Zhang Rui, Zhang Jinlin, Zhang Hongkai, Zhao Mingfeng
Department of Hematology, Tianjin First Central Hospital, Tianjin, China.
The First Central Clinical College of Tianjin Medical University, Tianjin, China.
Clin Transl Med. 2025 Dec;15(12):e70536. doi: 10.1002/ctm2.70536.
Acute myeloid leukaemia (AML) remains the most common type of leukaemia in adults. Despite advances in conventional therapies, high relapse rates persist, underscoring the need for novel approaches such as chimeric antigen receptor T (CAR-T) cell therapy. C-type lectin-like molecule-1 (CLL1)-targeted CAR-T emerges as a promising treatment for relapsed/refractory (R/R) AML. Although approximately 70% patients achieved remission, only a subset achieved minimal residual disease-negative remission, which still has much room for improvement. The main reasons for the failure of CLL1 CAR-T-cell therapy include: (1) persistence of CLL1-negative AML cells persist due to antigen escape; (2) downregulation of interleukin (IL)-12 and other cytokines by the immunosuppressive tumour microenvironment (TME), contributing to the exhaustion of both endogenous T cells and CLL1 CAR-T cells. We synthesise a combination of CAR-engineered dendritic cells (CAR-DCs) and CLL1 CAR-T cells to overcome current limitations. CAR-DCs enhance antigen cross-presentation to activate endogenous T cells against antigen-negative clones, secrete immunostimulatory cytokines (e.g., IL-12) to sustain CAR-T activity, and remodel the TME. Key challenges involve optimising CAR designs (e.g., incorporating Fms-like tyrosine kinase 3 ligand [FLT-3L] or CD40 signalling domains), mitigating toxicity and establishing clinical administration protocols. In this review, a focused discussion was provided on the specific challenges limiting CLL1-targeted CAR-T-cell therapy in R/R AML, namely antigen escape and the TME, and a novel combination strategy of CAR-DCs with CLL1 CAR-T cells was proposed as a promising approach to mitigate these barriers. Here, the rationale, current research advances, and future perspectives of this synergistic strategy were critically examined. HIGHLIGHTS: Our earlier clinical trials showed that C-type lectin-like molecule-1 (CLL1)-targeted therapy for refractory/relapse acute myeloid leukaemia (AML) was validated, which still has a considerable room for improvement. We summarise the clinical trials and basic research on the dendritic cell (DC) therapy and chimeric antigen receptor-engineered DC (CAR-DC) therapy. We explored the synergistic mechanism and prospects of CLL1 CAR-DC cells combined with CLL1 CAR-T cells in AML.
急性髓系白血病（AML）仍然是成人中最常见的白血病类型。尽管传统疗法取得了进展，但高复发率依然存在，这凸显了对嵌合抗原受体T（CAR-T）细胞疗法等新方法的需求。靶向C型凝集素样分子-1（CLL1）的CAR-T成为复发/难治性（R/R）AML的一种有前景的治疗方法。尽管约70%的患者实现了缓解，但只有一部分患者达到了微小残留病阴性缓解，仍有很大的改进空间。CLL1 CAR-T细胞疗法失败的主要原因包括：（1）由于抗原逃逸，CLL1阴性AML细胞持续存在；（2）免疫抑制性肿瘤微环境（TME）下调白细胞介素（IL）-12和其他细胞因子，导致内源性T细胞和CLL1 CAR-T细胞耗竭。我们合成了CAR工程化树突状细胞（CAR-DC）和CLL1 CAR-T细胞的组合，以克服当前的局限性。CAR-DC增强抗原交叉呈递，以激活针对抗原阴性克隆的内源性T细胞，分泌免疫刺激性细胞因子（如IL-12）以维持CAR-T活性，并重塑TME。关键挑战包括优化CAR设计（如纳入Fms样酪氨酸激酶3配体[FLT-3L]或CD40信号域）、减轻毒性以及建立临床给药方案。在本综述中，重点讨论了限制R/R AML中靶向CLL1的CAR-T细胞疗法的具体挑战，即抗原逃逸和TME，并提出了CAR-DC与CLL1 CAR-T细胞的新型联合策略，作为减轻这些障碍的一种有前景的方法。在此，对这种协同策略的原理、当前研究进展和未来前景进行了批判性审视。要点：我们早期的临床试验表明，靶向C型凝集素样分子-1（CLL1）治疗难治性/复发性急性髓系白血病（AML）得到了验证，但仍有相当大的改进空间。我们总结了树突状细胞（DC）疗法和嵌合抗原受体工程化DC（CAR-DC）疗法的临床试验和基础研究。我们探讨了CLL1 CAR-DC细胞与CLL1 CAR-T细胞在AML中联合的协同机制和前景。
