The treatment of cancer with adoptive cell therapy is largely limited to platforms based on circulating, patient-derived, engineered autologous αβ T cells. Although successful in some hematological malignancies, this approach comes with challenges including associated toxicities, high production costs and a requirement to gene edit cells to avoid graft vs host disease if used in an allogeneic setting. While engineered αβ T cells have shown therapeutic activity in haematological malignancies, clinical activity in solid tumors has been challenging. In contrast to αβ T cells, Vδ1 γδ T cells are a subset of innate T cells defined by expression of T cell receptors composed of a γ chain paired to a Vδ1 chain. In mice, Vδ1 γδ T cells are predominantly tissue resident where they are highly protective against a broad spectrum of carcinomas by mediating anti-tumor responses via pattern and natural cytotoxicity receptor recognition. Similarly, in humans, Vδ1 γδ T-cell predominantly reside within epithelial tissues, mediate target cell recognition that is not MHC restricted and are not allo-HLA reactive. HLA matching of patients is therefore not required for γδ T-cell adoptive cell therapies. The innate Vδ1 γδ T-cell biology which enables antigen independent tumour recognition, lack of necessity for HLA matching, and inherent migration to and residence in human tissues makes Vδ1 γδ T-cells an attractive platform for cellular therapy. We have developed a good manufacturing practice (GMP) compliant, scalable processes to isolate tissue-resident Vδ1 γδ T-cells from healthy human skin tissue. Using organotypic culture methods, the process generates a mixture of tissue resident lymphocytes that is easily cryopreservable. This frozen intermediate (termed ‘DermaPack') serves as qualified starting material for expansion and highly efficient transduction of γδ T cells to generate allogeneic ‘off-the-shelf' CAR γδ T-cell therapies for the treatment of solid tumors. CAR Vδ1 γδ T-cells show excellent recoverability and viability post cryopreservation, an activated innate phenotype and produce high levels of IFNγ and chemokines which can attract and stimulate activation of other immune effector cells like APCs and αβ T cells. Vδ1 CAR-T cells show potent cytotoxic activity against solid tumor cell lines in vitro. These data demonstrate a novel method for a unique, off the shelf CAR-T cell platform for targeting solid tumor that combines the specificity of a CAR with the innate features of tissue resident Vδ1 γδ T cells.

Citation Format: Andrew Hutton, Shristi Bhandari, Mahdieh Hassanjani, Daniel Adams, Madeline Dalziel, Peter Mitchell, Ines Sa Pereira, Sean O'Farrell, Rebecca Alade, Istvan Kovacs, Michael Koslowski, Alice C. Brown, Oliver Nussbaumer. Vδ1γδ T-cells: A unique tissue-derived, allogeneic cell therapy platform for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1533.