Abstract 5542: ASTX660, a non-peptidomimetic antagonist of cIAP1/2 and XIAP, enhances immune mediated tumor killing and induction of immunogenic cell death

Abstract

Abstract Introduction: ASTX660 is a potent, non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), which is currently being tested in a first in human phase I-II study in patients with advanced solid tumors and lymphomas (NCT02503423). IAP antagonists enhance tumor necrosis factor receptor superfamily mediated cell death and enhance anti-tumor immune responses. Herein, we describe the profile of ASTX660 in a range of preclinical tumor models and evaluate ASTX660's ability to enhance immune mediated killing of tumor cells, both in vitro and in vivo. Methods: ASTX660 was tested in a panel of human and mouse tumor cell lines, assessing proliferation, apoptosis and immunogenic cell death (ICD). ASTX660 was tested alone or with recombinant Death Receptor ligands. Additionally, we used a novel co-culture system of tumor cell lines with anti-CD3 activated human peripheral blood mononuclear cells (PBMC) to assess ASTX660 effects on immune mediated cell killing. Target engagement along with induction of apoptosis and ICD markers were analysed by Western blotting and flow cytometry. Murine tumor models in immunocompetent and immunocompromised mice were utilised to evaluate the efficacy of ASTX660 in the presence or absence of an effective immune response. Results: ASTX660 antagonised IAPs in cell lines, as indicated by a decrease in cIAP1 protein levels and disruption of the XIAP:SMAC protein complex. In murine T cell lymphoma cell lines ASTX660 treatment was associated with an increase in apoptosis and ICD. In immunocompetent mice, administration of ASTX660 delivered a complete regression of BW5147 tumor growth which was not seen in mice deficient in T and B cells. To confirm human relevance, ASTX660 also enhanced anti-CD3 stimulated PBMC-dependent killing of tumour cell lines. Conclusion: The combination of the direct effects of ASTX660 on tumor cells and ASTX660 dependent effects on immune responses adds to the description of ASTX660's mode of action and our ongoing understanding of the clinical efficacy in T cell Lymphoma(1). Reference: A Hollebecque et al. 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. Citation Format: Nicola Ferrari, George Ward, Joanne Munck, Simone Jueliger, Matthew Davis, Christina Gewinner, Roberta Ferraldeschi, John Lyons, Martin John Sims. ASTX660, a non-peptidomimetic antagonist of cIAP1/2 and XIAP, enhances immune mediated tumor killing and induction of immunogenic cell death [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5542.