The success of gene therapy for cancer will eventually depend on delivering genes specifically to tumor cells in vivo. However, systemic administration of viral stocks has not so far achieved therapeutic targeting of metastatic disease, due to low titres, immune inactivation, non-specific adhesion and loss of viral paticles in the circulation. It would, therefore, be valuable if vectors could be carried to local sites of tumor growth and be released in response to externally applied signals (such as drugs) or environmental cues supplied by the biological properties of the tumor itself. Several cell types could serve as tumor homing cell carriers of vectors, including tumor antigen specific T cells. We have recently shown that systemic delivery of surface targeted T cells, engineered to produce a transcriptionally tumor targeted retroviral vector upon recognition by the T cell of a specific tumor antigen, generated highly significant therapeutic effects in a model of metastatic disease. However, our T cell studies used human T cells lacking cytolytic effector functions, in mice lacking a functional immune system. We now propose to expand the concept of T cell carriers for the gene therapy of cancer. As summarized in Figures 18 and 19 we will 1: Demonstrate that antigen specific, murine cytotoxic T cells can be converted into retroviral producer cells in vitro, that they can be adoptively transferred in vivo to tumor bearing hosts and that they can traffick to and specifically transduce antigen positive tumors in the presence of a fully intact immune system: 2: Characterise the therapeutic enhancement produced by combining tumor localized production of cytotoxic retrovirus with the T cells' natural effector functions (target cell killing and cytokine release) in a protocol of adoptive T cell therapy in an immunocompetent murine model of malignant melanoma: and 3; Investigate the potential of antigen specific T cell based retroviral vector production at the tumor site to enhance the recruitment of further doses of adoptively transferred T cells and the recruitment/activation of endogenous anti tumor immune effectors. Clinically, these experiments should rapidly lead to improved patient trials for adoptive T cell therapy of cancer and they will develop the potential of cell-based carriers for in vivo gene delivery to metastatic disease.
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