A general view of CD33+ leukemic stem cells and CAR-T cells as interesting targets in acute myeloblatsic leukemia therapy

Abstract

Acute myeloblastic leukemia (AML) is the most frequent acute leukemia in adulthood with very poor overall survival rates. In the past few decades, significant progresses had led to the findings of new therapeutic approaches and the better understanding of the molecular complexity of this hematologic malignancy. Leukemic stem cells (LSCs) play a key role in the initiation, progression, regression, and drug resistance of different types of leukemia. The cellular and molecular characteristics of LSCs and their mechanism in the development of leukemia had not yet been specified. Therefore, determining their cellular and molecular characteristics and creating new approaches for targeted therapy of LSCs is crucial for the future of leukemia research. For this reason, the recognition of surface maker targets on the cell surface of LSCs has attracted much attention. CD33 has been detected on blasts in most AML patients, making them an interesting target for AML therapy. Genetic engineering of T cells with chimeric antigen receptor (CAR-T cell therapy) is a novel therapeutic strategy. It extends the range of antigens available for use in adoptive T-cell immunotherapy. This review will focus on CAR-T cell approaches as well as monoclonal antibody (mAB)-based therapy, the two antibody-based therapies utilized in AML treatment.

Keywords: Acute myeloblastic leukemia; CAR-T cell; CAR-T cell immunotherapy; CD33+ leukemic stem cells; Cancer stem cells; mAB-based therapy.

Fig. 1. Suggested models of AML transformation. Three suggested scenarios of step by step transformation in human AML, leading from a normal cell (orange) to a premalignant cell (pink) and, finally, to a malignant cell (brown) with clonal expansion: Scenario 1; both the initial transforming incident and following mutations leading to clonal expansion occur at the level of multipotent precursors; Scenario 2; the initial transforming incident occurs at the level of multipotent precursors, whiles the cooperating mutational event leading to clonal expansion occurs at the level of committed myeloid progenitors; and Scenario 3; both initial and following mutations occur at the level of committed myeloid precursors [2].

Fig. 2. (A) Chimeric antigen receptor (CAR). CARs include of an extracellular domain created by attaching the light and heavy chain variable regions of a monoclonal antibody with a linker to form a single-chain Fv (scFv) molecule. The scFv is attached via a hinge region to the transmembrane and intracellular receptor portion. The three generation of CARs has been shown. (B) Innovative CAR design. Suicide gene strategies are investigated as control mechanisms for better toxicity management of CAR T cells. The inducible caspase 9 (iCasp9) is one of the example in this field. The details are explained in Hoffman et al. (2019). In brief, when the small molecule is administered, iCasp9 domains activate apoptosis independently of CAR activation. Bispecific CARs bear two linked scFV within one CAR construct, whereas dual CARs express two different antigen-specific CARs. TCR-mimic (TCRm) CARs directing the scFv domain against a peptide- human leukocyte antigen (HLA) complex have been developed for addressing the HLA [5].

Fig. 3. CAR T-cell therapy for AML.