INTERNATIONAL CONGRESS OF
CancerGenetics
Potential of CAR T-Cell Therapy in Leukemia, Acute Myeloid Leukemia AML
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Neda Zahmatkesh,1,*
1. Msc of Molecular Genetic Department of Genetics, Zanjan Branch, Islamic Azad University, Zanjan, Iran.
- Introduction: Because different patients have different chromosomal abnormalities, gene mutations, or gene fusions, AML is a very heterogeneous disease. In ELN risk stratification, 17 genetic subtypes have been found thus far; however, there could be more molecular entities in the future. The biological functions of the recurring somatic mutations—such as those of signaling and kinase pathway genes—are classified. Uncontrolled cell growth and proliferation are caused by mutations in FLT3, a receptor tyrosine kinase, and KRAS/NRAS, a small GTPase; leukemogenesis is promoted by mutations in JAK2, a tyrosine kinase. There are epigenetic modifiers that encode a DNA methyltransferase enzyme (DNMT3A), isocitrate dehydrogenase enzymes (IDH1/2), and a DNA demethylase (TET2). The mutation in ASXL1 can lead to the alteration of DNA methylation patterns, dysregulation of gene expression, and altered hematopoietic differentiation. The dysregulation of transcription factors (CEBPA, RUNX1, MLL, EVI1.); nucleophosmin (NPM1); and cohesin complex genes can lead to impaired differentiation and uncontrolled cell growth. The initiating leukemogenic NPM1, TET2, and SMC1A mutations emerge in self-renewing cells that Jan et al. 18 The aim of this study was investigating CAR T Cell Therapy in leukemia, acute myeloid leukemia AML.
- Methods: The promise of CAR T cell therapy in leukemia, acute myeloid leukemia (AML), is the title of the current study. It was conducted by scanning academic databases, including Science Direct, Springer, Google Scholar, and PubMed.
- Results: Human leukocyte antigen (HLA) molecules on the surface of leukemic cells present tumour-associated antigens (TAAs), via which T cell receptor (TCR) designed T cells function. Either the cell surface or intracellular expression of the target protein is possible. Compared to CAR T cells, TCR-T cells require less antigens to activate T cells. There are still issues with TCR-T cell immunotherapy for AML that need to be resolved. The main disadvantages are that TAAs may be expressed by non-cancerous cells, which could lead to dose-related toxicity, immune evasion, and on-target and off-tumor toxicities. The drawbacks of using TCR-T cells could be addressed by optimizing the dose of the cells, combining the treatment with exogenous cytokines (IL-21, IL-7, and IL-15), or including genetically modified signaling during cell expansion and demethylating drugs like decitabine. Mispairing of endogenous and exogenous TCR components, which impairs function, is another limitation of TCR transfer. This limitation can be avoided by exchanging the constant regions of human and mouse TCRs or by using codon-optimized cysteine-modified TCRs, in which the T2A sequence links the TCR. An alternative strategy makes use of scFv-containing TCR-like CAR T cells and CAR signaling pathways that identify peptides in the presence of MHC class I molecules. Anti-leukemic activities of TCR-T cells against WT1, PRAME, and HA-1 were shown both in vitro and in a clinical scenario with AML.
- Conclusion: The ability to regulate the immune system and BM niches has been made possible by the great progress in understanding the molecular and cellular underpinnings of AML. CAR T cell therapy for AML is still in its infancy. Other targeted medicines are guided by lessons learned from allogeneic stem cell transplantation, the most successful immune cellular therapy for AML. The absence of an appropriate antigen that is expressed exclusively on AML cells presents one of the main obstacles to the development of CAR T cell therapy for AML. The optimization of CARs will be aided by locating and isolating target antigens that are uniformly and steadily expressed in all leukemic blasts and leukemic stem cells with minimal on-target off-tumor toxicity, by examining intricate interactions within the AML microenvironment, and by locating an appropriate cell source. Advanced techniques for ex vivo production are currently altering the characteristics of the finished product and the in vivo dynamics. With platforms that standardize the best CAR design for the target antigen or antigens by patient-specific immunophenotyping findings, the choice of a suitable carrier cell, and the cellular subtype, personalization in AML should be taken a step further in directed cellular therapies.
- Keywords: CAR T-Cell, leukemia, acute myeloid leukemia AML, T cell receptor
