In vivo CAR T cell therapy; An alternative solution

The chimeric antigen receptor(CAR) therapy has been a revolution in the treatment of relapsed/refractory hematological malignancies.Also,today this technology is used to treat autoimmune diseases such as Systemic lupus erythematosus (SLE)and infectious diseases such as HIV.During the manufacturing process of CAR T cell,T lymphocytes are collected, received receptors to recognize target cells, often using viral vectors.Then they are reinjected to the body.Given the tremendous potential of CAR T cells, it has been accompanied by many challenges. To prepare the patient, lymphodepletion is carried out with special regimen including cyclophosphamide and fludarabine in order to reduction endogenous lymphocytes, which may expose the patient to various infections.Viruses used to manufacture CAR T cells can also cause immunogenicity.Solid tumor resistance,cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are the other limitations of using in vitro CAR T cells. Among the solutions offered to overcome some of these limitations is the manufacture of CAR T cells in vivo. Methods:Scopus, Pub Med and Google Scholar were searched with four key words up to September ۲۰۲۴.A total of ۱۵ articles were selected based on inclusion and exclusion criteria. Results:In order to In vivo manufacture of CAR T cell, genetic information of CAR construction is delivered to the cells in the form of mRNA,pDNA or RNP with the help of gene editing tools such as CRISPR/Cas۹.This strategy bypasses the time-consuming high cost process of in vitro CAR T cell.Besides remaining cells inside the body and not being exposed to supra-physiological levels, reduces the possibility of complications such as CRS.The use of CRISPR/Cas۹ will have positive effects on CAR T cell activity.Disrupting inhibitory receptors and immune checkpoints such as PD۱ increases the resistance of CAR T cells against tumor cells. The genetic cargo must be able to be preserved in the blood and properly reach the target cell. The recent use of Lipid nano particles (LNPs) containing mRNA to construct Pfizer-BioNTech and Moderna vaccines against COVID-۱۹ has shown the possibility of mass production and safety of this gene delivery system.In vivo CAR T cells production also has its own limitations.Off-target effect is one of the challenges that have been proposed to increase the specificity of CAR T cells to cancer cells with the help of safety switches or dual-targeting strategies. Also, the power of complete eradication of cancer cells is less compared to in vitro CAR T cells, so enhancing T cell expansion protocols,or incorporating co-stimulatory molecules have been suggested to solve this problem. For more precise control of T cell expansion and modification, real-time imaging or biomarker tracking, which are advanced monitoring methods, can be used. Conclusion:In-vivo CAR therapy as an off-the-shelf treatment overcomes many limitations related to drug production and patient preparation which existed in the in vitro system.Considering that all the processes of preparing the modified immune cells are done inside the body,it is more difficult to control the correct progress of the treatment compared to the in vitro method,and it has its own challenges that require more detailed designs and more controls.

کلیدواژه ها:

Chimeric antigen receptor ، In vivo CAR T cell ، In vitro CAR T cell ، Adoptive cell therapy