View Poster:
Combining the IAP antagonist, tolinapant, with a DNA hypomethylating agent enhances anti-tumour mechanisms in preclinical models of T-cell lymphoma

Introduction
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).

References

1. Johnson C.N. et al.,J. Med. Chem, 2018, 61(16), 7314-7329.
2. Ward G.A. et al., Mol. Can. Ther., 2018, 17(7), 1381-1391.
3. Ferrari N. et al., Blood Adv., 2021, 5(20), 4003-4016.
4. Samaniego F. et al., HematologicalOncology, 2019,37(S2), 527.
5. Lemonnier F. et al., Blood, 2018, 132(21),2305-2309.
6. Wong, J. et al., Leukemia, 2022.
7. Koo G.-B. et al., Cell Res., 2015, 25,707-725.
8. Ward G.A. et al., Blood(2021) 138 (Supplement 1): 3986
9. YauH.L. et al., Mol. Cell, 81, 1-15.