Antagonism of inhibitors of apoptosis proteins reveals a novel, immune response-based therapeutic approach for T-cell lymphoma.

Abstract

Tolinapant (ASTX660) is a potent, nonpeptidomimetic antagonist of cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) and X-linked IAP, which is currently being evaluated in a phase 2 study in T-cell lymphoma (TCL) patients. Tolinapant has demonstrated evidence of single-agent clinical activity in relapsed/refractory peripheral TCL and cutaneous TCL. To investigate the mechanism of action underlying the single-agent activity observed in the clinic, we have used a comprehensive translational approach integrating in vitro and in vivo models of TCL confirmed by data from human tumor biopsies. Here, we show that tolinapant acts as an efficacious immunomodulatory molecule capable of inducing complete tumor regression in a syngeneic model of TCL exclusively in the presence of an intact immune system. These findings were confirmed in samples from our ongoing clinical study showing that tolinapant treatment can induce changes in gene expression and cytokine profile consistent with immune modulation. Mechanistically, we show that tolinapant can activate both the adaptive and the innate arms of the immune system through the induction of immunogenic forms of cell death. In summary, we describe a novel role for IAP antagonists as immunomodulatory molecules capable of promoting a robust antitumor immune response in TCL.

• Authors: Nicola Ferrari, George Ward, Christina Gewinner, Matthew P Davis, Simone Jueliger, Harpreet Saini, Joanne Munck, Tomoko Smyth, Roberta Ferraldeschi, Harold Keer, John Lyons, Martin J Sims
• Journal: Blood advances (Blood Adv) Vol. 5 Issue 20 Pg. 4003-4016 (10 26 2021) ISSN: 2473-9537 [Electronic] United States
• PMID: 34474469 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Chemical References

• Morpholines
• Piperazines
• Pyrroles
• ASTX-660

Topics

• Apoptosis
• Humans
• Immunity
• Lymphoma, T-Cell
• Morpholines
• Neoplasm Recurrence, Local
• Piperazines
• Pyrroles
• Skin Neoplasms