| Her-2, human ErbB-2, is an oncogene and a tumor-associated antigen in several human cancers. Due to overexpression on tumor cells compared to normal tissues and intrinsic propensity to be presented to the immune cells and antibodies, it is also a target for cancer immunotherapy by Her-2 DNA vaccines. We established Her-2 transgenic (Tg) mouse model to mimic human immunological tolerance to Her-2. Her-2 Tg mice in three different backgrounds responded differently to Her-2 DNA vaccine suggesting genetic regulation of Her-2 vaccine efficacy in tolerant hosts. BALB Her-2 Tg mice were more responsive to Her-2 vaccine, while B6 Her-2 or F1 Her-2 Tg mice exhibited more profound tolerance. To overcome Her-2 tolerance, heterologous vaccine encoding rat ErbB-2, neu, was tested in Her-2 Tg mice. In less tolerant BALB Her-2 Tg mice, self Her-2 DNA vaccine was superior, while in B6 Her-2 Tg mice neither vaccine induced robust Her-2 immunity, suggesting that self Her-2 vaccine may be superior, particularly at inducing Her-2-specific Abs. To enhance immunogenicity of Her-2, we generated a panel of adjuvant-containing Her-2 DNA vaccines to overcome tolerance. Two constructs containing PADRE or tetC adjuvant sequences have shown enhanced Her-2 immunity and were selected for further testing. Tumors are vast reservoirs of antigens with the potential to be recognized by the immune system, but immunosuppressive tumor environment inhibits generation of anti-tumor immunity. To take advantage of this antigen reservoir, we expressed foreign antigen, tetC, by intratumoral DNA electroporation to make tumor microenvironment permissive to immune priming. Expression of SecTetC by intratumoral DNA electroporation combined with regulatory T cell depletion induced immune response to endogenous tumor antigens and inhibited tumor growth. With addition of IL-12 DNA electroporation, regression of established mammary tumors was achieved, and immunological memory to tumor antigens was established protecting against tumor recurrence. |
