Checkpoint Inhibitors and Other Immune-Based Therapies in Acute Myeloid Leukemia

Abstract

Immune checkpoint inhibitors have been investigated in acute myeloid leukemia (AML) with an intent to harness the immune microenvironment components to generate an immune response against leukemia. Anti-cytotoxic T-lymphocyte-associated antigen 4 and anti-programmed cell death 1/programmed cell death ligand 1 antibodies have been evaluated in combination with low-intensity therapy and cytotoxic chemotherapy, both in the pretransplant and posttransplant settings. Although the objective response rates with programmed cell death 1-and programmed cell death ligand 1-based therapies have been relatively low, durable stable disease and hematologic improvement were noted in a subset of patients, important endpoints in patients with limited therapeutic options. Novel AML and myelodysplastic syndrome-specific checkpoints such as TIM3 antibodies in combination with azacitidine are showing encouraging efficacy, especially durability of response, in ongoing studies. Anti-CD47/SIRPα therapy in combination with azacitidine has shown encouraging efficacy and safety in frontline AML, especially in TP53-mutated AML, a population of significant unmet need. Other T cell-based immune therapies are under investigation. T-cell and natural killer cell bispecific and trispecific engagers have shown modest activity in patients with relapsed and/or refractory AML albeit with frequent cytokine release syndrome. Chimeric antigen receptor T-cell therapy showed immense success in many lymphoid malignancies and is being evaluated in AML. Future trials should be designed to select patients based on markers of response and tailor therapies according to predictive biomarkers.

Preclinical Characterization of the Anti-Leukemia Activity of the CD33/CD16a/NKG2D Immune-Modulating TriNKET® CC-96191

“…The success of T cell-engaging bispecific antibodies (BsAbs) in lymphoid malignancies has raised enthusiasm for similar therapeutics in AML-targeting CD33. Several CD33/CD3 BsAbs have entered clinical testing, with initial results indicating some efficacy [ 17 , 18 , 19 , 20 , 21 ]. However, toxicities from activated T cells cause significant challenges for their use, providing a strong rationale to explore drugs engaging other immune cells such as natural killer (NK) cells that might elicit potent anti-AML activity more safely due to their production of reduced levels of cytokines compared with T cells and their ability to discriminate healthy and malignant cells [ 22 , 23 , 24 , 25 , 26 ].…”