Abstract A93: The Smac mimetic Debio 1143 synergizes with radiotherapy and immune checkpoint inhibitors to enhance antitumor immunity

Introduction: Radiotherapy (RT) kills cancer cells, increases tumor antigenicity, and stimulates the immune response which can be further augmented by systemic immune-modulating agents. Debio 1143 is an oral antagonist of the inhibitors of apoptosis proteins (IAPs) currently in clinical development, which sensitizes tumor cells to RT- or chemotherapy-induced apoptosis, and modulates NFκ-B signalling. We hypothesized that, in addition to its activity on apoptosis, Debio 1143 could improve antitumor immunity by increasing the effects of RT and anti-PD1 treatment. Experimental procedures: Using immunocompetent mouse models of lung cancer (Lewis lung cancer) and melanoma (B16F10), the anti-tumor activity of RT and anti-PD-1 was tested either alone or in combination with Debio 1143. The effects of the treatment on the immunological components were determined by FACS. Results: Combining radiotherapy and Debio 1143 in vivo potently prevented tumor growth and increased the local accumulation of cytotoxic T cells. Activation of cytotoxic T cells proved to be mediated through the release of tumor necrosis factor alpha in the tumor microenvironment. In addition, Debio 1143 was able to potently stimulate the ability of an anti-PD1 antibody to kill tumor cells in vivo. Conclusions: These data offer a new paradigm to improve the tumor immune response elicited by RT and immune checkpoint inhibitors and serve as the foundation for future clinical translation of combination therapy between Debio 1143, radiotherapy and immune-oncology agents. Citation Format: Darryll BARKHOUSE, Zhen TAO, Carey MYERS, Norbert WIEDEMANN, Bruno GAVILLET, Larry HARSHYNE, Adam DICKER, D.Craig HOOPER, Gregoire VUAGNIAUX, Bo Lu. The Smac mimetic Debio 1143 synergizes with radiotherapy and immune checkpoint inhibitors to enhance antitumor immunity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A93.