CAR-T细胞在肿瘤治疗中的机遇与挑战

Opportunities and challenges of CAR-T cell for tumor therapy

近年来,嵌合抗原受体基因修饰T(CAR-T)细胞作为"活的药物"在血液肿瘤治疗中取得了令人振奋的效果,成为肿瘤治疗新的发展方向,得到了医学界广泛的认可。纵观免疫细胞治疗技术的发展历程,任何一项新的治疗手段从实验室到临床应用都需要一个不断完善的过程,CAR-T细胞治疗技术同样如此。虽然它在血液系统恶性肿瘤的治疗中显示出前所未有的疗效,如对晚期复发难治性急性淋巴细胞白血病(ALL)治疗的完全缓解(CR)可达到90%,对慢性淋巴细胞白血病(CLL)和部分B细胞淋巴瘤的CR达到50%以上,但目前CAR-T细胞疗法在血液肿瘤的治疗过程中尚存在脱靶效应、毒副作用、体内持续时间短、复发率高等问题;在CAR-T细胞治疗实体瘤方面,其安全性和有效性已得到证实,但疗效还有待提高。针对上述问题,笔者总结出提高CAR-T细胞治疗效果的六大策略:(1)克服患者本身T细胞的缺陷;(2)选择CAR-T细胞的最佳培养条件;(3)制定靶细胞刺激的最佳方案;(4)确定化疗预处理的方案;(5)实现CAR的人源化;(6)加强共刺激信号的组合。本文对近年来CAR-T细胞治疗技术的研究进展及该领域中亟需解决的问题作一分析与展望。

Currently, chimeric antigen receptor gene-modified T（CAR-T） cell as a viable medicine has achieved exciting efficacy in therapies of blood cancers, which has been widely recognized as a new direction of tumor treatment by the medical community. Throughout the development course of cellular immunotherapy technology, any novel therapy approach needs a continuous improvement process from laboratory to clinical application, does as the CAR-T cell therapy technique. Although it showed unprecedented efficacy in the therapy for hematologic malignancies ： the CR rate of advanced recurent relapsed refractory acute lymphoblastic leukemia （ALL） can reach 90%, and the CR rate of chronic lymphocytic leukemia （CLL） and partial B-cell lymphoma can also reach more than 50%, some problems still exsist in the course of treating hematologic malignancies with the CAR-T, such as off-target effect, toxic side effects, short duration of in vivo, high rate of recurrence and so on. It has been conformed that treatment of solid tumors with the CAR-T is safe and effective, but its efficacy remains to be improved. In view of the above problems, the author summarizes six strategies to improve the thera- peutic efficacy of the CAR-T ： （ 1 ） Overcoming defects of T cells in the patients ; （2） Selecting optimal culture conditions for the CAR-T cell; （3） Instituting Optimal program of target cell stimulation; （4） Confirming approach of pre-condition by chemotherapy; （5） Achieving the humanized CAR; （6） Enhancing combination of co-stimulatory signals. This article reviewed recent progresses of the CAR-T cytotherapy technique and urgently solved problems in this field.