Anti-thymocyte globulin triggers TNF-dependent cell death in T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) accounts for one of the most aggressive hematological tumors associated with poor prognosis, notably for relapsed and refractory patients. Hence, an unmet medical need persists for T-ALL patients who fail to durably respond to conventional treatments. Herein, we report the antileukemic efficacy of anti-thymocyte globulin (ATG), a polyclonal cocktail of IgG enriched in antibodies directed against human thymocyte antigens. The treatment of preclinical models of T-ALL reveals a cytotoxic mechanism of ATG mediated by TNFα signaling. We demonstrate that ATG resistance may occur via the induction of negative regulators of TNFα-induced cell death and can be circumvented by SMAC mimetic birinapant ex vivo and in vivo. These results are validated in a series of prospective primary relapsed/refractory T-ALL samples. Here, we provide a strong rationale for clinically relevant ATG-based immunotherapy in combination with birinapant to treat T-ALL patients. Anti-thymocyte globulin (ATG) is a potent immunosuppressant used to prevent and treat acute organ transplant rejection and severe aplastic anemia. Here, the authors discover that ATG can be repurposed to induce TNF-driven cell death in T cell acute lymphoblastic leukemia.