Prostate cancer gene therapy: Comparison of adenovirus-mediated expressionof interleukin 12 with interleukin 12 plus B7-1 for in situ gene therapy and gene-modified, cell-based vaccines

We have documented previously that adenovirus-mediated interleukin 12 (IL-1 2) gene therapy is effective for orthotopic tumor control and suppression o f pre-established metastases in a preclinical prostate cancer model (Y, Nas u et at, Gene Ther,, 6: 338-349, 1999), In this report, we directly compare the effectiveness of an adenovirus that expresses both IL-12 and the costi mulatory molecule B7-1 (AdmIL-12/B7) with one that expresses IL-12 alone (A dmIL-12) using the poorly immunogenic RM-9 orthotopic murine model of prost ate cancer. We document AdmIL-12/B7-mediated secretion of IL-12 and increas ed surface expression of B7-1 in infected RM-9 tumor cells, A significant r eduction in orthotopic tumor size and increased survival was demonstrated i n mice treated with a single orthotopic injection of AdmIL-12/B7 compared w ith AdmIL-12 or controls, Six of 19 animals treated with AdmIL-12/B7 surviv ed long term with apparent eradication of the primary tumor in contrast to one of 38 animals in the Admit-12-treated group. Orthotopic treatment of tu mors with both vectors led to an infiltration of both CD4+ and CD8+ immunor eactive cells, with AdmIL-12/B7 treatment having a more prolonged infiltrat ion of CD8+ cells. AdmIL-12/B7 was also more effective than AdmIL-12 or con trols at suppression of pre-established metastases, We further developed a vaccine model based on s,c, injection of infected, irradiated RM-9 cells an d found that both AdmIL-12 and AdmIL-12/B7 are effective at suppressing the development and growth of challenge orthotopic tumors using this protocol.