Chimeric Antigen Receptor (CAR)-Modified Immune Effector Cell Therapy for Acute Myeloid Leukemia (AML)

SIMPLE SUMMARY: Adoptive cell transfer with chimeric antigen receptor (CAR)-modified immune effector cells (IECs) has quickly emerged as a paradigm-shifting approach for the management of B cell malignancies given its ability to induce high rates of remission. This is reflected by the regulatory approval of three CD19-directed CAR T cell products to date for the treatment of several non-Hodgkin lymphomas and pediatric/young adult B-acute lymphoblastic leukemia (B-ALL). While fueled by this success, the use of CAR-modified IECs in acute myeloid leukemia (AML) is still in its infancy, with recognized challenges involving the selection of suitable target antigens, immune resistance due to a hostile tumor microenvironment, and potentially fatal toxicity to normal cells, in particular hematopoietic cells. Here, we will summarize the emerging landscape and therapeutic challenges with the use of such cells in patients with AML. ABSTRACT: Despite the availability of an increasing number of targeted therapeutics and wider use of allogeneic hematopoietic stem cell transplantation, many patients with acute myeloid leukemia (AML) ultimately succumb to this disease. Given their remarkable efficacy in B-acute lymphoblastic leukemia and other CD19-expressing B cell malignancies, there is hope adoptive cellular transfer, particularly chimeric antigen receptor (CAR)-modified immune effector cell (IEC) therapies, may afford a novel, potent immune-based approach for the treatment of AML that complements or replaces existing ones and improves cure rates. However, it is unclear how best to translate the success of these therapies from B cell malignancies, where use of highly potent immunotherapies is facilitated by identified target antigens with near ubiquitous expression on malignant cells and non-fatal consequences from “on-target, off-tumor cell” toxicities. Herein, we review the current status of CAR-modified IEC therapies for AML, with considerations regarding suitable, relatively leukemia-restricted target antigens, expected toxicities, and interactions of the engineered cells with a profoundly immunosuppressive tumor microenvironment that restricts their therapeutic efficacy. With these challenges in mind, we will discuss possible strategies to improve the cells’ potency as well as their therapeutic window for optimal clinical use in AML.