DNA-based Vaccine for Treatment of Oral Carcinoma

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DESCRIPTION: Vaccine development for oral carcinoma is the current major research objective of my laboratory. The long-term objective is to develop a vaccine that can be used in the overall management of patients with squamous cell carcinoma of the head and neck (SCCHN). The vaccination strategy combines known requirements for generation of a robust anti tumor immune response--antigen presentation, allogeneic stimulation and the secretion of immune-augmenting cytokines. The vaccine is prepared by transfer of DNA from squamous carcinoma cells into a highly immunogenic syngeneic/allogeneic cell line in which genes specifying tumor associated antigens (TAAs) are expressed. The recipient cells are modified in advance of DNA-transfer to secrete cytokines. This type of vaccine is based on the principle that TAAs are the products of mutant and dysregulated genes in cancer cells and that transfer of tumor-DNA into recipient cells results in stable integration and long-term expression of the genes specifying TAAs. Prior published data in mice indicate that immunization with transfected cells induced strong anti tumor immune responses, immunological memory and prolongation of survival. Our recent studies (PNAS, 99: 9415-9420, 2002) confirm the immunogenic properties of recipient cells transfected with DNA from human oral carcinomas. This type of vaccine has a number of advantages, including the selection of immunogenic recipient cells, in which the transferred DNA is replicated. Thus, the vaccine can be prepared with DNA derived from small amounts of tumor tissue. Further studies in a mouse model of oral carcinoma are now required to define the mechanisms of the immunotherapeutic effects of the vaccine and to optimize this promising strategy. Using murine antigen presenting cells transfected with DNA from squamous carcinomas, the minimum amount of tumor tissue required to prepare an effective vaccine and the cell types mediating tumor rejection will be determined. The transfected cell-population will be enriched for cells that express TAAs, to increase the therapeutic potential of the vaccine. Its possible toxic effects will be evaluated. These studies will provide insights into the mechanism of tumor rejection and guidelines for optimization of the vaccination strategy. It is expected that development of an effective vaccine to be used alone or in combination with conventional therapy will expand the future therapeutic options available for patients with oral cancer.