Tolinapant (ASTX660) is a potent, non-peptidomimetic antagonist of cIAP1, cIAP2 and XIAP 1, 2, and has demonstrated immunomodulatory properties in pre-clinical models of T cell lymphoma (TCL) 3. In an ongoing Phase 2 trial (NCT02503423), tolinapant has shown activity against highly pre-treated peripheral and cutaneous T-cell lymphoma 4.
Hypomethylating agents (HMAs) have also shown clinical responses in some subsets of PTCL 5, 6, suggesting thar reduction of methylation can deliver efficacy in PTCL. In addition, HMAs and IAP antagonists show immunomodulatory anti-cancer potential in pre-clinical studies.
Here we have investigated the potential for HMA-induced reversal of epigenetic silencing or altered cell signalling to promote the induction of immunogenic forms of cell death (ICD), such as necroptosis, driven by tolinapant treatment in pre-clinical models of T-cell lymphoma (TCL).
- Johnson C.N. et al.,J. Med. Chem, 2018, 61(16), 7314-7329.
- Ward G.A. et al., Mol. Can. Ther., 2018, 17(7), 1381-1391.
- Ferrari N. et al., Blood Adv., 2021, 5(20), 4003-4016.
- Samaniego F. et al., HematologicalOncology, 2019,37(S2), 527.
- Lemonnier F. et al., Blood, 2018, 132(21),2305-2309.
- Wong, J. et al., Leukemia, 2022.
- Koo G.-B. et al., Cell Res., 2015, 25,707-725.
- Ward G.A. et al., Blood(2021) 138 (Supplement 1): 3986
- YauH.L. et al., Mol. Cell, 81, 1-15.