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

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.