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

Abstract

Tolinapant (ASTX660) is a potent, non-peptidomimetic antagonist of cIAP1/2 and XIAP, 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 T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). 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 T-cell lymphoma 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 anti-tumor immune response in TCL.

Epigenetic Priming by Hypomethylation Enhances the Immunogenic Potential of Tolinapant in T-cell Lymphoma

“…The study protocol was approved by the Institutional Review Board or independent ethics committee prior to study initiation. Cytokine analysis was performed using the Human ExplorerMAP v. 1.0 (Myriad RBM), as described previously ( 11 ). Samples from the first two cycles of 63 patients with PTCL were analyzed.…”

“…In an ongoing phase II trial (NCT02503423), tolinapant showed activity against extensively pretreated peripheral and cutaneous T-cell lymphomas (PTCL and CTCL; refs. 12, 13 ) and patient samples from this trial have demonstrated some preliminary evidence of immune modulation ( 11 ).…”

“…Tolinapant (ASTX660), a potent non-peptidomimetic antagonist of cIAP1, cIAP2, and XIAP ( 9, 10 ), has been shown to induce an immunogenic (necroptotic) form of cell death and elicit further immunomodulatory effects in preclinical models of T-cell lymphoma (TCL; ref. 11 ). In an ongoing phase II trial (NCT02503423), tolinapant showed activity against extensively pretreated peripheral and cutaneous T-cell lymphomas (PTCL and CTCL; refs.…”

Frontiers in Medicinal Chemistry 2022 Goes Virtual

“…A fragment with a millimolar activity (XIAP: IC 50 >5 mM, cIAP >5 mM) served as a starting point for development, [23] and they managed to generate low nanomolar compounds by means of structure‐based design [24] . Tolinapant/ASTX660 ( 2 , Figure 5, XIAP=3 nM; cIAP1=0.2 nM) was selected as the final clinical candidate that is currently being evaluated in a phase II study in T‐cell lymphoma patients [25] …”

“…[24] Tolinapant/ASTX660 (2, Figure 5, XIAP = 3 nM; cIAP1 = 0.2 nM) was selected as the final clinical candidate that is currently being evaluated in a phase II study in T-cell lymphoma patients. [25]…”