title: Clinical applications of gamma delta T cells with multivalent immunity.
abstract: γδ 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 Vγ9Vδ2 subset of γδ T cells and have been used in clinical trials of cancer where objective responses were detected. The Vγ9Vδ2 T cell receptor (TCR) heterodimer binds multiple ligands and results in a multivalent attack by a monoclonal T cell population. Alternatively, populations of γδ 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-Vγ9Vδ2 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 major histocompatibility complex Class-I chain-related A was a stimulus for γδ T cells expressing TCRδ1 isotypes, and plate-bound activating antibodies have expanded Vδ1 and Vδ2 cells ex vivo. Clinically sufficient quantities of TCRδ1, TCRδ2, and TCRδ1(neg)TCRδ2(neg) 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 αβ TCRs, chimeric antigen receptors, and drug-resistance genes. This represents a promising future for the clinical application of oligoclonal or polyclonal γδ T cells in autologous and allogeneic settings that builds on current trials testing the safety and efficacy of Vγ9Vδ2 T cells.
authors.affiliation: Surgery Branch, National Cancer Institute , Bethesda, MD , USA.
authors.forename: Drew C
authors.initials: DC
authors.lastname: Deniger
authors.affiliation: Division of Pediatrics, University of Texas MD Anderson Cancer Center , Houston, TX , USA.
authors.forename: Judy S
authors.initials: JS
authors.lastname: Moyes
authors.affiliation: Division of Pediatrics, University of Texas MD Anderson Cancer Center , Houston, TX , USA ; The University of Texas Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center , Houston, TX , USA.
authors.forename: Laurence J N
authors.initials: LJ
authors.lastname: Cooper
keywords: T-cell receptor; adoptive T-cell therapy; allogeneic transplantation; artificial APC; cancer; chimeric antigen receptors; immunotherapy; γδ T cells