Localized adoptive cellular therapy of Ex Vivo expanded Gamma Delta T cells for solid tumors

Abstract

In recent years, adoptive cellular immunotherapy has emerged as a promising approach to treat cancers, particularly haematological cancers. However, its clinical utility in solid tumours is limited partly due to the requirement of transferred T cells to travel from the intravenous injection site to the tumour bed. Local administration of transferred T cells directly into the tumour mass or in the vicinity of a freshly resected tumour may be better suited to capitalize the full therapeutic potential of T cell adoptive therapy. This study explored the therapeutic potential of local delivery of gamma delta (Vγ9Vδ2) T cells (effector cells) in combination with zoledronate (cancer cell sensitiser) when embedded into biomaterial scaffolds for the local control of solid tumours using various cellular and animal models of breast cancer and glioblastoma. In vitro, ex vivo expanded Vγ9Vδ2 T cells maintained cell viability in Matrigel scaffolds and time-lapse video fluorescence imaging demonstrated progressive release of large numbers of Vγ9Vδ2 T cells from the scaffolds into surrounding area within just a few hours, rapidly killing cancer cells in their path. However, unlike the strong Vγ9Vδ2 T cell-mediated cytotoxicity observed in vitro, the effects seen in vivo using xenograft models of both breast cancer and glioblastoma were highly disappointing with only marginal anticancer efficacy observed. To explore the reasons for this, FACS was used to analyse the tumours at 72 hrs after the co-delivery of fluorescently labelled Vγ9Vδ2 T cells and fluorescent ZOL in Matrigel scaffolds. The data showed that, whereas Vγ9Vδ2 T cells were abundantly present in the tumour tissue, ZOL, on the other hand, could not be detected in cancer cells but rather accumulated selectively in the tumour resident macrophages and was preferentially rooted to the skeleton of mice due to its calcium binding characteristics. Collectively the data presented in this thesis clearly indicate that ZOL given locally, is unlikely to be of sufficient benefit in potentiating Vγ9Vδ2 T cell function in vivo and is therefore destined to fail clinically despite the overwhelming cytotoxicity observed in many cellular models. In this regard, the use of nanotechnology to improve cancer cell uptake of ZOL may open up a new therapeutic scenario for ZOL and Vγ9Vδ2 cell-based local immunotherapy.