de Oliveira Canedo Gustavo, Roddie Claire, Amrolia Persis J
Molecular and Cellular Immunology Section, University College London Great Ormond Street Institute of Child Health, London, United Kingdom.
Department of Bone Marrow Transplant, Great Ormond Street Hospital, London, United Kingdom.
Blood Adv. 2025 Feb 25;9(4):704-721. doi: 10.1182/bloodadvances.2024013586.
Relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy remains a major challenge in B-cell acute lymphoblastic leukemia (ALL) and B-cell non-Hodgkin lymphoma (B-NHL). One of the main strategies to avoid CD19-negative relapse has been the development of dual CAR T cells targeting CD19 and an additional target, such as CD22 or CD20. Different methods have been used to achieve this, including coadministration of 2 products targeting 1 single antigen, cotransduction of autologous T cells, use of a bicistronic vector, or the development of bivalent CARs. Phase 1 and 2 trials across all manufacturing strategies have shown this to be a safe approach with equivalent remission rates and initial product expansion. CAR T-cell persistence remains a significant issue, with the majority of relapses being antigen-positive after CAR T-cell infusion. Further, despite adding a second antigen, antigen-negative relapses have not yet been eliminated. This review summarizes the state of the art with dual-targeting CAR T cells for B-cell ALL and B-NHL, the challenges encountered, and possible next steps to overcome them.
在B细胞急性淋巴细胞白血病（ALL）和B细胞非霍奇金淋巴瘤（B-NHL）中，CD19导向的嵌合抗原受体（CAR）T细胞治疗后的复发仍然是一个主要挑战。避免CD19阴性复发的主要策略之一是开发靶向CD19和另一个靶点（如CD22或CD20）的双特异性CAR T细胞。实现这一目标的方法有多种，包括共同给药两种靶向单一抗原的产品、自体T细胞的共转导、使用双顺反子载体或开发二价CAR。所有制造策略的1期和2期试验均表明，这是一种安全的方法，缓解率相当，初始产品扩增效果良好。CAR T细胞的持久性仍然是一个重要问题，大多数复发发生在CAR T细胞输注后抗原呈阳性的情况下。此外，尽管增加了第二个抗原，但抗原阴性复发尚未消除。本综述总结了用于B细胞ALL和B-NHL的双靶点CAR T细胞的最新进展、遇到的挑战以及克服这些挑战的可能后续步骤。
