Image: Li Feng.

Researchers have developed a new biomimetic platform that could enhance CAR T cell therapy against leukaemia.

Chimeric antigen receptor T (CAR T) cell therapy represents a milestone in leukaemia treatment.

CAR T works by genetically engineering a chimeric antigen receptor on the surface of the patient’s T cells to target specific antigens on leukaemia cells, with the goal of identifying and eliminating them.

However, clinical data show that more than 50% of patients eventually relapse after CAR T treatment.

One major reason is that leukaemia cells can reduce or lose expression of the targeted antigen under therapeutic pressure.

When this occurs, CAR T cells can no longer effectively recognise and eliminate leukaemia cells.

Previous efforts to address this limitation have relied heavily on redesigning CAR structures through additional genetic engineering, a process that is time-consuming, costly, and technically complex.

Now, researchers from the Institute of Process Engineering (IPE) of the Chinese Academy of Sciences have developed a biomimetic platform that significantly enhances CAR T cell therapy for relapsed and refractory leukaemia without requiring any genetic modification of CAR T cells.

The strategy was validated in vivo in multiple relapsed and refractory leukaemia mouse models, as well as in vitro using a large number of patient-derived samples.

Collaboration

The researchers collaborated with Zhujiang Hospital and the Institute of Hematology & Blood Diseases Hospital to analyse a large number of clinical samples.

Their analysis revealed that CD71 – a protein involved in transporting iron into cells – is highly expressed on leukaemia cells across different leukaemia types and disease stages, as well as on autologous CAR T cells.

Based on this finding, the researchers precisely controlled the solvent environment and assembly conditions to induce the ordered self-assembly of ferritin, the natural ligand of CD71, thereby creating a biomimetic ferritin aggregation cell engager (FACE), a molecular ‘bridge’ that reinforces the interface between CAR T cells and leukaemia cells.

During CAR T cell preparation, FACE binds firmly to CD71 on the surface of CAR T cells. After infusion, the FACE on CAR T cells also attaches to CD71 on leukaemia cells.

By linking the two cell types, FACE strengthens their interaction and enhances CAR T cell recognition and elimination of leukaemia cells.

In leukaemia patient-derived xenograft (PDX) models with normal antigen expression, FACE-CAR T cells achieved the same therapeutic effect as conventional CAR T cells using only one-fifth of the cell dose, while significantly reducing the risk of cytokine release syndrome.

Even when leukaemia antigen levels dropped below 10% of normal, a condition under which conventional CAR T cells were largely ineffective, FACE-CAR T cells were still able to effectively eliminate leukaemia cells, achieving 100% survival in PDX models.

Further development

The researchers further developed a drug-loaded FACE, termed FACED, by utilising ferritin’s cage-like structure.

FACED-CAR T cells effectively treated PDX models with an initial leukaemia burden of up to 40% and low antigen expression. They also eliminated antigen-negative leukaemia cells, which are often responsible for relapse.

Professor. Wei Wei, corresponding author of the study from IPE, said: “Our FACE platform is composed of an endogenous protein and FDA-approved polymer derivatives and can be prepared through a simple and scalable process.

“Importantly, it can be seamlessly integrated into existing CAR T cell manufacturing workflows as a culture supplement that is co-incubated with CAR T cells prior to infusion, without any additional genetic engineering of CARs.”

Professor Ma Guanghui from IPE said: “By systematically evaluating FACE across diverse patient-derived leukaemia samples and clinically relevant PDX models, we demonstrated its broad applicability across disease subtypes and treatment-resistant settings.”

The researchers also established an efficacy database and developed an AI-assisted predictive framework capable of accurately forecasting FACE-mediated enhancement.

In summary, this study presents a biomimetic platform that enhances CAR T cell performance through improved cell engagement and targeted drug delivery.

Supported by strong preclinical validation, the strategy offers a practical approach to improving outcomes in relapsed and refractory leukaemia.

The study is published in Cell.