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 and has a highly restricted tissue distribution. Prostatic malignancies in 95% of patients continue to express PSA, making this antigen a good candidate for targeted immunotherapy. The goals of our studies are to generate a recombinant PSA adenovirus type 5 (Ad5-PSA) that is safe and effectively activates 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 Ad5-PSA induced PSA-specific cellular and humoral immunity that was protective against a subcutaneous challenge with RM11 prostate cancer cells expressing PSA (RM11psa), but not mock-transfected RM11 tumor cells (RM11neo). Mice immunized with recombinant adenovirus type 5 encoding beta-galactosidase (Ad5-lacZ) did not generate protective immunity. Antitumor activity was predominantly mediated by CD8(+) T lymphocytes. Although Ad5-PSA immunization prior to RM11psa challenge was protective, Ad5-PSA immunization alone was not able to control the growth of existing 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 canarypox viruses (ALVAC) encoding interleukin-12 (IL-12), IL-2, and tumor necrosis 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 in a protective immune response to prostate cancer and demonstrate the utility of an Ad5-PSA vaccine combined with cytokine gene delivery to eliminate large established tumors that are refractory to other interventional methods.
Elzey
B D
BD
Department of Microbiology, University of Iowa, Iowa City, IA 55242, USA.
Siemens
D R
DR
Ratliff
T L
TL
Lubaroff
D M
DM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D028121:Canarypox virus / Q000235:genetics; D016207:Cytokines / Q000235:genetics*; D015316:Genetic Therapy; D006801:Humans; D007114:Immunization; D018664:Interleukin-12 / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017430:Prostate-Specific Antigen / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000628:therapy*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014614:Vaccines, Synthetic / Q000276:immunology*
D016207:Cytokines; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D014614:Vaccines, Synthetic; D018664:Interleukin-12; D017430:Prostate-Specific Antigen