مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
Potential Risks of Unintended Cellular Expansion in Cell Therapy: Genotoxicity and Tumorigenesis
Potential Risks of Unintended Cellular Expansion in Cell Therapy: Genotoxicity and Tumorigenesis
Marziyeh Esmaeilzadeh Kashi,1,*
1. Iran university of medical sciences institue of endocrinology and metabolism
Introduction: Cell therapies, particularly those using gene-manipulated hematopoietic stem/progenitor cells (HSPCs) and targeted engineered T cells such as CAR-T cells, have revolutionized the management of the vast majority of cancers. Uncontrolled growth of such cells following infusion, though, has created serious safety concerns, such as genotoxicity and tumorigenesis, primarily due to viral vector insertion and potential clonal dominance by mutant cells.
Methods: A strict examination of recent scientific publications was undertaken and utmost care was taken in the case of peer-reviewed publications like PubMed, ScienceDirect, and Scopus. Careful selection of model papers taking into account vector safety, in vivo tumorigenicity testing, and adverse cellular growth effects was made since they pertained to cell therapy genotoxicity and tumorigenesis.
Results: Grafting of viral vectors like lentiviral and gamma-retroviral vectors has been linked to insertional mutagenesis and at least disrupts tumor suppressor genes or activates oncogenes. Leukemias that occur in some patients from induced leukemias by early gamma-retroviral vector trials in diseases like X-linked severe combined immunodeficiency (XSCID) have been proved. Though safer under most circumstances, lentiviral vectors are genotoxic and especially so when used in HSPC-based therapies. Uncontrolled cell growth with faulty genes may result in clonal overgrowth and enhance the risk of malignant transformation. It has been disproven that mature T cells are untransformable by the demonstration of gene-manipulated T cells with evidence of malignant transformation. This justifies the appropriateness of watchfulness on strict adherence to cell growth after infusion. Soft agar colony-forming assay (SACF) and in vivo and in vitro models are currently used to evaluate tumorigenicity. While these are useful in preclinical safety assessment, they cannot predict long-term effects in human beings either. To establish the safety of gene-transduced cell therapy, more predictive biomarkers and models need to be accelerated.
Conclusion: Though cell-based therapies hold promise for treatment, genotoxicity and carcinogenesis by virtue of induction of undesired proliferation of mutagenic cells pose severe threats. To curtail such threats, stringent safety measures have to be followed, such as extensive preclinical assessment and continuous monitoring of the patients. Genome editing drugs like CRISPR/Cas9 and newer safer drugs being developed and vector design like inactivating vectors can decrease the incidence of off-target events. More research and development must be undertaken to ensure cell-based therapies are both safe and effective.