过继细胞疗法(ACT)通过给患者输注肿瘤反应性的免疫细胞来调节机体自身的免疫功能,以达到杀伤肿瘤细胞的 目的。 嵌合抗原受体-T(CAR-T)细胞疗法是一种利用基因工程修饰的过继 T 细胞疗法,与传统的抗肿瘤过继细胞疗法相 比,CAR-T 细胞具有特异性高、致肿瘤细胞死亡强、疗效持久等优点,在血液系统恶性肿瘤的治疗中取得了显著成效。 越来越 多的临床前研究及相应的临床研究相继开展以将 CAR-T 细胞疗法延伸到实体肿瘤的治疗,如转移性黑色素瘤、非小细胞肺 癌、乳腺癌、结直肠癌等,然而并未取得良好的疗效。 这是由于实体瘤异于血液系统恶性肿瘤,使得 CAR-T 细胞疗法在治疗 实体瘤的实践中面临多种挑战,如靶外毒性、肿瘤抗原异质性导致免疫逃逸、免疫抑制性微环境造成的 CAR-T 细胞耗竭 等,导致治疗疗效不明确及免疫毒性。 根据实体瘤的特点,目前正在进行多种对应策略与技术方法的研究,例如,过表达趋化 因子受体和细胞因子、双靶点 CAR-T 细胞、改善 T 细胞代谢、调整 CAR 的亲和力等,旨在提高 CAR-T 细胞进行实体瘤治疗的 临床疗效及安全性。 本文将对 CAR-T 细胞的发展历程、CAR-T 细胞对实体瘤治疗的挑战及相应的优化策略进行系统的综 述,以期为 CAR-T 细胞治疗实体肿瘤提供参考。

Adoptive cell therapy is the process of regulating patients ' own immune system through the administration of tumor-reactive immune cells to achieve the goal of eliminating tumor cells. CAR-T cell is genetically modified T cell and the CAR-T cell therapy is a kind of adoptive T-cell therapy. Compared with generally adoptive cell therapy for tumors CAR-T cell therapy offers the advantages of higher specificity and stronger cytotoxicity on tumor cells and prolonged curative efficacy. In the treatment of hematological malignancies CAR - T cell therapy proves effective. An increasing number of preclinical studies and corresponding clinical studies have been carried out to extend CAR - T cell therapy to the treatment of some solid tumors such as metastatic melanoma non-small cell lung cancer breast cancer and colorectal cancer. However it has not achieved good curative efficacy. Owing to the differences in properties between solid solid tumors and hematological malignancies CAR-T cell therapy is challenged for the treatment of the solid tumors such as on - target off - tumor toxicity immune escape caused by tumor antigen heterogeneity CAR- T cell exhaustion due to the immunosuppressive tumor microenvironment resulting in the limited therapeutic efficacy and immune toxicity. To improve the clinical efficacy and safety of CAR-T cell therapy in the treatment of the solid tumors many different strategies are developing currently based on the unique characteristics of solid tumors such as overexpressing chemokine receptors and cytokines dual CAR-T cells improving T cell metabolism adjusting the affinity of CAR. To provide a reference for future CAR-T cell therapy for solid tumors the development of CAR-T cells current challenges and associated optimization strategies for CAR-T cells in solid tumor treatment are reviewed in this paper.