The long-term objective of this project is to develop innovative therapeutic modes for the treatment of advanced forms of human oral cancers. Oral cancer is a major health problem not only because of the significant mortality rates associated with the disease, but also because of the functional defects and disfigurement often associated with its treatment. Early stage tumors can usually be managed through surgery and radiotherapy, however, successful treatment is inversely proportional to the extent of the disease at the time of treatment. Unfortunately, diagnosis is often delayed until the tumor is in a later stage as early lesions frequently do not show symptoms. Of oral cancers diagnosed between 1986-1991, 52 percent were at an advanced stage and the five-year survival rate of these cases was 55 percent among whites and 33 percent among blacks. These bleak statistics warrant extensive experimentation for treating advanced head and neck tumors. A particularly promising approach involves stimulating the host's immune system to identify and destroy tumor cells. There is strong evidence that oral cancers can be detected by the immune system, as infiltrating lymphocytes have been reported in the majority of tumors examined to date. The presence of T-lymphocytes has been associated with a favorable prognosis in early studies of animal models and human biopsies. The possibility of treating tumors using immunostimulatory cytokine therapy is beginning to gain acceptance. IL-2 is one of the leading candidates for therapy of cancers as exogenously administered IL-2 stimulates the activation and proliferation of infiltrating T- lymphocytes. Administration of IFN-gamma, has resulted in the reduction of tumors as well as rendering tumors more susceptible to IL-2 immunotherapy, possibly by up regulating MHC I/II or co-stimulatory molecules (B7-1), resulting in effective tumor-antigen presentation to T lymphocytes. Toxic effects, however, are a major problem when high doses of cytokines are administered. Since oral cancers are easily accessible, we propose to deliver the genes for IL-2 and IFN-gamma into the tumor cells where they will be expressed using non-replicating adenovirus vectors. We hope to produce high concentrations of IL-2 and IFN-gamma within the micro-environment of the tumor and stimulate anti- tumor immune responses. Although levels of cytokines will be high in the micro-environment, the systemic levels will remain low to avoid the toxicity problems associated with high exogenous cytokine dosage. We will test the usefulness of cancer gene therapy using non-replicating adenovirus vectors expressing immunostimulatory cytokines in a mouse model of oral cancers.
