Abstract A33: ASTX660, a dual XIAP and cIAP antagonist, potentiates the anti-PD-L1 antibody therapy in mouse tumor models
Authors: Smyth Tomoko , Tsuji Shingo , Tanaka Gotaro , Nakatsuru Yoko , Lyons John , Thompson Neil 
Published: March 2017

Antagonists of cellular inhibitor of apoptosis proteins (cIAPs) have been shown to activate the alternative NF-κB pathway and to cause release of pro-inflammatory cytokines, including TNFα. In addition to a direct effect on tumor cell apoptosis, this cytokine generation may be detected by the immune system and result in priming of tumor killing by cytotoxic T cells. The release of pro-inflammatory cytokines following treatment with a cIAP antagonist could have several different effects on the innate and adaptive immune system dependent, in part, on where precisely the cytokines are generated or sensed by the immune cells. For example, this pro-inflammatory effect may co-stimulate the maturation of dendritic cells and enhance antigen presentation to naïve T cells. Alternatively, it may boost the effector phase of the adaptive response by enhancing CD8 differentiation or cytotoxic T cell killing of tumor cells. Here we report that ASTX660, an oral IAP antagonist, can potentiate the anti-tumor effect of anti-PD-L1 treatment in a range of syngeneic mouse tumor models. Subcutaneous CT26 and H22 tumors in BALB/c wild type mice were insensitive to intermittent parenteral anti-PD-L1 antibody therapy (250 µg per animal). Daily oral ASTX660 treatment (16 – 25 mg/kg Days 1-7) caused stasis of H22 tumor growth and modest but significant CT26 tumor growth inhibition. The combination of both anti-PD-L1 antibody and ASTX660 resulted in enhanced tumor growth inhibition over ASTX660 alone in both models. Survival of mice bearing CT26 tumors was significantly prolonged by the combination therapy. While other models were sensitive to both agents as single-agents (e.g. EMT6), some were insensitive to single-agents and combination (e.g. 4T1, B6F10). Previously, we have reported ASTX660 elevates plasma inflammatory signals, such as serum amyloid P (analogous to human C-reactive protein), in mice. We have also found it increases TNFα expression in cells in vitro. To understand whether these effects mediate the potentiation of the anti-PD-L1 antibody, we are investigating the consequences of the combination on the immune phenotype within these tumor models, including characterization of the tumor-infiltrating leukocytes and cytokine release. ASTX660 is currently being evaluated in a Phase I clinical trial (NCT02503423). Our investigation into the effects of combining ASTX660 with immune checkpoint inhibitors will not only evaluate the potential of such combination therapies in the clinic but also contribute towards understanding of the mechanism of immune-mediated tumor cell killing in vivo.

Citation Format: Tomoko Smyth, Shingo Tsuji, Gotaro Tanaka, Yoko Nakatsuru, John Lyons, Neil Thompson. ASTX660, a dual XIAP and cIAP antagonist, potentiates the anti-PD-L1 antibody therapy in mouse tumor models. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A33.