CAR T cells : potential therapeutic option of multiple cancers

CAR T cells : potential therapeutic option of multiple cancers
Melika Lotfi,^1,*
1. Zanjan University of Medical sciences
Introduction: CAR T cell therapy, as a novel immunotherapy approach, has indicated successful results in the treatment of hematological malignancies; however, distinct results have been achieved regarding solid tumors. Tumor immunosuppressive microenvironment has been identified as the most important barrier in CAR T cell therapy of solid tumors. Developing novel strategies to augment the CAR T cell safety and efficacy could be useful to overcome the solid tumor hurdles. CAR T cell therapy, similar to other cancer treatments, can cause some side effects which can disturb the healthy tissues. In this review, we will discuss the effective breakthroughs in CAR T Cell therapeutic approaches by using the multi-targeted and programmable CAR T cells instead of conventional CAR T cells. These superior types of CAR T cells have been developed to increase the T cells' functionality and safety in a controllable manner. Also, by the use of multi-targeted and programmable CAR T cells, the incidence of side effects would be diminished. Moreover, we will describe the capability of these powerful CARs in targeting multiple tumor antigens, redirecting the CAR T cells into specific target cells, incrementing the safety of CARs, and other advantages that lead to promising outcomes in improving the CAR T cell therapy of cancers.
Methods: Searching online on google scholar, PubMed, and Scopus based on the keywords including Chimeric antigen receptor T cell, CAR T cells, cancer, and malignancy.
Results: Cancer is the most substantial death cause in the world, with several unknown complex mechanisms that usually lead to treatment failure. Based on immunotherapy, diverse treatment approaches have been developed to improve the success rate of cancer treatment in recent years. Adoptive cell therapy (ACT), as an immunotherapy strategy, has been developed to target the tumor cells by using the patient's immune cells after ex-vivo engineering and expansion . Interestingly, chimeric antigen receptor T cell therapy (CAR T cell), as an ACT therapy, emerged as a breakthrough in cancer remission during recent years. The chimeric antigen receptor is a recombinant receptor that is composed of the antigen-binding portion and T cell function portion. The antigen-binding domain usually is originated from tumor antigen-specific monoclonal antibody named ScFv. The functional domain consists of a signaling domain with or without the co-stimulatory domain. CAR T cells are clustered into four-generations based on having or not having the co-stimulatory domain. The CAR T cell proliferation, cytotoxicity, and persistence in tumor sites are improved in the 2nd, 3rd, and 4th generations. To date, Chimeric Antigen Receptor (CAR) T cell therapy has made revolutions in the treatment of refractory and/or relapsed (R/R) hematological malignancies. Targeting CD19 antigen on B cells has demonstrated long-lasting remissions in some B cell lymphoid malignancies such as non-Hodgkin Lymphoma (NHL) and Acute Lymphocytic Leukemia (ALL). Although encouraging results using CAR T cells have been indicated in hematological, limited efficacy has been demonstrated in solid tumors. The most important limiting cause is the presence of an immunosuppressive microenvironment in solid tumors. Despite abundant obstacles in solid tumors, some improvement strategies have been developed to engineer powerful CAR T cells to overcome solid tumors. Given that the CAR T cell therapy, the same as other treatments, causes some side effects which may lead to healthy tissue damage, it is critical to enhancing their specificity and security. Since conventional CAR T cells are designed with fixed specificity to target a specific tumor antigen without any potential to regulate their function. On the basis of this, some adjusting mechanisms have been developed to control the CAR T cell performance and inactivate it after tumor cell elimination. The multi-targeted and programmable CAR T cells are the most momentous regulation strategies promoting the safety and specificity of the CAR T cells. Most of them can also target multiple tumor antigens accurately and simultaneously, which leads to tumor elimination more efficient than targeting a single antigen by classical CARs. In this study, we will discuss distinct types of multi-targeted and programmable CAR T cells and the plentiful advantages of using them investigated in several studies previously.
Conclusion: CAR T cell therapy has demonstrated promising results in hematological cancers. However, in solid tumors, the low success of CAR T cell therapy has been reported due to the existence of several barriers. To overcome the hurdles of CAR T cell therapy in solid tumors, new approaches have been developed to armor the CAR T cell. Genetically alteration of the CAR T cell or the utilization of the regulatory mechanisms is some examples (4, 9). Production of conventional CAR T cells requires autologous T cells to engineer, which takes a long time, high cost, specialist individuals, and intricate equipment. Also, the lack of regulation system in Conventional CARs can lead to a high incidence of side effects, which is caused by the uncontrolled overactivity of CAR T cells. Some regulatory methods have been developed to manage the CAR T cell function, such as genetically modification of CARs, designing inhibitory CARs, editing CAR T cells using CRISPR/Cas9 system, designing on-switch/off switch mechanisms, and suicide genes. These approaches have been applied to improve the performance and safety of CAR T cells. Multi-targeted and programmable CAR T cells include Dual CAR, Tandem CAR, SynNothch CAR, Universal CAR, and SUPRA CARs, are a new generation of CAR T cells with a flexible receptor that can target various tumor antigens concurrently with high efficacy and low toxicity. Moreover, other useful programmable CAR structures consist of Physiological CAR, split CAR, and TRUCK cells that can hopefully improve the CAR T cell therapeutic approaches. According to several previous studies, the activity of the mentioned CAR T cells is regulated through the split structure of the receptor or other manageable mechanism that decreases the common side effects of CAR T cells. Additionally, more effective cytotoxicity, high concentration of cytokines production, long persistence of T cells, overcoming the antigen tumor escape, enclosed anti-tumor responses to the tumor microenvironment, and low incidence rate of "on-target/off-tumor toxicity are the superior advantages of using Multi-targeted and programmable CAR T cells compared to conventional CARs. Despite the related advantages to mentioned smart CAR T Cells, various measures and investigations about their efficacy and safety should be performed. Most of the multi-targeted CARs have the capability of eliminating tumor cells, which only present two or multiple antigens but no ones with expressing a single antigen. Therefore, it is better to say that some questions about the efficacy of multi-targeting CAR designing are unanswered. Additionally, target antigen loss is the only immune escape mechanism that multi-targeted CARs can solve it. Immunogenicity is another critical issue that should be considered due to the generation of unwanted autoimmune responses like human anti-mouse IgG antibodies (HAMAs), which can lead to anaphylaxis. To solving this problem, CAR T cells can be designed by the use of ScFv derived from humanized or human monoclonal antibodies. Further, using the autologous T cells instead of allogenic ones can improve the safety and efficacy of CAR T cells. CAR T cells proliferation and persistence are the other two crucial challenges required for the durable of CAR T cells in the tumor microenvironment during tumor eradication. For this reason, engineered CAR T Cells with long-live can increase the CAR T Cells' survival. In conclusion, the development of these dominant types of CAR T cells can significantly increase the CAR T cell efficacy and safety as a practical immunotherapy approach for various cancers treatment; however, our information about the in vivo function of these CARs and related side effects is limited. So, more studies in this field would be required.
Keywords: Chimeric antigen receptor T cell, CAR T cells, cancer, and malignancy.