Current Strategies to Improve Chimeric Antigen Receptor T (CAR-T) Cell Persistence

Chimeric antigen receptor T (CAR-T) cell therapy has transformed the field of immunology by redirecting T lymphocytes toward tumor antigens. Despite successes in attaining high remission rates as high as 90%, the performance of CAR therapy is limited by the survival of T cells. T cell persistence is crucial as it sustains immune response against malignancies, playing a critical role in cancer treatment outcomes. This review explores various approaches to improve CAR-T cell persistence, focusing on the choice between autologous and allogeneic cell sources, optimization of culture conditions for T cell subsets, metabolite adjustments to modify T cell metabolism, the use of oncolytic viruses (OVs), and advancements in CAR design. Autologous CAR-T cells generally exhibit longer persistence but are less accessible and cost-effective than their allogeneic counterparts. Optimizing culture conditions by promoting T_SCM and T_CM cell differentiation has also demonstrated increased persistence, as seen with the use of cytokine combinations like IL-7 and IL-15. Metabolic adjustments, such as using 2-deoxy-D-glucose (2-DG) and L-arginine, have enhanced the formation of memory T cells, leading to improved antitumor activity. OVs, when combined with CAR-T therapy, can amplify CAR-T cell penetration and persistence in solid tumors, although further clinical validation is needed. Advances in CAR design from second to fifth generations have progressively improved T cell activation and survival, with fifth-generation CARs demonstrating strong cytokine-mediated signaling and long-lasting persistence. Understanding the underlying mechanisms behind these strategies is essential for maximizing the potential of CAR-T therapy in treating cancer. Further research is needed to improve safety and efficacy and seamlessly integrate the discussed strategies into the manufacturing process.