Biomimetic platform enhances CAR T therapy for relapsed and refractory leukemia

Chimeric antigen receptor T (CAR T) cell therapy represents a milestone in leukemia 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 leukemia 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 leukemia cells can reduce or lose expression of the targeted antigen under therapeutic pressure. When this occurs, CAR T cells can no longer effectively recognize and eliminate leukemia 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 leukemia without requiring any genetic modification of CAR T cells.

The strategy, validated in vivo in multiple relapsed and refractory leukemia mouse models, as well as in vitro using a large number of patient-derived samples, was reported in Cell on March 9. 

The researchers collaborated with Zhujiang Hospital and the Institute of Hematology & Blood Diseases Hospital to analyze a large number of clinical samples. Their analysis revealed that CD71-a protein involved in transporting iron into cells-is highly expressed on leukemia cells across different leukemia 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 leukemia 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 leukemia cells. By linking the two cell types, FACE strengthens their interaction and enhances CAR T cell recognition and elimination of leukemia cells.

In leukemia 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 leukemia 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 leukemia cells, achieving 100% survival in PDX models.

The researchers further developed a drug-loaded FACE, termed FACED, by utilizing ferritin's cage-like structure. FACED-CAR T cells effectively treated PDX models with an initial leukemia burden of up to 40% and low antigen expression. FACED-CAR T cells also eliminated antigen-negative leukemia cells, which are often responsible for relapse.

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."

Prof. WEI Wei, corresponding author of the study from IPE

"By systematically evaluating FACE across diverse patient-derived leukemia samples and clinically relevant PDX models, we demonstrated its broad applicability across disease subtypes and treatment-resistant settings," said Prof. MA Guanghui from IPE. The researchers also established an efficacy database and developed an AI-assisted predictive framework capable of accurately forecasting FACE-mediated enhancement.

Peer reviewers at Cell described the findings as "highly relevant to the CAR T field" and a "promising translational approach" to improving responsiveness against hematologic malignancies. They emphasized that the strategy's lack of additional genetic engineering could be implemented in a wide variety of clinical settings and highlighted its potential to counteract the heterogeneity of leukemia antigens.

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 leukemia.