CAR-DC combined with CAR-T therapy for relapsed/refractory acute myeloid leukaemia: Research progress and future perspectives

Abstract

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.

Keywords

acute myeloid leukaemia / CAR-DCs / CLL1 CAR-T

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