An Update on Immune Based Therapies in Acute Myeloid Leukemia: 2021 and Beyond!

Abstract

Despite advances in the treatment of acute myeloid leukemia (AML), relapse is still widely observed and represents the major cause of death among patients with AML. Treatment options in the relapse setting are limited, still relying predominantly on allogeneic hematopoietic stem cell transplantation (allo-HSCT) and cytotoxic chemotherapy, with poor outcomes. Novel targeted and venetoclax-based combinations are being investigated and have shown encouraging results. Immune checkpoint inhibitors in combination with low-intensity chemotherapy demonstrated encouraging response rates and survival among patients with relapsed and/or refractory (R/R) AML, especially in the pre- and post-allo-HSCT setting. Blocking the CD47/SIRPα pathway is another strategy that showed robust anti-leukemic activity, with a response rate of around 70% and an encouraging median overall survival in patients with newly diagnosed, higher-risk myelodysplastic syndrome and patients with AML with a TP53 mutation. One approach that was proven to be very effective in the relapsed setting of lymphoid malignancies is chimeric antigen receptor (CAR) T cells. It relies on the infusion of genetically engineered T cells capable of recognizing specific epitopes on the surface of leukemia cells. In AML, different CAR constructs with different target antigens have been evaluated and demonstrated safety and feasibility in the R/R setting. However, the difficulty of potently targeting leukemic blasts in AML while sparing normal cells represents a major limitation to their use, and strategies are being tested to overcome this obstacle. A different approach is based on endogenously redirecting the patient's system cells to target and destroy leukemic cells via bispecific T-cell engagers (BiTEs) or dual antigen receptor targeting (DARTs). Early results have demonstrated the safety and feasibility of these agents, and research is ongoing to develop BiTEs with longer half-life, allowing for less frequent administration schedules and developing them in earlier and lower disease burden settings.

Keywords: AML; Azacitidine; BiTE; Checkpoint inhibitors; DART; Immunotherapy; Magrolimab; Nivolumab; Pembrolizumab; TriKE.