Canarypox Virus-Mediated Interleukin 12 Gene Transfer into Murine Mammary Adenocarcinoma Induces Tumor Suppression and Long-Term Antitumoral Immunity

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Abstract
The antitumoral activity of recombinant canarypox virus vectors (ALVAC) expressing murine interleukin 12 (IL-12) was evaluated in the syngeneic, nonimmunogenic murine mammary adenocarcinoma model (TS/A). Seven-day preestablished subcutaneous tumors (5- to 6-mm mean diameters) were injected on days 7, 10, 14, 17, 21, and 24 with the vector ALVAC-IL12 at 2.5 × 105 TCID50 (50% tissue culture infective dose). Total tumor regression occurred in 40 to 50% of the treated mice. Furthermore, 100% of the cured mice were protected against a contralateral subsequent challenge with the TS/A parental cells on day 28. The ALVAC-IL12 treatment is not effective in nude mice, suggesting the critical role of T cells. CD4 and CD8 T cells infiltrated the tumors treated with ALVAC-IL12 in the BALB/c model. Furthermore, in vivo depletion of CD4+ T cells totally abrogated the induction of the long-term antitumoral immune response by ALVAC-IL12. Interestingly, some tumor growth inhibition was also observed with ALVAC-βGal treatment and a vaccinal effect was found in 33% of the treated animals, suggesting an adjuvant effect of the vector itself. Other ALVAC vectors expressing murine cytokines (IL-2, GM-CSF, IFN-γ) were evaluated in the same model. Major antitumoral activity was observed with ALVAC-GM-CSF. However, a combination of ALVAC-GM-CSF and AL-VAC-IL12 had no synergistic effect. These results suggest that in vivo gene transfer with canarypox virus expressing IL-12 may provide an effective and safe strategy for the treatment of human cancers. In the present study, we evaluated the antitumoral effect of direct in vivo gene therapy, using a canarypox virus recombinant vector expressing IL-12 (ALVAC-IL12), in a poorly immunogenic tumor model. In humans, the recombinant ALVAC vectors expressing foreign viral proteins have already been shown to be safe and efficient for vaccination. Their ability to induce cytotoxic T lymphocyte (CTL) priming has led to interest in their use for cancer immunotherapy. We demonstrate here the antitumoral and vaccinal effects of repeated intratumoral injections of ALVAC-IL12 in a murine mammary adenocarcinoma (TS/A). The adjuvant effect of the vector, combined with the local secretion of the cytokine, induced the eradication of preestablished tumors and led to a long-term antitumoral immune response. Other ALVAC constructs expressing IL-2, GM-CSF, or IFN-γ were evaluated in the same model. Antitumoral activity was also observed with ALVAC-GM-CSF. These results support the feasibility of in vivo gene therapy with ALVAC-IL12 for the treatment of human cancer.