Prospect of CAR T-cell therapy in acute myeloid leukemia

ABSTRACT

Introduction

Long-term outcome of patients with acute myeloid leukemia (AML) remains dismal, especially for those with high-risk disease or who are refractory to conventional therapy. CAR T-cell therapy provides unique opportunity to improve outcome by specifically targeting leukemia cells through genetically engineered T cells.

Areas covered

We summarize the progress of CAR T-cells therapy in AML. We examine its shortcomings in AML therapy and the strategies that are being implemented to improve its safety and effectiveness. PubMed Central, ClinicalTrials.gov, and ASH annual meeting abstracts were searched. Search terms used to identify clinical trials were ‘CAR T-cells in AML’ OR CAR T-cells in leukemia”. Relevant clinical trials and CAR T-cell research data were reviewed from June 2009 till July 2021.

Expert opinion

CAR T-cell therapy has shown promise as a novel therapy, but there are number of barriers to overcome to achieve its full therapeutic potential in AML. Targeting leukemia-specific antigen such as CLL1, to avoid myelotoxicity, incorporating checkpoint inhibitors to overcome leukemia-induced immunosuppression and allogenic CAR T cells to increase accessibility to patients with proliferative disease are among the strategies that are being explored to make CAR T cell a successful immunotherapy for patient with AML.

KEYWORDS:

• CAR T-cells
• acute myeloid leukemia
• gene editing
• myelotoxicity secondary to AML CAR
• allogeneic CAR
• checkpoint inhibitors
• CLL1 CAR T-cells
• CD123/CD33 CAR T-cells

Article highlights

• CAR T-cell therapy in AML is evolving; however, its progress is stalled by off-target myelotoxicity and inadequate CAR T-cell persistence in vivo.

• Gene editing of CD33 on HSPC, enabling selective cytotoxicity of CD33 expressing myeloid blast, holds potential to overcome off-target myelotoxicity.

• Targeting CLL1 antigen for CAR T cell is gaining attraction, which has limited off-target effects and has shown success in early-stage studies.

• Incorporation of immune checkpoint inhibitors to modulate immunosuppressive microenvironment is also being explored to improve CAR T-cell potency.

• Off-the-shelf CAR T-cell from healthy donors is gaining optimism for providing cost-effective, quick access patients with aggressive leukemia.

This box summarizes key points contained in the article.

Author contributions

TB conceptualize and wrote the original draft. AM, MG, MKD, and HQ did review and editing.

Declaration of interest

T Badar has received developmental funds from Mayo Clinic Cancer Center; grant no. P30 CA015083. T Badar also served in advisory board for Pfizer Hematology and Oncology. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers disclosure statement

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.