Enhanced Tumor Protection by Granulocyte-Macrophage Colony-Stimulating Factor Expression at the Site of an Allogeneic Vaccine

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Abstract
Murine tumor models have demonstrated that whole tumor cell vaccines engineered to secrete certain cytokines in a paracrine fashion elicit systemic immune responses capable of eliminating small amounts of established tumor. In particular, autologous tumors that express the cytokine GM-CSF induce potent systemic immune responses against poorly immunogenic murine tumors. However, phase I clinical trials have demonstrated the technical difficulty of routinely expanding primary autologous human tumor cells to the numbers required for vaccination, making the generalization of autologous vaccines impractical. Dissection of the mechanism by which antitumor immunity is generated has demonstrated that GM-CSF recruits professional antigen-presenting cells that act as intermediates in presenting tumor antigen to and activating effector T cells. Furthermore, the identification of commonly recognized murine and human tumor antigens indicates that many are shared rather than unique. These findings would suggest that allogeneic as well as autologous tumor cells can be used as the vaccinating cells for activating antitumor immunity. A major concern in the application of allogeneic vaccines relates to the potential interference of allogeneic MHC expression at the vaccine site with priming of tumor-specific T cell responses. Here we describe a series of experiments that directly examines the effects of allogeneic MHC molecules on the immune-priming capabilities of a whole cell tumor vaccine engineered to secrete GM-CSF. The results demonstrate that the expression of an allogeneic MHC molecule by a vaccine cell can actually enhance the induction of systemic antitumor immunity. In addition, allogeneic MHC expression has no inhibitory effect on the ability of GM-CSF-transduced vaccines to induce systemic antitumor immunity. These findings support the design of clinical trials for testing this more feasible and generalizable allogeneic whole tumor cell vaccine approach. Autologous tumor cells genetically modified to express cytokines induce potent systemic antitumor immune responses in animal models. Although primary autologous human tumor cells are the best source of vaccine cells for clinical testing of this approach, the inability to reliably generate autologous tumor cell lines from tumor specimens has posed a major methodological obstacle to progress in cancer vaccine development for most human tumor types. Substitution of allogeneic cells is a potential solution to this problem. Recent findings provide the immunologic rationale for an allogeneic whole cell tumor vaccine. We performed a series of experiments to examine directly the effects of allogeneic MHC molecules on the immune-priming capabilities of a whole tumor cell vaccine engineered to secrete the cytokine GM-CSF. Our findings demonstrate that the allogeneic response results in systemic antitumor immunity against autologous tumor. In addition, this response can be markedly enhanced by coexpression of GM-CSF by the vaccine cells.