Engineering enhancement of immune responses to DNA-based vaccines in a prostate cancer model in rhesus macaques through the use of cytokine gene adjuvants.
DNA immunization is an important vaccination technique that is being explored as an immunotherapeutic strategy against a variety of infectious diseases as well as cancer. We have been investigating the utility of DNA-based vaccine strategy against prostate cancer. We have developed a DNA vaccine construct that encodes for the human prostate specific antigen (PSA) gene. PSA expression is limited to prostate cells, and the level of PSA expression is substantially increased in prostate cancer cells. This tissue specificity makes PSA a potential target for the development of immunotherapies against prostate cancer. A DNA-based PSA vaccine was used to elicit PSA-specific host immune responses in rodent and nonhuman primate models. In an effort to enhance the clinical utility of the DNA-based PSA vaccine, we also examined the use of cytokine gene adjuvants to modulate vaccine-induced immune responses in these animal models. We observed that pCPSA vaccine-induced humoral and cellular immune responses can be modulated through the coimmunization with cytokine genes in mice, and these enhancement effects on the PSA-specific cellular responses were extended in macaques. More specifically, coimmunization with interleukin (IL)-2 cDNA construct resulted in a significant enhancement of PSA-specific antibody responses in both mice and macaque models. In contrast, coinjection of IL-12 resulted in reduction of antibody responses in both models. In mice, the groups coimmunized with IL-2, IL-12, or IL-18 showed a dramatic increase in T helper cell proliferation over the results with pCPSA alone. These results support that further evaluation of this vaccination strategy to treat prostate cancer is warranted.
Kim
J J
JJ
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Yang
J S
JS
Dang
K
K
Manson
K H
KH
Weiner
D B
DB
D000818:Animals; D019496:Cancer Vaccines; D002455:Cell Division; D016207:Cytokines / Q000235:genetics*; D018076:DNA, Complementary / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D018664:Interleukin-12 / Q000627:therapeutic use; D020382:Interleukin-18 / Q000627:therapeutic use; D007376:Interleukin-2 / Q000627:therapeutic use; D008214:Lymphocytes / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D019444:Vaccines, DNA
D019496:Cancer Vaccines; D016207:Cytokines; D018076:DNA, Complementary; D020382:Interleukin-18; D007376:Interleukin-2; D019444:Vaccines, DNA; D018664:Interleukin-12; D017430:Prostate-Specific Antigen