Immunization with type 5 adenovirus recombinant for a tumor antigen in combination with recombinant canarypox virus (ALVAC) cytokine gene delivery induces destruction of established prostate tumors

Prostate-specific antigen (PSA) is expressed by prostate epithelial cells a nd has a highly restricted tissue distribution. Prostatic malignancies in 9 5% of patients continue to express PSA, making this antigen a good candidat e for targeted immunotherapy. The goals of our studies are to generate a re combinant PSA adenovirus type 5 (AdS-PSA) that is safe and effectively acti vates a PSA-specific T-cell response capable of eliminating prostate cancer cells, and to characterize the immunologic basis for this rejection. Here we show that immunization of mice with AdS-PSA induced PSA-specific cellula r and humoral immunity that was protective against a subcutaneous challenge with RM11 prostate cancer cells expressing PSA (RM11psa), but not mock-tra nsfected RM11 tumor cells (RM11neo). Mice immunized with recombinant adenov irus type 5 encoding beta -galactosidase (Ad5-lacZ) did not generate protec tive immunity. Antitumor activity was predominantly mediated by CD8(+) T ly mphocytes. Although Ad5-PSA immunization prior to RM11psa challenge was pro tective, Ad5-PSA immunization alone was not able to control the growth of e xisting RM11psa tumors. In contrast, established RM11psa tumors ranging in size from 500 to 1,000 mm(3) were efficiently eliminated if Ad5-PSA priming was followed 7 days later by intratumoral injection of recombinant canaryp ox viruses (ALVAC) encoding interleukin-12 (IL-12), IL-2, and tumor necrosi s factor-alpha. In this case, antitumor immunity was still dominated by CD8 (+) T lymphocytes, but natural killer cells became necessary for a maximal response. These data provide information on the effector cell populations i n a protective immune response to prostate cancer and demonstrate the utili ty of an Ad5-PSA vaccine combined with cytokine gene delivery to eliminate large established tumors that are refractory to other interventional method s. (C) 2001 Wiley-Liss, Inc.