Challenges and Prospects of CAR-T Cells in Cancer Immunotherapy

Introduction The landscape of cancer treatment became significantly changed by immunotherapy over the past decade, leading to FDA approval of numerous immunotherapeutic. Chimeric antigen receptor (CAR) T-cell therapy, has numerous advantages, including targeted cancer cell destruction, a high significant remission rate of cancer-induced symptoms, rapid tumor eradication, and long-lasting tumor immunity, opening up a new window for tumor treatment. However, challenges remain in CAR T-cell therapy for solid tumors due to the target diversity, tumor heterogeneity, and the complex tumor microenvironment. To address these issues, we need to develop innovative ways to produce more potent CAR-T cells with increased anti-tumor activity and less toxicity. Methods Articles describing major limitations of CAR-T cell therapy and potential strategies to overcome those limitations from various databases such as PubMed, Scopus, and ScienceDirect between ۲۰۱۴ to ۲۰۲۴ were reviewed and evaluated for their significance. Results Despite CAR-T cell therapy has shown remarkable outcomes in individuals with some subtypes of B cell leukemia and lymphoma, numerous challenges restrict CAR-T cells from being an effective therapy for solid tumors and hematological malignancies. Antigen escape is one of the limitations of CAR-T cell therapy. The potential strategy for this problem is targeting multiple antigens by dual or tandem CARs, as shown by clinical trial results of CD۱۹/CD۲۲ targeted CARs for treatment of ALL/DLBCL. Targeting tumor-restricted post-translational modifications is the strategy that has been used to address the challenge of on-target off-tumor toxicity. Regarding this issue, researchers have investigated four major CAR-T cell targets including TAG۷۲, B۷-H۳, MUC۱,and MUC۱۶. The third problem is CAR-T cell trafficking and tumor infiltration; therefore, local vs. systemic delivery administration should be considered, as intrapleural and intraventricular injections of CAR-T cells demonstrated superior therapeutic efficacy in mesothelioma and glioblastoma/brain cancer patients, respectively. Combination immunotherapy using CAR-T cells and checkpoint blockade can address the immunosuppressive microenvironment, another potential problem. Combining PD-۱ blockade with CD۱۹ CAR-T cells in B-ALL patients enhanced outcomes as well as CAR-T cell persistence. Additionally, it is possible to engineer CARs to produce immunostimulatory signals by secreting IL-۱۲, expressing IL-۱۵, and redirecting immunosuppressive cytokines (IL-۴), which can improve the cell survival, proliferation, and anticancer effects. Another problem is the toxicities associated with CAR-T cells. To address this challenge, a CAR "off-switches" system should be engineered to prevent cells from being activated before severe side effects occur. Universal CAR-T cells (SUPRA CAR) are the most recent platform for targeting multiple tumor antigens, avoiding the expensive manufacturing process of engineering T cells for each new target. Finally, gene editing technologies for producing universal CAR-T cells from healthy donors might be used as an allogeneic non-matched donor treatment, eliminating the requirement for harvesting from strongly treated patients and reducing the risk of leukemic blast transduction. Currently, it has been used in various clinical trials, including UCART۰۱۹, CTX۱۳۰, and CTX۱۲۰ that targeting CD۱۹, CD۷۰, BCMA, respectively. Conclusion Effective CAR-T cell therapy is constrained by life-threatening toxicities, inadequate antitumor efficacy, antigen escape, limited trafficking, and restricted tumor infiltration. This review summarizes novel approaches to generate more potent CAR-T cells that exhibit improved anti-tumor efficacy while reducing toxicity.

کلیدواژه ها:

Cancer Immunotherapy ، Targeted therapy ، Chimeric antigen receptor(CAR) T cell ، Universal CAR-T cell