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 are known regulators of cell death and have been reported to modulate immune responses (1). Herein, we describe the profile of ASTX660 in preclinical models with a specific focus on ASTX660's ability to harness a particular form of regulated cell death in T-cell lymphoma that directs an effective immune response and leads to sustained tumor regressions.
Methods: ASTX660 was profiled across a panel of T-cell lymphoma lines, assessing apoptosis, necroptosis, and immunogenic cell death (ICD). ASTX660 was tested in vitro with or without caspase-8/RIPK1 inhibitors to demonstrate mechanism of action. Target engagement along with induction of apoptosis, necroptosis, and ICD markers were analyzed by Western blotting and flow cytometry. Murine tumor models in immunocompetent and immunocompromised mice were utilized to evaluate the efficacy of ASTX660 in the presence or absence of an adaptive immune response.
Results: ASTX660 antagonized IAPs in cell lines, as indicated by a decrease in cIAP1 protein levels. In certain murine T-cell lymphoma cell lines, ASTX660 treatment was associated with an increase in cell death and release of biomarkers of ICD. Use of caspase and RIPK1 inhibitors indicated the cell death was via necroptosis. In a syngeneic model of T-cell lymphoma, administration of ASTX660 resulted in complete and sustained tumor regressions which were not seen in mice deficient in T and B cells. Mice cured of T-cell lymphoma by ASTX660 were resistant to a second inoculation of the same lymphoma.
Conclusion: These data add to the description of ASTX660's mode of action and our ongoing understanding of the preliminary clinical efficacy in T-cell lymphoma (2). We describe a new role for ASTX660 as an immunomodulatory molecule with potential to deliver a novel immune-based therapeutic approach in T-cell lymphoma.
References: 1. Michie J et al. Cells 2020;9(1). 2. Hollebecque A et al. 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.
Citation Format: Simone Jueliger, Nicola Ferrari, George Ward, Joanne Munck, Tomoko Smyth, Matthew Davis, Christina Gewinner, Roberta Ferraldeschi, John Lyons, Martin Sims. Activity of ASTX660, a small-molecule IAP antagonist, reveals a novel, immune-based therapeutic approach in T-cell lymphoma [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-12.