Chimeric Antigen Receptor-T Cell Therapy in Hematological Malignancies: Clinical Evidence and Challenges

Abstract

Chimeric antigen receptor-T (CAR-T) cell therapy has revolutionized the treatment of hematological malignancies, offering remarkable clinical responses in patients with refractory or relapsed disease. However, challenges such as toxicities, T-cell exhaustion, and manufacturing limitations hinder its broader application, necessitating a comprehensive review of current evidence and innovations. This review synthesizes clinical data, engineering advancements, and persistent barriers to optimize CAR-T therapy and guide future research. The review highlights key insights, including the superior efficacy of CAR-T therapy over conventional treatments in B-cell malignancies and multiple myeloma, as evidenced by high response rates (RR) and durable remissions. It explores the critical role of costimulatory domains in enhancing CAR-T cell persistence and the promise of dual-targeting strategies to overcome antigen escape. Clinical trials demonstrate manageable safety profiles, though cytokine release syndrome (CRS) and neurotoxicity remain significant concerns. Manufacturing advancements, such as induced pluripotent stem cell (iPSC) derived CAR-T cells, aim to improve scalability and reduce costs. The review also discusses emerging applications in T-cell neoplasms and the potential of allogeneic ‘off-the-shelf’ products to expand accessibility. Finally, it underscores the importance of combination therapies and personalized approaches to address tumor microenvironment immunosuppression. Future research should focus on optimizing CAR designs to reduce toxicity and enhance long-term efficacy, particularly in solid tumors and autoimmune diseases. Innovations in gene editing, logic-gated systems, and automation hold promises for democratizing CAR-T therapy globally. Collaborative efforts between academia and industry will be essential to overcome current limitations and realize the full potential of this transformative treatment modality.