Improving the Efficiency of Vγ9Vδ2 T-Cell Immunotherapy in Cancer

Abstract

Increasing immunological knowledge and advances in techniques lay the ground for more efficient and broader application of immunotherapies. gamma delta (γδ) T-cells possess multiple favorable anti-tumor characteristics, making them promising candidates to be used in cellular and combination therapies of cancer. They recognize malignant cells, infiltrate tumors, and depict strong cytotoxic and pro-inflammatory activity. Here, we focus on human Vγ9Vδ2 T-cells, the most abundant γδ T-cell subpopulation in the blood, which are able to inhibit cancer progression in various models in vitro and in vivo. For therapeutic use they can be cultured and manipulated ex vivo and in the following adoptively transferred to patients, as well as directly stimulated to propagate in vivo. In clinical studies, Vγ9Vδ2 T-cells repeatedly demonstrated a low toxicity profile but hitherto only the modest therapeutic efficacy. This review provides a comprehensive summary of established and newer strategies for the enhancement of Vγ9Vδ2 T-cell anti-tumor functions. We discuss data of studies exploring methods for the sensitization of malignant cells, the improvement of recognition mechanisms and cytotoxic activity of Vγ9Vδ2 T-cells. Main aspects are the tumor cell metabolism, antibody-dependent cell-mediated cytotoxicity, antibody constructs, as well as activating and inhibitory receptors like NKG2D and immune checkpoint molecules. Several concepts show promising results in vitro, now awaiting translation to in vivo models and clinical studies. Given the array of research and encouraging findings in this area, this review aims at optimizing future investigations, specifically targeting the unanswered questions.

γδ T cells in cancer: a small population of lymphocytes with big implications

“…This is consistent with previous reports, showing that expanded Vd1 + T cells possess broad cytotoxic potential in solid tumors, including colon cancer. 119 Ex vivo expansion of cd T cells using zoledronate and IL-2 has also been trialled in a number of studies, improving disease progression but failing to achieve improved overall survival in a number of solid tumor types (renal cell carcinoma, lung cancer, hepatocellular carcinoma). Their ability to recognise a broad range of tumor signals through NK receptors and their TCR allows them to avoid some of the most potent immune evasion mechanisms available to tumors.…”

“…114 This provides a unique advantage for cd T cells over conventional ab T cells. 119,120 These early trials should be interpreted with caution as they were designed for assessing safety of cd T-cell products and not their efficacy. However, Vd1 + T cells have been poorly characterised in solid tumors.…”

“…While this proved a safe treatment, the efficacy was disappointing and failed to prevent progression in most patients. 119 Ex vivo expansion of cd T cells using zoledronate and IL-2 has also been trialled in a number of studies, improving disease progression but failing to achieve improved overall survival in a number of solid tumor types (renal cell carcinoma, lung cancer, hepatocellular carcinoma). 119,120 These early trials should be interpreted with caution as they were designed for assessing safety of cd T-cell products and not their efficacy.…”

Phenotypic and functional changes in gamma delta T lymphocytes from HTLV-1 carriers

“…However, the quality of this activity can be associated to prevention or development of HAM/TSP . Interestingly, Sabouri et al . demonstrated that the expression of perforin in CD8 + T lymphocytes from HAM/TSP patients was reduced compared to cells from AC and uninfected individuals.…”

“…ciated to prevention or development of HAM/TSP 57,58. Interestingly, Sabouri et al59 demonstrated that the expression of perforin in CD8 + T lymphocytes from HAM/TSP patients was reduced compared to cells from AC and uninfected individuals. HTLV-1-specific CD8 + CTLs from HAM/TSP patients also showed significantly lower degranulation levels in comparison to AC, by a CD107a mobilization assay.…”