Antigen-specific tumor vaccines: Development and characterization of recombinant adenoviruses encoding MART1 or gp100 for cancer therapy

The human melanoma tumor Ags, MART1 and gp100, are specifically recognized by HLA-A2-restricted CD8⁺ CTLs derived from melanoma patients and appear to be involved in tumor regression. In order to develop immunizing vectors for the treatment of patients with metastatic melanoma, replication-defective recombinant adenoviruses, Ad2CMV-MART1 and Ad2CMV-gp100, which encode these tumor Ags, have been generated. Infection of non-Ag expressing HLA-A2⁺ cell lines A375 and MDA-231 with the vectors resulted in recognition by Ag- specific CTLs as demonstrated by specific target cell lysis and release of cytokines, including IFN-γ, TNF-α, and granulocyte-macrophage-CSF. Sodium butyrate and TNF-α can further augment adenovirus-mediated transgene expression and increase recognition by specific CTLs. Although adenovirus- infected cells expressed the E3/19K protein at detectable levels, significant reduction of surface MHC class I expression was observed in only 3 of 10 tumor cell lines infected with either Ad2CMV-MART1 or Ad2CMV-gp100. Because of the suspected homology between the human MART1 and gp100 genes and their murine counterparts, we immunized C57BL/6 mice with these recombinant adenoviruses and demonstrated that immunization with Ad2CMV-gp100 could protect mice from murine melanoma B16 challenge administered intradermally. Depletion of CD8⁺ but not CD4⁺ T cells in vivo from Ad2CMV-gp100-vaccinated mice eliminated the protective effect. The anti-gp100 T cells induced by Ad2CMV-gp100 vaccination appeared to be responsible for the protection. Thus, these recombinant adenoviruses encoding tumor Ags may be useful as vaccines to induce specific T cell immunity for cancer therapy.