肿瘤细胞治疗研究
英文原题：The landscape of genetic medicines for in vivo T cell reprogramming.
T 细胞的体内重编程代表了免疫治疗中一种变革性方法，有望克服传统体外工程化 T 细胞产品（如自体 CAR-T 疗法）的局限性。
体内重编程 T 细胞为免疫治疗提供了一种变革性策略，有望克服传统体外工程化 T 细胞产品（如自体 CAR-T 疗法）的局限。CAR-T 细胞已凭借多种获 FDA 批准的产品，在血液系统恶性肿瘤治疗中取得显著成功，但制造复杂、费用高、毒性和复发率等挑战仍然存在。本综述先简要介绍 T 细胞生物学和 CAR-T 细胞，再全面梳理新兴的体内直接重编程 T 细胞策略。我们讨论脂质纳米颗粒和病毒载体等关键平台技术，以及用于提高递送效率和疗效的靶向方法；同时评估重编程 T 细胞的功能状态，并探讨不同小鼠模型和报告系统在评估其治疗潜力中的作用。本文重点指出改造后 T 细胞在体内分布、激活和持留方面的关键挑战，并讨论这些策略治疗血液系统恶性肿瘤、实体瘤、自身免疫性疾病及其他疾病的潜力。最后，我们结合近期非人灵长类研究、正在开展的临床活动和代表关键创新的战略收购，展望未来方向，并讨论该领域仍待跨越的转化障碍。
In vivo reprogramming of T cells represents a transformative approach in immune-based therapies, with the potential to overcome the limitations of traditional ex vivo-engineered T cell products, such as autologous CAR-T therapies. While CAR-T cells have achieved remarkable success in treating hematological cancers with several FDA-approved products, challenges like manufacturing complexity, costs, toxicity, and relapse rates persist. In this review, we first provide a brief background on T cell biology and CAR T cells, and then present a comprehensive overview of emerging strategies for direct in vivo T cell reprogramming. We discuss the key platform technologies, including lipid nanoparticles and viral vectors, and the targeting methods employed to enhance delivery and efficacy. Moreover, we evaluate the functional state of reprogrammed T cells and the role of different mouse models and reporter systems in assessing their therapeutic potential. We highlight key challenges related to the biodistribution, activation, and persistence of modified T cells, with an emphasis on the potential of these strategies for treating not only blood cancers but also solid tumors, autoimmune diseases, and beyond. Finally, we provide an outlook on future directions by highlighting recent non-human primate studies, ongoing clinical activities, and strategic acquisitions representing key innovations, and discuss remaining translational hurdles in the field.
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