Chimeric antigen receptor T cells for acute myeloid leukemia

Abstract

The use of T cells expressing chimeric antigen receptors (CARs) that can target and eliminate cancer cells has revolutionized the treatment of B‐cell malignancies. In contrast, CAR T cells have not yet become a routine treatment for myeloid malignancies such as acute myeloid leukemia (AML) or myeloproliferative neoplasms (MPNs). For these disease entities, allogeneic hematopoietic cell transplantation (allo‐HCT) relying on polyclonal allo‐reactive T cells is still the major cellular immunotherapy used in clinical routine. Here, we discuss major hurdles of CAR T‐cell therapy for myeloid malignancies and novel approaches to enhance their efficacy and reduce toxicity. Heterogeneity of the malignant myeloid clone, CAR T‐cell induced toxicity against normal hematopoietic cells, lack of long‐term CAR T‐cell persistence, and loss or downregulation of targetable antigens on myeloid cells are obstacles for successful CAR T cells therapy against AML and MPNs. Strategies to overcome these hurdles include pharmacological interventions, for example, demethylating therapy to increase target antigen expression, multi‐targeted CAR T cells, and gene‐therapy based approaches that delete the CAR target antigen in the hematopoietic cells of the recipient to protect them from CAR‐induced myelotoxicity. Most of these approaches are still in preclinical testing but may reach the clinic in the coming years. In summary, we report on barriers to CAR T‐cell use against AML and novel therapeutic strategies to overcome these challenges, with the goal of clinical treatment of myeloid malignancies with CAR T cells.

Innovations in conditioning and post-transplant maintenance in AML: genomically informed revelations on the graft-versus-leukemia effect

“…Challenges in the myeloid space include the identification of antigens which can be targeted on leukemic clones while sparing healthy hematopoietic stem cells and precursors. Recent advances in target identification and selection are showing promise in realizing this specificity, and we refer readers to a recent review summarizing this rapidly evolving field ( 200 , 201 ). Yao and colleagues report a case utilizing donor CD123 CAR-T as part of reduced intensity conditioning prior to haploidentical transplantation in a highly aggressive leukemia relapsing post allogeneic transplantation ( 153 ).…”

Broadening the horizon: potential applications of CAR-T cells beyond current indications

“…Acute myeloid leukemia (AML) comprises a group of acute hematologic malignancies that arise from myeloid precursor cells and is often associated with a variety of genetic aberrations. As AML is the second most common type of leukemia in adults, there are numerous approaches to make this type of disease feasible to CAR-T-cell therapy ( 108 , 109 ). Previous studies using CAR-T-cell therapy in AML patients have shown that the technique could prove a potentially valid strategy for patients with relapsed or refractory disease ( 110 – 114 ), a patient group that currently has only very limited therapy options.…”

Mechanisms of leukemic stem cell interaction in AML: insights from complementary mathematical modeling approaches.

“…However, chemotherapeutic treatment is generally not curative as a typically small fraction of the malignant cells remains and eventually fuels disease recurrence 8 . There is a widespread hope that the recent introduction of targeted therapies or immunotherapies can improve treatment success by specifically eliminating cells with certain genetic mutations or enhancing the immune system's ability to fight the malignant cell pool [11][12][13] . However, as of now the only curative option for AML patients is allogeneic hematopoietic stem cell transplantation (SCT).…”