ACTIVE IMMUNOTHERAPY OF PANCREATIC-CANCER WITH TUMOR-CELLS GENETICALLY-ENGINEERED TO SECRETE MULTIPLE CYTOKINES

Background. Vaccination of tumor-bearing animals with tumor cells gene tically engineered to secrete cytokines including interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) has been shown to induce effective t umor-specific immune responses capable of inhibiting local and metasta tic disease. Previous unsuccessful attempts to enhance this immune res ponse by means of the secretion of multiple cytokines possessing diffe rent immunologic mechanisms of action may have been due to the inheren t inefficiency of the gene transfer systems used. We postulated that t umor cells genetically engineered by means of a novel gene transfer me thod resulting in high level secretion of both cytokines would be more effective than tumor cells secreting a single cytokine in inhibiting the growth existing tumors. Methods. Nonimmunogenic, murine pancreatic cancer cells (Panc02) were engineered to secrete IL-2, IFN-gamma, IL- 2 and IFN-gamma, or neomycin phosphotransferase. Mice were inoculated with 5 x 10(5) parental Panc02 tumors cells subcutaneously. Beginning 3 days later, animals then received a series of four weekly vaccinatio ns with irradiated Panc02/Neo, Panc02/IL2, Panc02/IFN, or Panc02/IL-2/ IFN. Results. Treatment with Panc02/Neo, Panc02/IL-2, or Panc02/IFN re sulted in 0%, 40%, and 30% tumor-free survival, respectively. In contr ast, 80% of animals vaccinated with Panc02/IL2/IFN were free of tumor at 100 days. All animals free of disease were resistant to subsequent tumor challenges. Conclusions. These data show that vaccination with t umor cells that secrete high levels of multiple cytokines was more eff ective in treating established pancreatic tumors and represents an imp rovement over existing single cytokine strategies.