Acute myeloid leukemia chimeric antigen receptor T-cell immunotherapy: how far up the road have we traveled?

Abstract

Chemotherapy resistance and relapse remain significant sources of mortality for children and adults with acute myeloid leukemia (AML). Further intensification of conventional cytotoxic chemotherapy is likely not feasible due to the severity of acute and long-term side effects upon normal tissues commonly induced by these drugs. Successful development and implementation of new precision medicine treatment approaches for patients with AML, which may improve leukemia remission and diminish toxicity, is thus a major priority. Tumor antigen-redirected chimeric antigen receptor (CAR) T-cell immunotherapies have induced remarkable responses in patients with relapsed or chemorefractory B-lymphoblastic leukemia, and similar strategies are now under early clinical study in adults with relapsed/refractory AML. However, potential on target/off tumor toxicity of AML CAR T-cell immunotherapies, notably aplasia of normal myeloid cells, may limit broader implementation of such approaches. Careful selection of optimal target antigens, consideration of toxicity mitigation strategies, and development of methodologies to circumvent potential CAR T-cell resistance are essential for successful implementation of cellular immunotherapies for patients with high-risk AML.

Prevention of relapse after allogeneic stem cell transplantation in acute myeloid leukemia: Updates and challenges

“…Chimeric antigen receptor T‐cell constructs targeting CD123, CD33, CD38, folate receptor β, FLT3, and NKG2D are in clinical trials and the results of these trials are eagerly awaited …”

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…Given that a long-term pan-myeloablation following AML-directed CAR T cells infusion may not be tolerable, unlike B cell aplasia due to CD19targeted therapy, different solutions are being tested (68). AlloHSCT represents the logical rescue strategy, but the persistence of even a few CAR T cells after transplantation could lead to graft rejection (67). Therefore, some groups explored the possibility of developing short-term living CAR T cells as a "bridge to transplant".…”

Current challenges for CAR T‐cell therapy of acute myeloid leukemia

“…Several alternative target antigens have been used in CAR‐based immunotherapy of AML including CD174 (Lewis‐Y antigen), CD44v6, CLL‐1 (CLEC12A), CD7, folate receptor beta (FRβ), and CD135 (FLT3 receptor). T cells expressing CARs against these molecules have shown promising antileukemia activity in vitro and in in vivo models, and the list of potential target molecules that are under preclinical evaluation is continuously expanding . However, none of the molecules proposed are exclusively expressed on leukemic blasts—they are also detectable on progenitor and/or mature hematopoietic cells, for example, CD7 on T cells or CLL‐1 on monocytes, and in some cases on cells of nonhematopoietic tissues, for example, CD44v6 on keratinocytes and CD135 on neurons.…”

“…T cells expressing CARs against these molecules have shown promising antileukemia activity in vitro and in in vivo models, and the list of potential target molecules that are under preclinical evaluation is continuously expanding. 4 However, none of the molecules proposed are exclusively expressed on leukemic blasts-they are also detectable on progenitor and/or mature hematopoietic cells, for example, CD7 on T cells or CLL-1 on monocytes, and in some cases on cells of nonhematopoietic tissues, for example, CD44v6 on keratinocytes and CD135 on neurons. Thus, prolonged on-target/off-tumor toxicity due to persisting CAR T cells remains a legitimate concern and will likely require CAR T-cell termination approaches to limit toxicity.…”