Therapeutic potential of BH3-mimetics and NK cell-mediated immunotherapy in T-ALL.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of T-cell precursors. Although the survival rates have improved with the use of intensive chemotherapy, the emergence of relapse as well as treatment-related morbidity and mortality remain major challenges. Novel treatment approaches include the inhibition of anti-apoptotic regulators or cellular immunotherapies. Here, we analyzed the sensitivity of T-ALL to inhibitors of BCL-2 (venetoclax), BCL-XL (A1331852), MCL-1 (AZD5991) and dual inhibition of BCL-2/BCL-XL (AZD4320) and evaluated their combination effects with natural killer (NK) cells. While only early T-cell precursor (ETP) ALL was sensitive to BCL-2 inhibition, MCL-1 inhibition alone was not effective in most cell lines and patient-derived xenograft (PDX) samples. For BCL-XL and dual BCL-2/BCL-XL inhibition, we observed heterogeneous sensitivities, which were associated with anti-apoptotic dependencies on the respective BCL-2 family members as assessed by BH3-profiling. Moreover, we identified functional shifts in anti-apoptotic dependencies upon exposure to AZD4320 or AZD5991 alone and synergistic effects when both inhibitors were combined with each other, allowing cell death induction in resistant samples. We then explored the potential use of apoptosis-inducing drugs as sensitizers for immunotherapy. Therefore, we investigated the potential of NK cell-mediated killing in T-ALL and found heterogeneous sensitivity, with some cell lines showing responses even at low effector-to-target (E:T) ratios. Importantly, NK cell-mediated killing could be further enhanced by combining NK cells with AZD4320, proposing this combination as a potential effective treatment. Taken together, we demonstrated promising potential of BH3-mimetics and NK cells for the treatment of T-ALL alone and in combination, warranting further preclinical and potential clinical evaluation.