Breaking the relapse barrier: innovative approaches to improve CAR T-cell efficacy by targeting leukemic stem cells (LSCs) and measurable residual disease (MRD) in acute myeloid leukemia.

Abstract

Acute Myeloid Leukemia (AML) is biologically heterogeneous, clinically aggressive and is characterized by the uncontrolled clonal expansion of immature myeloid progenitors in the bone marrow microenvironment. Despite the achievement of remission with frontline treatments, relapse is disturbingly common and is the major determinant of therapeutic failure and patient mortality. Underlying this recurrence is the insidious partnership between leukemic stem cells (LSCs) and measurable residual disease (MRD) cells, which are rare, therapy-refractory cells that reside deep in the bone marrow niche and are protected by cellular and molecular signals that support immune evasion and survival. These malignant reservoirs are the silent relapse architects that launch disease recurrence even in clinically disease-free patients. Advances in cellular immunotherapy have revealed the promise of Chimeric Antigen Receptor (CAR) T cells as precision-guided bullets that break through this sanctuary. With the specific modification of CAR T cells to specifically recognize and target LSCs and MRD, it is now possible to target the real cause of AML persistence. This review critically reviews the molecular signatures and protective mechanisms of relapse-initiating cells and introduces innovative CAR T cell engineering strategies, especially hypoxia-responsive, multi-target, logic-gated, and armored CAR approaches that are aimed at disrupting the bone marrow niche, eliminating malignant stemness, overcoming exhaustion of engineered T cells and redefining the therapeutic horizon of AML.