北京理工大学生命学院,北京理工大学前沿交叉科学研究院,北京 100081
School of Life Science, Advanced Research Institute of Multidisciplinary Science, Beijing Institute of Technology, Beijing100081, China
This work was supported by grants from The National Natural Science Foundation of China (32171394, 82302387).
嵌合抗原受体T(chimeric antigen receptor T,CAR-T)细胞疗法在血液系统肿瘤的治疗中取得了显著成就。然而,由于CAR-T细胞的体外制备过程复杂且成本高昂,加之在实体肿瘤治疗中面临靶向浸润困难、免疫抑制环境以及潜在的毒性副作用等科学问题,其治疗效果并不尽如人意。幸运的是,纳米技术的进步为这一领域带来了新的希望。特别是纳米药物递送系统,已成为抗肿瘤药物研发中一个极为活跃的研究方向。本文聚焦于CAR-T疗法与实体肿瘤治疗的相关背景,系统地综述了近年来纳米技术在体外与体内CAR-T细胞制备和实体瘤治疗中的应用,并对未来的发展方向进行了前瞻性的展望。
Chimeric antigen receptor T (CAR-T) cell therapy is an innovative and cutting-edge treatment in the field of adoptive cell therapy. It represents an important milestone in personalized and precision medicine. T cell immunotherapy has gone through more than 30 years of development, making CAR-T cell therapy increasingly mature. Currently, CAR-T cell therapy has achieved significant success in the treatment of hematological system tumors, and the FDA has approved 6 CAR-T cell therapies for the treatment of hematopoietic cancers. However, on one hand, the preparation of CAR-T cells is a highly technical process involving multiple steps, each requiring precise operation and strict condition control to ensure the quality and activity of the cells. The high-quality materials, specialized equipment, and highly specialized personnel required in the production process have led to very high preparation costs for CAR-T cell therapy. The high cost has led to increased treatment fees, which may limit the popularization and accessibility of CAR-T therapy. On the other hand, CAR-T cell therapy faces a series of difficulties and challenges in the treatment of solid tumors. The first is the insufficient targeting and infiltration ability of CAR-T cells to tumors. The tumor microenvironment (TME) of solid tumors is usually composed of dense extracellular matrix, forming a physical barrier that severely limits the targeting and penetration ability of CAR-T cells to tumors. The second is the immunosuppressive factors in the TME. In the TME, there are a large number of immunosuppressive factors, such as interleukin-10, transforming growth factor-β, and suppressive cells including regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. These factors not only weaken the persistence of CAR-T cells but also severely hinder their effective anti-tumor effect. Finally, CAR-T cell therapy can cause serious cytotoxicity. The activation of CAR-T cells may cause cytokine release syndrome and attack normal cells expressing the CAR-T target antigen, causing “off-target” toxicity, and thus causing systemic inflammatory reactions and potential serious side effects. These factors lead to unsatisfactory therapeutic effects of CAR-T cell therapy. Fortunately, the advancement of nanotechnology has brought new hope to this field. In particular, nano drug delivery systems have become an extremely active research direction in the development of anti-tumor drugs. Nanoparticle delivery systems can address the challenges encountered by CAR-T cell therapy in treating solid tumors through various mechanisms. These mechanisms include enhancing tumor targeting and CAR-T cell penetration ability, regulating the tumor’s suppressive microenvironment, and overcoming the side effects of CAR-T cell therapy. The implementation of these strategies is expected to significantly improve the efficacy of CAR-T cell therapy in the treatment of solid tumors, thereby bringing more significant therapeutic effects to patients. This article focuses on the background of CAR-T therapy and solid tumor treatment, systematically reviews the application of nanotechnology in CAR-T cell preparation and solid tumor treatment in vitro and in vivo in recent years, and provides a forward-looking perspective on future development directions.
徐霖,胡泊,郑露露,蒋邵平,阮少波,黄渊余.纳米技术在肿瘤嵌合抗原受体T细胞疗法中的应用[J].生物化学与生物物理进展,2024,51(12):3103-3122
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