846. Enhanced Antitumor Effect of Oncolytic Adenovirus Expressing Interleukin-12 and B7.1 in an Immuneocompetenet Mouse Model

Abstract

Interleukin (IL)-12 is reported to exhibit potent anti-tumor effect by promoting NK cell and cytotoxic T cell activities. The B7 family has been shown to take an important role in stimulating anti-tumor response, and synergy between IL-12 and B7-1 for cancer immunotherapy has previously been demonstrated. To increase the potential antitumor activity of the oncolytic adenovirus, we have constructed an E1B 55kDa deleted oncolytic adenoviral vector, YKL-IL12/B, which expresses murine IL-12 and B7.1. The therapeutic efficacy of YKL-IL12 and YKL-IL12/B was evaluated in an immunocompetent mouse bearing murine melanoma B16F10 tumor. The results showed significant inhibition of tumor growth following YKL-IL12/B treatment compared to PBS treated tumors. Moreover, YKL-IL12/B adenoviral vector elicited enhanced antitumor activity and a higher incidence of complete tumor regression compared to tumors treated with the analogous vector (YKL-1) that lacks IL-12 and B7.1. Survival was also significantly prolonged in YKL-IL12/B-treated mice, and immunohistochemistry analysis demonstrated robust CD4+ and CD8+ T-cell infiltration in these mice compared to the YKL-1 subjects. In addition, we observed that YKL-IL12/B induced significantly higher CTL activity than YKL-1, demonstrating that anti-tumor effect is associated with the generation of tumor-specific immune response. In summary, these data indicate that local expression of IL-12 and B7.1 in tumor bed may be an attractive alternative treatment against metastatic carcinoma. Interleukin (IL)-12 is reported to exhibit potent anti-tumor effect by promoting NK cell and cytotoxic T cell activities. The B7 family has been shown to take an important role in stimulating anti-tumor response, and synergy between IL-12 and B7-1 for cancer immunotherapy has previously been demonstrated. To increase the potential antitumor activity of the oncolytic adenovirus, we have constructed an E1B 55kDa deleted oncolytic adenoviral vector, YKL-IL12/B, which expresses murine IL-12 and B7.1. The therapeutic efficacy of YKL-IL12 and YKL-IL12/B was evaluated in an immunocompetent mouse bearing murine melanoma B16F10 tumor. The results showed significant inhibition of tumor growth following YKL-IL12/B treatment compared to PBS treated tumors. Moreover, YKL-IL12/B adenoviral vector elicited enhanced antitumor activity and a higher incidence of complete tumor regression compared to tumors treated with the analogous vector (YKL-1) that lacks IL-12 and B7.1. Survival was also significantly prolonged in YKL-IL12/B-treated mice, and immunohistochemistry analysis demonstrated robust CD4+ and CD8+ T-cell infiltration in these mice compared to the YKL-1 subjects. In addition, we observed that YKL-IL12/B induced significantly higher CTL activity than YKL-1, demonstrating that anti-tumor effect is associated with the generation of tumor-specific immune response. In summary, these data indicate that local expression of IL-12 and B7.1 in tumor bed may be an attractive alternative treatment against metastatic carcinoma.