist of a large, relatively homogeneous, pro-inflammatory effector T-cell subset. Healthy individuals typically harbor in the order of 50-500 million Vγ9Vδ2 T-cells in the peripheral blood alone (1-10% of the total CD3+ T-cell population), which can rapidly expand upon stimulation. The Vγ9Vδ2 T-cell receptor senses intracellular phosphorylated metabolites, which accumulate in cancer cells as a result of mevalonate pathway dysregulation or upon pharmaceutical intervention. Early clinical studies investigating the therapeutic potential of Vγ9Vδ2 T-cells were based on either ex vivo expansion and adoptive transfer or their systemic activation with aminobisphosphonates or synthetic phosphoantigens, either alone or combined with low dose IL-2. Immune-related adverse events (irAE) were generally \mild, but the clinical efficacy of these approaches provided overall limited benefit. In recent years, critical advances have renewed the excitement for the potential of Vγ9Vδ2 T-cells in cancer immunotherapy. Here, we review γδ T-cell-based therapeutic strategies and discuss the prospects of those currently evaluated in clinical studies in cancer patients as well as future therapies that might arise from current promising pre-clinical results.https://www.frontiersin.org/articles/10.3389/fimmu.2022.915837/fullgamma delta T-cellcancerimmunotherapyphosphoantigensaminobisphosphonatesadoptive cell transfer |
| spellingShingle | José Saura-Esteller Milon de Jong Lisa A. King Erik Ensing Benjamin Winograd Tanja D. de Gruijl Paul W. H. I. Parren Paul W. H. I. Parren Hans J. van der Vliet Hans J. van der Vliet Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future Frontiers in Immunology gamma delta T-cell cancer immunotherapy phosphoantigens aminobisphosphonates adoptive cell transfer |
| title | Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future |
| title_full | Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future |
| title_fullStr | Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future |
| title_full_unstemmed | Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future |
| title_short | Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future |
| title_sort | gamma delta t cell based cancer immunotherapy past present future |
| topic | gamma delta T-cell cancer immunotherapy phosphoantigens aminobisphosphonates adoptive cell transfer |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.915837/full |
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