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Prostate Cancer Gene Therapy: Comparison of Adenovirus-mediated Expression of Interleukin 12 with Interleukin 12 plus B7-1 for in Situ Gene Therapy and Gene-modified, Cell-based Vaccines¹

Scott Department of Urology [G. W. H., M. A. M, Y. N., C. H. B., G. Y., S. S., H-M. L., J. W., J. A., S. E., T. S., T. L. T., T. C. T.] and Departments of Cell Biology [T. C. T.] and Radiology [T. C. T.], Baylor College of Medicine, Houston, Texas 77030, and Veterans Affairs Medical Center, Houston, Texas 77030 [T. L. T., T. C. T.]

We have documented previously that adenovirus-mediated interleukin 12 (IL-12) gene therapy is effective for orthotopic tumor control and suppression of pre-established metastases in a preclinical prostate cancer model (Y. Nasu et al., Gene Ther., 6: 338–349, 1999). In this report, we directly compare the effectiveness of an adenovirus that expresses both IL-12 and the costimulatory molecule B7-1 (AdmIL-12/B7) with one that expresses IL-12 alone (AdmIL-12) using the poorly immunogenic RM-9 orthotopic murine model of prostate cancer. We document AdmIL-12/B7-mediated secretion of IL-12 and increased surface expression of B7-1 in infected RM-9 tumor cells. A significant reduction in orthotopic tumor size and increased survival was demonstrated in mice treated with a single orthotopic injection of AdmIL-12/B7 compared with AdmIL-12 or controls. Six of 19 animals treated with AdmIL-12/B7 survived long term with apparent eradication of the primary tumor in contrast to one of 38 animals in the AdmIL-12-treated group. Orthotopic treatment of tumors with both vectors led to an infiltration of both CD4+ and CD8+ immunoreactive cells, with AdmIL-12/B7 treatment having a more prolonged infiltration of CD8+ cells. AdmIL-12/B7 was also more effective than AdmIL-12 or controls at suppression of pre-established metastases. We further developed a vaccine model based on s.c. injection of infected, irradiated RM-9 cells and found that both AdmIL-12 and AdmIL-12/B7 are effective at suppressing the development and growth of challenge orthotopic tumors using this protocol.

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