Abstract 5617: Enhancement of antitumor radiation efficacy and the abscopal effect by ECI301 mediated TLR4 dependent innate immunity in mice

Abstract

Abstract [Background] We have previously demonstrated that ECI301, a variant form of human MIP-1α, induced marked inhibition of tumor growth at the irradiated site, with complete tumor eradication and consistent induction of prevention of tumor growth at a non-irradiated site, designated as an abscopal effect (Clin Cancer Res. 2008;14(4):1159-66). This abscopal effect was tumor type independent. In current study, we further studied the action of ECI301 using C3H/HeN, C3H/HeJ and athymic mice implanted with tumor cells. Using RT-PCR analysis, we had found that high mobility group box 1 (HMGB1) RNA level, an important mediator of local and systemic inflammation was up-regulated by ECI301 in tumor tissue. So we also carried out anti-HMGB1 antibody treatment in tumor-bearing mice with ECI301 and radiation. [Methods] FM3A cells were subcutaneously implanted in the both flanks of C3H/HeN and C3H/HeJ mice. When tumor size reached approximately 10 mm in diameter, local irradiation (6 Gy) was delivered from just above the right tumor and ECI301 was administrated as a single dose intravenously once a day for 5 consecutive days, beginning at day 1 after irradiation. Athymic nude mice bearing subcutaneous colon26 tumor cells were treated with local irradiation and ECI301 was administrated as the same manner. [Results] ECI301 inhibited the tumor growth not only in the right flank but also in the left flank (non-irradiation site) in C3H/HeN mice implanted with FM3A cells. In C3H/HeJ mice, however, ECI301 did not enhance the effect of irradiation on the tumor in both flanks. In C3H/HeN study, HMGB1 RNA level was up-regulated in both sides of tumor. Moreover, anti-HMGB1 antibody treatment eliminated the anti-tumor effect of ECI301 in both sides. Furthermore, ECI301 did not inhibit the tumor growth in athymic mice implanted with colon26 cells. These results suggest that the ECI301-induced abscopal effect may be exerted via TLR4 and depend on the activation of T cells, and indicates that the effect of ECI301 may be promoted via inflammation in irradiated tumor tissue with HMGB1-dependent mechanism. [Conclusion] Ionizing radiation induces inflammation and immune response in irradiated tumor tissue. This immunological mechanism is greatly enhanced by ECI301, resulting in the abscopal effect that is essentially intriguing for clinical setting. Our data will encourage future therapeutic application of ECI301 in the treatment of advanced or metastatic cancer with radiation therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5617.