Abstract 4386: Effects of interferon-α-transduced tumor cell vaccines and blockade of programmed cell death 1 on the growth of established tumors

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Progress in treatments for cancer has improved the prognosis of patients with colorectal cancer. However, there is a strong need for the development of a new intervention therapy that suppresses the occurrence or recurrence effectively with fewer side effects. Immunotherapy may be such a treatment and gene therapy using tumor cells that are genetically modified to produce cytokines has been studied in several therapeutic models. We have previously reported that the interferon (IFN)-α gene-transduced tumor-based vaccination therapy suppresses the outgrowth of established tumors. Although the suppressive effects on established tumors were observed, we did not see reductions in the size of all of the parental tumors. Therefore, further improvements in the treatment are needed before clinical application, we focused on programmed cell death 1 (PD-1), which has been identified as a marker of exhausted T cells. In this study, we evaluated the efficacy of the combination of IFN-γ-transduced tumor cell vaccines and PD-1 blockade, and investigated the mechanisms of the antitumor effects of the combined therapy. A poorly immunogenic murine colorectal cancer cell line, MC38, was transduced to overexpress IFN-γ (MC38-IFNα). In a therapeutic model, parental tumor-bearing mice were inoculated with MC38-IFNα cells and an anti-PD-1 antagonistic antibody. Significant suppression of outgrowth of the established tumors was observed in the IFN-γ and anti-PD-1 combination treatment group (IFN+ anti-PD-1, 174.17 ± 35.54 mm2 vs control, 328.67 ± 26.36 mm2 on day 28, P = 0.0114 vs controls). Immunohistochemical analyses showed marked infiltration of CD4+ cells as well as CD8+ cells in the established tumors of mice treated with both IFN-γ and anti-PD-1. To investigate induction of tumor-specific immune responses, we stimulated splenocytes of IFN-γ or/and anti-PD-1 treated mice twice weekly by DCs in vitro. Significant tumor-specific cytolysis was detected when splenocytes of mice treated with both IFN-γ and anti-PD-1 were used as effector cells (58.1% ± 6.7% for MC38 and 14.1% ± 1.7% for YAC-1, effector:target = 20, P < 0.001). Our findings suggest that blockade of the PD-1 PD-ligand enhanced the Th1-type antitumor immune responses induced by IFN-γ. The combination of IFN-γ gene-transduced tumor cell vaccines and PD-1 blockade may be a possible candidate for a cancer vaccine for clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4386. doi:1538-7445.AM2012-4386