SMACing down relapsed T-ALL

In this issue of Blood , & Aacute;vila & Aacute;vila et al 1 report that T-cell acute lymphoblastic leukemia (T-ALL) cells overcome anti-CD3 monoclonal antibody (mAb)-directed therapy by inducing tumor necrosis factor receptor (TNFR) signaling, leading to activation of the NF- kappa B pathway (see fi gure). Combining teplizumab, an inhibitor of CD3, with etanercept, a decoy receptor for tumor necrosis factor- alpha (TNF- alpha ), inhibited human T-ALL patient-derived xenograft (PDX) growth in mouse models, suggesting the importance of this pathway. Remarkably, coadministration of birinapant, which mimics the downstream regulator secondary mitochondrial-derived activator of caspases (SMAC), redirected prosurvival TNFR signaling into a parallel, apoptotic program and led to growth suppression and even complete cure in one human T-ALL model. This combination therapy demonstrates how an unwanted cell-signaling outcome can be rechanneled to improve overall treatment ef fi cacy. Anti-CD3 combination therapy can be a new bridge to allogeneic stem cell transplant.