Department of Immunology, Hebei Medical University, Key Laboratory of Immune Mechanism and Intervention for Serious Diseases in Hebei Province, Shijiazhuang 050017, Heibei, China.
Department of Immunology, Hebei Medical University, Key Laboratory of Immune Mechanism and Intervention for Serious Diseases in Hebei Province, Shijiazhuang 050017, Heibei, China.
Pharmacol Res. 2022 Jan;175:106036. doi: 10.1016/j.phrs.2021.106036. Epub 2021 Dec 15.
Chimeric antigen receptor T cell (CAR-T) therapy is a late-model of immune cell therapy that has been shown to be effective in refractory/recurrent B-cell leukemia and lymphoma. Compared with the traditional anti-tumor methods, CAR-T cell therapy has the advantages of higher specificity, stronger lethality and longer-lasting efficacy. Although CAR-T cells have made significant progress in the treatment of hematologic malignancies, diverse difficulties remain in the treatment of solid tumors, including immune escape due to tumor antigen heterogeneity, preventing entry or limiting the persistence of CAR-T cells by physical or cytokine barriers and along with other immunosuppressive molecule and cells in the tumor microenvironment (TME). Otherwise, the intracellular signaling of CAR also impact on CAR-T cells persistence. Appropriate modification of intracellular costimulatory molecular signal in the structure of CAR or coexpression of CAR and cytokines can provide a way to enhance CAR-T cells activity. Additionally, CAR-T cells dysfunction due to T cell exhaustion is associated with multi-factors, especially transcription factors, such as c-Jun, NR4A. Engineering CAR-T cells to coexpress or knockout transcription factors in favor of T memory CAR-T cells differentiation was proved to prolonged the survival of CAR-T cells. Finally, combination of CAR-T cells with oncolytic viruses, nanoparticles or immune checkpoint inhibitors provides an effective measure to improve CAR-T cells function. Here, we discuss all of these advances and challenges and review promising strategies for treating solid tumors. In particular, we also highlight that CAR-T cells have enormous potential to be used in combination with other immunotherapies.
嵌合抗原受体 T 细胞（CAR-T）疗法是一种新型免疫细胞疗法，已被证明在难治性/复发性 B 细胞白血病和淋巴瘤中有效。与传统的抗肿瘤方法相比，CAR-T 细胞疗法具有更高的特异性、更强的杀伤力和更长的疗效持续时间。尽管 CAR-T 细胞在血液恶性肿瘤的治疗中取得了重大进展，但在实体瘤的治疗中仍存在多种困难，包括由于肿瘤抗原异质性导致的免疫逃逸、物理或细胞因子屏障阻止或限制 CAR-T 细胞进入或持续存在以及肿瘤微环境（TME）中的其他免疫抑制分子和细胞。此外，CAR 的细胞内信号也会影响 CAR-T 细胞的持久性。在 CAR 的结构中适当修饰细胞内共刺激分子信号或共表达 CAR 和细胞因子，可以提供增强 CAR-T 细胞活性的方法。此外，由于 T 细胞耗竭，CAR-T 细胞功能障碍与多种因素有关，特别是转录因子，如 c-Jun、NR4A。工程 CAR-T 细胞共表达或敲除转录因子有利于 T 记忆 CAR-T 细胞分化，已被证明可延长 CAR-T 细胞的存活时间。最后，CAR-T 细胞与溶瘤病毒、纳米颗粒或免疫检查点抑制剂联合使用提供了一种提高 CAR-T 细胞功能的有效措施。在这里，我们讨论了所有这些进展和挑战，并回顾了治疗实体瘤的有前途的策略。特别是，我们还强调了 CAR-T 细胞与其他免疫疗法联合使用具有巨大的潜力。
