Overcoming Resistance and Relapse in CAR-T and CAR-NK Cell Therapies: From Bench to Bedside

As pioneering immunotherapy approaches, chimeric antigen receptor T cell (CAR-T) and natural killer cell (CAR-NK) therapies have shown notable clinical effectiveness when addressing different kinds of hematologic malignancies. For example, the application and efficacy of CAR-T cell therapy in acute lymphocytic leukemia, large B cell lymphoma, mantle cell lymphoma, and multiple myeloma have been widely recognized. In addition, the safety and feasibility of CAR-NK therapy when used to treat refractory/recurrent large B cell lymphoma have been verified. In particular, CD19-targeted CAR-T cell therapy has achieved marked efficacy and breakthrough progress in treating relapsed and refractory B cell leukemia and lymphoma. Although CAR-T cell therapy has achieved significant effectiveness in treating these diseases, patients still face challenges, including primary resistance and secondary recurrence after treatment. The complex mechanisms of resistance and recurrence involve multiple factors, such as target cells, CAR cell characteristics, and immune suppression conditions. This review examines resistance and recurrence mechanisms in CAR-T and CAR-NK therapies while exploring current therapeutic strategies and future research directions.