GENERATION OF EFFECTIVE CANCER VACCINES GENETICALLY-ENGINEERED TO SECRETE CYTOKINES USING ADENOVIRUS-ENHANCED TRANSFERRINFECTION (AVET)

Cancer vaccines are based on the concept that tumors express novel ant igens and thus differ from their normal tissue counterparts. Such puta tive tumor-specific antigens should be recognizable by the immune syst em. However, malignant cells are of self origin and only poorly immuno genic, which limits their capability to induce an anticancer immune re sponse. To overcome this problem, tumor cells have been isolated, gene tically engineered to secrete cytokine gene products and administered as cancer vaccines. We used adenovirus-enhanced transferrinfection (AV ET), which allows high-level transient transgene expression, to introd uce cytokine gene expression vectors into murine melanoma cells. The e fficiency of AVET makes laborious selection and cloning procedures obs olete. We administered such modified tumor cells as cancer vaccines to syngeneic animals and investigated their impact on the induction of a nticancer immunity. We found that IL-2 or GM-CSF gene-transfected muri ne melanoma cells are highly effective vaccines. Both of these cytokin e-secreting vaccines cured 80% of animals which bore a subcutaneous mi crometastasis prior to treatment, and induced potent antitumor immunit y. The generation of antitumor immunity by these cytokine-secreting va ccines requires three different steps: (1) tumor antigen uptake and pr ocessing by antigen-presenting cells (APCs) at the site of vaccination ; (2) migration of these APCs into the regional lymph nodes where T-ce ll priming occurs; (3) recirculation of specific, activated T-cells th at recognize distinct tumor load and initiate its elimination. Extendi ng our previously reported studies, we have now comprehensively analys ed the requirements for effective antitumor vaccination in animals. Th is may also become the basis for treatment of human cancer patients.