Recombinant DNA vaccines protect against tumors that are resistant to recombinant vaccinia vaccines containing the same gene

Antigen-specific cancer immunotherapy involves the delivery of tumor-associ ated antigen to the host for the generation of tumor-specific immune respon ses and antitumor effects. We hypothesized that different delivery systems may influence the pattern of antigen-specific immune response and the outco me of antitumor effect. We therefore evaluated recombinant vaccinia virus a nd naked DNA for the generation of antigen-specific immune responses and an titumor effects. We previously found that recombinant vaccinia and naked DN A vaccines containing the chimeric Sig/E7/LAMP-1 gene were capable of contr olling the growth of HPV-16 E7-expressing tumor cells (TC-1). In this study , we performed a head-to-head comparison of optimized delivery of Sig/E7/LA MP-1 vaccinia and DNA vaccines using dose-escalating tumor challenge. At a dose of 1 x 10(6) TC-1 cells per mouse, Sig/E7/LAMP-1 DNA provided 100% pro tection against subcutaneous growth of tumors, while Vac-Sig/E7/LAMP-1 prot ected only 40% of the mice. Furthermore, Sig/E7/LAMP-1 DNA Vaccines are cap able of protecting against challenge with a more stringent subclone of TC-1 (TC-1 P2) established from TC-1 tumors that survived initial Sig/E7/LAMP-1 vaccinia vaccination. Immunological assays revealed that both vaccines ind uced comparable levels of CD8(+) T cell precursors and anti-E7 antibody tit ers. Interestingly, Sig/E7/LAMP-1 vaccinia induced both E7-specific IFN-gam ma- and IL4-secreting CD4(+) T cell precursors while Sig/E7/LAMP-1 DNA indu ced only E7-specific IFN-gamma -secreting CD4(+) T cell precursors. We also found that IL-4 knockout C57BL/6 mice vaccinated with Sig/E7/LAMP-1 vaccin ia exhibited a more potent antitumor effect than vaccinated wild-type C57BL /6 mice in our tumor protection experiments. These results suggest that IL- 4 may play a detrimental role in the antitumor effect mediated by vaccinia vaccines. Our findings suggested that DNA vaccines may provide better tumor protection than vaccinia vaccines employing the same gene, which may have implications in the future design of antigen-specific cancer immunotherapy.