TNF-mediated cell death: an actionable target for immunotherapy in T-ALL [1]

Unlike leukemias of myeloid or B-cell origin, T-ALL has not benefited from the major advances in immune and cell-based therapies. Hence, an unmet medical need persists for underserved T-ALL patients who fail to durably respond to conventional treatments.

Herein, we report the robust antileukemic efficacy of ATG, a polyclonal cocktail of IgG enriched in human thymocyte antigens, in vivo. The treatment of a large series of preclinical models of T-ALL revealed a genuine cytotoxic mechanism of ATG mediated by TNF signaling. Critically, we revealed that ATG resistance may occur via the induction of negative regulators of TNF-induced cell death, and can be circumvented by SMAC mimetic birinapant ex vivo and in vivo.