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.

Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy

“…6 ). 363 In 1992, Bernstein et al determined that CD33 − precursors isolated from AML patients who underwent long-term culture were non-clonal hematopoietic cells. 364 Later, the findings of Bernstein et al were confirmed when xenotransplantation studies showed that 99% of human AML cells that engrafted into the BM of NOD-SCID mice were CD33 + .…”

“…1 ). 363 Further clinical trials were conducted to determine safety and efficacy of gemtuzumab ozogamicin at lower doses in combination with currently approved therapies, it was shown to prolong OS in AML patients, and it was well tolerated. This led to the approval of gemtuzumab ozogamicin in September 2017 for the treatment of newly diagnosed CD33-positive AML in adults and in pediatrics aged ≥2 years (Fig.…”

CAR-T cell therapy in T-cell malignancies: Is success a low-hanging fruit?

“…This incidence results in impaired CAR-T persistence and antitumor effects [21]. Alongside the well-known CAR-T-targeted T-cell neoplasm antigens, there are also other target antigens whose targeting might be beneficial in T-cell malignancies, even if with case-to-case variability [22,23]. For instance, the aberrant expression of myeloid markers such as CD13 and CD33 has been detected in precursor T-cell leukemias which may presage a poor prognosis in comparison with T-cell leukemia cases without the expression of myeloid antigens [22,23].…”

“…Alongside the well-known CAR-T-targeted T-cell neoplasm antigens, there are also other target antigens whose targeting might be beneficial in T-cell malignancies, even if with case-to-case variability [22,23]. For instance, the aberrant expression of myeloid markers such as CD13 and CD33 has been detected in precursor T-cell leukemias which may presage a poor prognosis in comparison with T-cell leukemia cases without the expression of myeloid antigens [22,23]. Such alternative target antigens might also be considered as immunotherapy targets alongside the conventional T-cell malignancy target antigens for achieving improved clinical responses.…”

Recent Clinical Update of Acute Myeloid Leukemia: Focus on Epigenetic Therapies

“…Recently, along with the advancement of cancer immunotherapy, chimeric antigen receptor T cell (CAR-T) therapy targeting AML cells is undergoing active development. 3 The treatment strategy for AML is changing from being limited to only 2 options (cytotoxic chemotherapy followed by HSCT or hypomethylating agent) to the availability of various novel target therapies.…”