Department of Medical Oncology, The Christie NHS Foundation Trust.
Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UK.
Curr Opin Oncol. 2019 Sep;31(5):430-438. doi: 10.1097/CCO.0000000000000562.
PURPOSE OF REVIEW: The remarkable and durable clinical responses seen in certain solid tumours using checkpoint inhibitors and in haematological malignancies using chimeric antigen receptor (CAR) T therapy have led to great interest in the possibility of using engineered T-cell receptor (TCR) and CAR T therapies to treat solid tumours. RECENT FINDINGS: In this article, we focus on the published clinical data for engineered TCR and CAR T therapy in solid tumours and recent preclinical work to explore how these therapies may develop and improve. We discuss recent approaches in target selection, encouraging epitope spreading and replicative capacity, CAR activation, T-cell trafficking, survival in the immunosuppressive microenvironment, universal T-cell therapies, manufacturing processes and managing toxicity. SUMMARY: In haematological malignancies, CAR T treatments have shown remarkable clinical responses. Engineered TCR and CAR therapies demonstrate responses in numerous preclinical models of solid tumours and have shown objective clinical responses in select solid tumour types. It is anticipated that the integration of efficacious changes to the T-cell products from disparate preclinical experiments will increase the ability of T-cell therapies to overcome the challenges of treating solid tumours and note that healthcare facilities will need to adapt to deliver these treatments.
目的综述:在某些实体瘤中,使用检查点抑制剂,在血液恶性肿瘤中,使用嵌合抗原受体(CAR)T 治疗,观察到显著且持久的临床反应,这使得人们对使用工程 T 细胞受体(TCR)和 CAR T 治疗来治疗实体瘤的可能性产生了极大的兴趣。
最近的发现:在本文中,我们重点介绍了工程 TCR 和 CAR T 治疗实体瘤的已发表临床数据,以及最近的临床前研究工作,以探讨这些疗法的发展和改进途径。我们讨论了最近在靶标选择、促进表位扩散和复制能力、CAR 激活、T 细胞迁移、在免疫抑制微环境中的存活、通用 T 细胞治疗、制造工艺和管理毒性方面的方法。
总结:在血液恶性肿瘤中,CAR T 治疗已显示出显著的临床反应。工程 TCR 和 CAR 治疗在许多实体瘤的临床前模型中显示出了反应,并在某些实体瘤类型中显示出了客观的临床反应。预计将不同临床前实验中对 T 细胞产品的有效改变整合起来,将提高 T 细胞治疗克服治疗实体瘤挑战的能力,并指出医疗保健机构将需要适应这些治疗方法。
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