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

T-cell acute lymphoblastic leukemia (T-ALL) accounts for one of the most aggressive hematological tumors and remains associated with poor prognosis and dismal outcomes, notably for relapsed and refractory patients. 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. These promising results were validated in an important series of prospective primary R/R T-ALL samples. This study provides a strong rationale for clinically relevant ATG-based immunotherapy in combination with birinapant to better treat T-ALL patients.