Fine-Tuning through Generations: Advances in Structure and Production of CAR-T Therapy

SIMPLE SUMMARY: Chimeric antigen receptor (CAR)-T cell therapy has been highly successful in treating hematological malignancies like leukemia and lymphoma, leading to advancements in immunotherapy. The approval of anti-CD19 CAR-T cells by the FDA in 2017 has paved the way for CAR-T therapies to be extended to various cancers, autoimmune disorders, viral infections, and fibrosis. However, the therapy faces challenges, including severe side effects like cytokine release syndrome and graft-versus-host disease. Additionally, CAR-T therapy has limited efficacy against solid tumors and antigen escape, poor persistence, and difficulties in industrialization. Overall, this review provides a comprehensive understanding of the challenges and opportunities associated with CAR-T cell therapy, highlighting the need for further advancements in CAR-T cell construction and production. By facilitating future research and development, CAR-T therapy has the potential to become a powerful tool in the fight against cancer and other diseases. ABSTRACT: Chimeric antigen receptor (CAR)-T cell therapy is a promising form of immunotherapy that has seen significant advancements in the past few decades. It involves genetically modifying T cells to target cancer cells expressing specific antigens, providing a novel approach to treating various types of cancer. However, the initial success of first-generation CAR-T cells was limited due to inadequate proliferation and undesirable outcomes. Nonetheless, significant progress has been made in CAR-T cell engineering, leading to the development of the latest fifth-generation CAR-T cells that can target multiple antigens and overcome individual limitations. Despite these advancements, some shortcomings prevent the widespread use of CAR-T therapy, including life-threatening toxicities, T-cell exhaustion, and inadequate infiltration for solid tumors. Researchers have made considerable efforts to address these issues by developing new strategies for improving CAR-T cell function and reducing toxicities. This review provides an overview of the path of CAR-T cell development and highlights some of the prominent advances in its structure and manufacturing process, which include the strategies to improve antigen recognition, enhance T-cell activation and persistence, and overcome immune escape. Finally, the review briefly covers other immune cells for cancer therapy and ends with the discussion on the broad prospects of CAR-T in the treatment of various diseases, not just hematological tumors, and the challenges that need to be addressed for the widespread clinical application of CAR-T cell therapies.