T-Cell Engagers in Acute Myeloid Leukemia: Molecular Targets, Structure, and Therapeutic Challenges

TL;DR

T-cell engagers are being explored as a new treatment for acute myeloid leukemia, but challenges remain in finding the right targets and managing side effects.

Contribution

This review summarizes the current state of T-cell engager development for AML, focusing on targets, formats, and clinical challenges.

Findings

CD33 and CD123 are the most common targets for T-cell engagers in AML.

TCE formats like BiTEs and DARTs are being developed to improve treatment effectiveness and safety.

No TCEs for AML have advanced beyond early-phase clinical trials due to safety and target limitations.

Abstract

Acute myeloid leukemia remains difficult to treat due to its high relapse rates after standard therapies. T-cell engagers are a promising new approach that redirects the body’s own T cells to attack leukemia cells by binding both T cells and specific markers to AML cells. Targets such as CD33, CD123, and others have been studied. Several TCE formats—including BiTEs and DARTs—are being developed to improve effectiveness and reduce side effects. However, no TCEs in AML have moved beyond early-stage (Phase I/II) clinical trials, mainly due to the lack of an optimal target in AML and safety concerns with immune-related side effects like cytokine release syndrome. This review explores the current progress, key targets, and challenges in developing TCEs for AML treatment.

The treatment of acute myeloid leukemia (AML) remains challenging, largely due to high relapse rates following standard therapies. T-cell engagers (TCEs) offer a promising immunotherapeutic approach by redirecting T cells to recognize and kill AML cells. These therapeutic proteins bind CD3 to T cells and a tumor-associated antigen to AML cells, facilitating targeted immune activation. While CD33 and CD123 are the most commonly targeted AML antigens, others such as CD135, CD38, and CLEC12A/CLL-1 are being evaluated in preclinical and clinical studies. In parallel, various TCE formats—including BiTEs, DuoBodies, DARTs, and DARPin-based constructs—have been developed to optimize pharmacokinetics, stability, and immune engagement. Despite the growing number of TCEs entering clinical evaluation, none have advanced beyond early Phase (I/II) trials, primarily due to the lack of optimal target antigens and challenges in balancing antileukemic activity with the risks of immune-related toxicities such as cytokine release syndrome (CRS). This review aims to summarize the current landscape of TCE development in AML, highlighting key targets, formats, and challenges.