Acute T-cell lymphoblastic leukemia: chimeric antigen receptor technology may offer a new hope

Abstract

Acute lymphoblastic leukemia (ALL) is a prevalent malignancy affecting the hematopoietic system, encompassing both B-cell ALL (B-ALL) and T-cell ALL (T-ALL). T-ALL, characterized by the proliferation of T-cell progenitors in the bone marrow, presents significant treatment challenges, with patients often experiencing high relapse rates and poor long-term survival despite advances in chemotherapy and hematopoietic stem cell transplantation (HSCT). This review explores the pathogenesis and traditional treatment strategies of T-ALL, emphasizing the promising potential of chimeric antigen receptor (CAR) technology in overcoming current therapeutic limitations. CAR therapy, leveraging genetically modified immune cells to target leukemia-specific antigens, offers a novel and precise approach to T-ALL treatment. The review critically analyzes recent developments in CAR-T and CAR-NK cell therapies, their common targets, optimization strategies, clinical outcomes, and the associated challenges, providing a comprehensive overview of their clinical prospects in T-ALL treatment.

Keywords: CAR-NK; CAR-T; T-ALL; chimeric antigen receptor; pathogenesis.

Figure 1

Pathogenesis of T-ALL. Abnormal changes in molecular pathways (such as NOTCH, IL7-IL7R-JAK-STAT, and PI3K-Akt-mTOR) lead to aberrant T cell proliferation and differentiation, resulting in disease onset, progression, and drug resistance (Malignant mutations are indicated in italics). This figure was drawn using Biorender.

Figure 2

Flowchart of CAR-T therapy for T-ALL: T cells are first isolated from peripheral blood mononuclear cells (PBMC). These T cells undergo gene editing to silence the CAR-targeting antigen gene. Lentiviral vectors are then used to introduce the CAR construct into the T cells, creating CAR-T cells. Once engineered, the CAR-T cells are expanded and infused back into the patient, where they target and kill malignant T cells in vivo. This figure was drawn using Biorender.

Figure 3

Flowchat and mechanistic diagram of CAR-NK therapy for T-ALL: NK cells from various sources are first isolated. Using lentiviral vectors, these NK cells are infected to create CAR-NK cells. Once engineered, the CAR-NK cells are expanded and infused back into the patient. In vivo, they target and kill malignant T cells through multiple mechanisms, including CAR-mediated targeting, Fas/FasL interactions, TRAIL/DR4 pathways, antibody-dependent cellular cytotoxicity (ADCC), and NKG2D/NKG2DL interactions. This figure was drawn using Biorender.