Canarypox virus expressing wild type p53 for gene therapy in murine tumorsmutated in p53

The antitumor activity of a recombinant canarypox virus expressing wild typ e murine p53 (ALVAC-p53) was investigated in two murine syngeneic tumors ha rboring an endogenous p53 mutation (CMS4 and TS/A). Direct intratumor injec tions of ALVAC-p53 in CMS4 pre-established subcutaneous tumors induced tota l tumor regression in 66% of mice. Furthermore, 100% of the cured mice was protected against a contralateral subsequent challenge with the parental tu mor cells. The intravenous treatment of experimental lung metastasis by ALV AC-p53 also induced significant tumor growth inhibition in both models. The antitumor effect of ALVAC-p53 was only observed in immunocompetent animals and was associated with the generation of a specific antitumor immune resp onse. ALVAC-p53 induced the expression of a functional p53 wild type protei n as demonstrated by up-regulation of p21(waf1) and induction of apoptosis. A vaccine strategy using intravenous or subcutaneous ALVAC-p53/NYVAC-p53 p rime boost protocol failed to induce CTL against p53 wild type used as targ et tumor antigen, and failed to protect mice against challenge with the mut ated tumor cells. The mechanism of the curative and protective effects obse rved after direct intratumor injections results from the induction of a spe cific antitumor response directed against other antigens than p53. Our resu lts suggest that the local induction of tumor apoptosis, combined with the adjuvant effect of ALVAC vector, enhances the immunogenicity of the intratu mor environment and allows induction of specific antitumor immune response.