Clinical applications of gamma delta T cells with multivalent immunity
Gamma delta T cells hold promise for adoptive immunotherapy because of their reactivity to bacteria, viruses, and tumors. However, these cells represent a small fraction (1-5%) of the peripheral T-cell pool and require activation and propagation to achieve clinical benefit. Aminobisphosphonates spec...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2014-12-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fimmu.2014.00636/full |
| _version_ | 1811302816155697152 |
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| author | Drew C Deniger Judy S Moyes Laurence JN Cooper |
| author_facet | Drew C Deniger Judy S Moyes Laurence JN Cooper |
| author_sort | Drew C Deniger |
| collection | DOAJ |
| description | Gamma delta T cells hold promise for adoptive immunotherapy because of their reactivity to bacteria, viruses, and tumors. However, these cells represent a small fraction (1-5%) of the peripheral T-cell pool and require activation and propagation to achieve clinical benefit. Aminobisphosphonates specifically expand the Vgamma9Vdelta2 subset of gamma delta T cells and have been used in clinical trials of cancer where objective responses were detected. The Vgamma9Vdelta2 TCR heterodimer binds multiple ligands and results in a multivalent attack by a monoclonal T cell population. Alternatively, populations of gamma delta T cells with oligoclonal or polyclonal TCR repertoire could be infused for broad-range specificity. However, this goal has been restricted by a lack of applicable expansion protocols for non-Vgamma9Vdelta2 cells. Recent advances using immobilized antigens, agonistic monoclonal antibodies (mAbs), tumor-derived artificial antigen presenting cells (aAPC), or combinations of activating mAbs and aAPC have been successful in expanding gamma delta T cells with oligoclonal or polyclonal TCR repertoires. Immobilized MHC Class-I chain-related A was a stimulus for gamma delta T cells expressing TCRdelta1 isotypes, and plate-bound activating antibodies have expanded Vdelta1 and Vdelta2 cells ex vivo. Clinically-sufficient quantities of TCRdelta1, TCRdelta2, and TCRdelta1negTCRdelta2neg have been produced following co-culture on aAPC, and these subsets displayed differences in memory phenotype and reactivity to tumors in vitro and in vivo. Gamma delta T cells are also amenable to genetic modification as evidenced by introduction of alpha beta TCRs, chimeric antigen receptors (CARs), and drug-resistance genes. This represents a promising future for the clinical application of oligoclonal or polyclonal gamma delta T cells in autologous and allogeneic settings that builds on current trials testing the safety and efficacy of Vgamma9Vdelta2 T cells. |
| first_indexed | 2024-04-13T07:36:02Z |
| format | Article |
| id | doaj.art-b189a17eb0cf4561b471412e69719960 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-13T07:36:02Z |
| publishDate | 2014-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-b189a17eb0cf4561b471412e697199602022-12-22T02:56:09ZengFrontiers Media S.A.Frontiers in Immunology1664-32242014-12-01510.3389/fimmu.2014.00636120793Clinical applications of gamma delta T cells with multivalent immunityDrew C Deniger0Judy S Moyes1Laurence JN Cooper2National Institutes of HealthUniversity of Texas MD Anderson Cancer CenterUniversity of Texas MD Anderson Cancer CenterGamma delta T cells hold promise for adoptive immunotherapy because of their reactivity to bacteria, viruses, and tumors. However, these cells represent a small fraction (1-5%) of the peripheral T-cell pool and require activation and propagation to achieve clinical benefit. Aminobisphosphonates specifically expand the Vgamma9Vdelta2 subset of gamma delta T cells and have been used in clinical trials of cancer where objective responses were detected. The Vgamma9Vdelta2 TCR heterodimer binds multiple ligands and results in a multivalent attack by a monoclonal T cell population. Alternatively, populations of gamma delta T cells with oligoclonal or polyclonal TCR repertoire could be infused for broad-range specificity. However, this goal has been restricted by a lack of applicable expansion protocols for non-Vgamma9Vdelta2 cells. Recent advances using immobilized antigens, agonistic monoclonal antibodies (mAbs), tumor-derived artificial antigen presenting cells (aAPC), or combinations of activating mAbs and aAPC have been successful in expanding gamma delta T cells with oligoclonal or polyclonal TCR repertoires. Immobilized MHC Class-I chain-related A was a stimulus for gamma delta T cells expressing TCRdelta1 isotypes, and plate-bound activating antibodies have expanded Vdelta1 and Vdelta2 cells ex vivo. Clinically-sufficient quantities of TCRdelta1, TCRdelta2, and TCRdelta1negTCRdelta2neg have been produced following co-culture on aAPC, and these subsets displayed differences in memory phenotype and reactivity to tumors in vitro and in vivo. Gamma delta T cells are also amenable to genetic modification as evidenced by introduction of alpha beta TCRs, chimeric antigen receptors (CARs), and drug-resistance genes. This represents a promising future for the clinical application of oligoclonal or polyclonal gamma delta T cells in autologous and allogeneic settings that builds on current trials testing the safety and efficacy of Vgamma9Vdelta2 T cells.http://journal.frontiersin.org/Journal/10.3389/fimmu.2014.00636/fullImmunotherapyCancerchimeric antigen receptorsT-cell receptorAllogeneic transplantationAdoptive T-Cell Therapy |
| spellingShingle | Drew C Deniger Judy S Moyes Laurence JN Cooper Clinical applications of gamma delta T cells with multivalent immunity Frontiers in Immunology Immunotherapy Cancer chimeric antigen receptors T-cell receptor Allogeneic transplantation Adoptive T-Cell Therapy |
| title | Clinical applications of gamma delta T cells with multivalent immunity |
| title_full | Clinical applications of gamma delta T cells with multivalent immunity |
| title_fullStr | Clinical applications of gamma delta T cells with multivalent immunity |
| title_full_unstemmed | Clinical applications of gamma delta T cells with multivalent immunity |
| title_short | Clinical applications of gamma delta T cells with multivalent immunity |
| title_sort | clinical applications of gamma delta t cells with multivalent immunity |
| topic | Immunotherapy Cancer chimeric antigen receptors T-cell receptor Allogeneic transplantation Adoptive T-Cell Therapy |
| url | http://journal.frontiersin.org/Journal/10.3389/fimmu.2014.00636/full |
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