Department of Clinical and Experimental Hematology, Institute Jules Bordet (ULB), Brussels, Belgium.
Curr Opin Oncol. 2020 Sep;32(5):434-441. doi: 10.1097/CCO.0000000000000671.
Chimeric antigen receptor (CAR) T-cell therapy is an innovative form of adoptive cellular immunotherapy targeting CD19 in its most advanced form. Up to 30% of infused patients achieve long-term survival, meaning that 70% of patients still fail to respond or relapse after therapy. This review will address the unresolved issues relating to responders' characterization, relapse prediction, and prevention, CAR T-cell construct optimization, rational combination with other therapies and treatment toxicity, focusing on the management of relapsed/refractory lymphoma patients.
Many new antigenic targets are currently investigated and raise the hope of broader successes. However, literature data report that treatment failure is not only related to CAR T construct and infusion but is also due to hostile tumor microenvironment and poor interaction with the host effector cells. Further research should not only target CAR T structure, toxicity and associated therapies, but also tumor-related and host-related microenvironment interactions that lead to treatment failure in relapsed/refractory lymphoma patients.
Poor persistence of CAR T and loss of CD19 antigen are well established mechanisms of relapse in Acute Lymphoblastic Leukemia (ALL). A fourth generation of CAR T construct is currently investigated to overcome this issue. In non-Hodgkin lymphoma, mechanisms of treatment failure remain poorly understood but tumor and host microenvironment are undoubtedly involved and should be further investigated. A deeper understanding of CAR T-cell therapy failure in individuals will help personalize CAR T-cell therapy in the future.
嵌合抗原受体 (CAR) T 细胞疗法是一种针对 CD19 的最先进的过继细胞免疫疗法，具有创新性。多达 30%的输注患者实现了长期生存，这意味着 70%的患者在治疗后仍无法响应或复发。本综述将解决与应答者特征、复发预测和预防、CAR T 细胞构建体优化、与其他疗法的合理联合以及治疗毒性相关的未解决问题，重点关注复发/难治性淋巴瘤患者的管理。
目前正在研究许多新的抗原靶点，这增加了更广泛成功的希望。然而，文献数据表明，治疗失败不仅与 CAR T 构建体和输注有关，还与恶性肿瘤微环境和与宿主效应细胞的不良相互作用有关。进一步的研究不仅应针对 CAR T 结构、毒性和相关疗法，还应针对导致复发/难治性淋巴瘤患者治疗失败的肿瘤相关和宿主相关微环境相互作用。
在急性淋巴细胞白血病 (ALL) 中，CAR T 持久性差和 CD19 抗原丢失是复发的明确机制。目前正在研究第四代 CAR T 构建体来克服这个问题。在非霍奇金淋巴瘤中，治疗失败的机制仍知之甚少，但肿瘤和宿主微环境无疑都有涉及，应进一步研究。在个体中更深入地了解 CAR T 细胞疗法的失败将有助于未来对 CAR T 细胞疗法进行个性化。
