Smart Multipurpose Conjugated CAR T cell for Solid Tumor Treatment

Smart Multipurpose Conjugated CAR T cell for Solid Tumor Treatment
Fatemeh Meshkini,^1,* Shahin Hallaj,² Samin Alihosseini,³ Amir Mohammadzadeh,⁴
1. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
2. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
3. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
4. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
Introduction: The development of novel targeted therapies with acceptable safety profiles is critical for successful cancer consequences with better survival rates. Cancer immunotherapy is aimed to enhance immune response against tumor cells. Engineered Chimeric Antigen Receptors (CARs) are genetically engineered receptors that combine the specific binding domains from a tumor targeting antibody with T cell signaling domains that allow specifically targeted antibody redirected T cell activation. Despite this effective consequences in patients with several hematological malignancies, some clinical experiences such as poorly controlled activity, high bystander toxicities and limited life span of conventional CAR T cells, leads to treatment challenges related to CAR T cell therapy specially in solid tumors.
Methods: So we have designed a new multipurpose conjugated engineered CAR T cells that would act more effective, safer and reliable against a wide range of solid tumor cells. In our unique system, we would have scFvs which are personalized to each patient and fused to FcεRI and make a discrete part named εFv, being our switch molecule and is infused separately from CAR T cell. Moreover, our newly designed CAR T cell is flexible which indicates the ability to target different antigens with the desired affinity. Another promising aspect of CAR T cell is its smart targeting which would target multiple distinct tumor-associated antigens simultaneously. And an oxygen-sensitive sub-domain is placed in our system for the specific accumulation of CAR T cells in tumor sites.
Results: In this system we have designed εFv fragments by replacing Fab portion of IgE immunoglobulin with anti-tumor scFv. In order to prevent cross reaction with serum IgE and its receptors on mast cells and basophils, we would also create a mutation in the gene-coding FcεRI and FcIgE. Moreover, we would prepare multiple antibodies with different affinities to determine the specific binding affinity of εFvs based on amount of target antigen expression. At last, genetic manipulations on CAR T cells would be done in order to express FcεRI. So, we would have personalized scFvs fused to FcεRI and make a discrete part named εFv take a role as a switch molecule and is infused separately from CAR T cell. In other words, the smart tunable multi target CAR T cell is being designed to target multiple cancer antigens with different affinities without further demand to design new CAR T Cell. The HIF-1α subdomain is fused to intracellular alpha chain of receptor leads to particular activation of CAR T cell in hypoxic TME, while this subdomain would break down in healthy tissues with normoxic microenvironment. Regarding an important role of PD-1/PDL-1 and CTLA-4 inhibitory pathway in the tumor microenvironment, we would have a combination therapy with FDA-approved antibody against PD-1 and CTLA-4 called Pembrolizumab and Ipilimumab, respectively to increase the efficacy and feasibility of CAR T cells and prevent their exhaustion.
Conclusion: CAR T cell therapy has become a promising practical therapy for patients with hematological malignancies. Nevertheless, as discussed major challenges with conventional CAR T cell therapies in vivo such as the incapability to tune its activity, insufficient trafficking of CAR T cell, limited tumor specific antigens, inhibitory microenvironment of solid tumors, off target toxicity, definite durability of CAR T cells, cytokine release syndrome and immunologic response of the host to the administered cells has led to the treatment-associated side effects. To overcome these limitations and improve patient safety, the use of soluble switch molecules which is not immunogenic encouraged us to develop a newly designed multipurpose CAR T cell that incorporates solutions for all the mentioned challenges in a unique system, as it has the ability to target different antigens with the desired affinity. Regarding the adjustability of conjugated CAR T cell, it will be an excellent opportunity for personalized medicine to get involved in this area and determine the optimum concentrations, regimen, and method of cell therapy for each person. As CAR T cells are newly developed, it is an open field, and there are lots to do to minimize its side effects. Overall, CAR T cells have a bright future ahead in cancer treatment, and it would definitely promote community health in the next ten years.
Keywords: conventional CAR T cell, tumor microenvironment, conjugated CAR T cell, cancer treatment