CAR T Cells for Acute Myeloid Leukemia: State of the Art and Future Directions

Abstract

Relapse after conventional chemotherapy remains a major problem in patients with myeloid malignancies such as acute myeloid leukemia (AML), and the major cause of death after diagnosis of AML is from relapsed disease. The only potentially curative treatment option currently available is allogeneic hematopoietic stem cell transplantation (allo-HSCT), which through its graft-vs.-leukemia effects has the ability to eliminate residual leukemia cells. Despite its long history of success however, relapse following allo-HSCT is still a major challenge and is associated with poor prognosis. In the field of adoptive therapy, CD19-targeted chimeric antigen receptor (CAR) T cells have yielded remarkable clinical success in certain types of B-cell malignancies, and substantial efforts aimed at translating this success to myeloid malignancies are currently underway. While complete ablation of CD19-expressing B cells, both cancerous and healthy, is clinically tolerated, the primary challenge limiting the use of CAR T cells in myeloid malignancies is the absence of a dispensable antigen, as myeloid antigens are often co-expressed on normal hematopoietic stem/progenitor cells (HSPCs), depletion of which would lead to intolerable myeloablation. This review provides a discussion on the current state of CAR T cell therapy in myeloid malignancies, limitations for clinical translation, as well as the most recent approaches to overcome these barriers, through various genetic modification and combinatorial strategies in an attempt to make CAR T cell therapy a safe and viable option for patients with myeloid malignancies.

Keywords: acute myeloid leukemia; adoptive therapy; chimeric antigen receptor; engineered T cells; immunotherapy.

Figure 1

Mechanisms of AML-induced immunosuppression. There are several immunosuppressive pathways that have been described for AML. Both direct and indirect mechanisms can ultimately lead to AML immune escape. (A) Enzymes such as arginase II and IDO can be expressed by AML blasts, leading to production of metabolites that hinder effector cell function and proliferation, while polarizing the tumor microenvironment to become more immunosuppressive by favoring Treg and MDSC expansion. (B) AML blasts can express ectonucleotideases such as CD38, CD39, and CD73 that are involved in the breakdown of ATP and NAD+ to adenosine, which subsequently dampens effector cell function and enhances the activity of immunosuppressive cells. (C) Inhibitory ligands such as PD-L1 and PD-L2 can be expressed by AML blasts, and upon binding with their cognate PD-1 receptor may lead to effector cell suppression. Expression of other inhibitory receptors such as GITR, TIGIT, TIM-3, and CTLA-4 have also been shown in AML. (D) AML blasts are able to produce large amounts of ROS that subsequently trigger apoptosis of effector cells. (E) AML blasts can also downregulate their MHCI and/or MHCII expression, thus impairing their antigen presentation resulting in immune evasion.