Broadened Clinical Utility of Gene Gun-Mediated, Granulocyte-Macrophage Colony-Stimulating Factor cDNA-Based Tumor Cell Vaccines as Demonstrated with a Mouse Myeloma Model

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Abstract
Effective immunization against the murine B16 melanoma by a nonviral approach in which a gene gun is used to transfer GM-CSF cDNA into tumor cells has been described. We have extended this nonviral approach by using the poorly immunogenic murine myeloma MPC11 model. Vaccination with the transfected, GM-CSF-expressing MPC11 cells induced a potent antitumor cytotoxic T lymphocyte response associated with tumor rejection in the majority of the test mice. Furthermore, nearly 100% (27 of 28) of the tumor-free mice were able to reject a tumor rechallenge. While this approach is clinically attractive because of minimal tissue manipulation/culturing and the absence of infectious agents, a number of tested human primary tumors, including myeloma cells, have failed to produce high levels of GM-CSF after gene gun transfection. To circumvent the low transfection efficiency in certain human tumor cells, we showed that combining irradiated tumor cells to provide tumor antigens together with gene gun-transfected fibroblasts to provide GM-CSF induced effective tumor rejection. We also report that normal human skin fibroblasts transfected by the gene gun produce high levels of human GM-CSF (250 ng/106 cells/24 hr). These results suggest that combining irradiated tumor cells with gene gun-transfected fibroblasts results in antitumor immune responses and may allow for a wider application of this approach to cancer immunotherapy. Antitumor immune responses were induced in mice that had been immunized with poorly immunogenic murine myeloma MPC11 cells transfected with a mouse GM-CSF cDNA expression vector by gene gun. Induction of a potent antitumor immune response was at least in part due to activation of CTLs. Because of the difficulty in transfecting human tumor explants, we explore the use of transfected fibroblasts to provide GM-CSF in combination with irradiated MPC11 cells as tumor vaccine. Our results showed that immunizations with GM-CSF cDNA-transfected fibroblasts combined with irradiated MPC11 cells resulted in effective tumor rejection. In addition, normal human skin fibroblasts can be efficiently transfected to produce high levels of human GM-CSF, making the gene gun-mediated, cytokine cDNA-based tumor cell vaccine a more broadly applicable approach for human cancer therapy.