Leukemia therapy tackles relapse risks

Chinese scientists, with the aim of enhancing leukemia treatment, have developed a kind of "double-sided tape" that helps the body's own soldiers — engineered immune cells — hold onto cancer cells more tightly, making treatment far more effective without complicated genetic modifications.

The breakthrough, published recently in the journal Cell, offers a promising new strategy to combat relapse, which occurs in more than half of patients following CAR-T therapy. The approach works by both enhancing the CAR-T cells' ability to spot their target and delivering chemotherapy drugs directly to leukemia cells.

CAR-T therapy, hailed as "groundbreaking" after its introduction, involves extracting a patient's immune cells, known as T cells, modifying them in a laboratory and then reinfusing them into the patient to target and destroy leukemia cells. However, leukemia cells can evade this attack by altering or losing the antigens that CAR-T cells are designed to recognize, which can ultimately lead to relapse.

The traditional method to address this problem involves returning to the lab and redesigning the CAR-T cells through additional gene editing — a process that is time-consuming, expensive and technically challenging. Now Chinese scientists have developed a novel biomimetic platform to address the problem after analyzing 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 CAR-T cells.

Based on this feature, the researchers precisely controlled the solvent environment to induce the ordered self-assembly of CD71 in the lab, creating a molecular "double-sided tape" known as the ferritin aggregation cell engager, or FACE.

During CAR-T cell preparation, the FACE platform can be anchored to the surface of CAR-T cells through CD71 after just 30 minutes of co-incubation. Once infused, FACE also attaches to CD71 on leukemia cells, bridging the two cell types to enhance their interaction and boost the CAR-T cells' ability to recognize and eliminate leukemia cells.

In mouse models using patient-derived leukemia cells, the approach achieved the same therapeutic effect as conventional CAR-T therapy using only one-fifth of the cell dose, while also significantly reducing side effects.

Notably, even when antigen levels dropped below 10 percent of normal — a condition that makes leukemia cells almost "invisible" to conventional CAR-T cells — the FACE-enabled CAR-T cells were still able to target and kill cancer cells, with all tested mice surviving.

Taking advantage of the platform's cage-like structure, the researchers also developed a drug-loaded version that delivers chemotherapy directly to leukemia cells. This integration of CAR-T therapy and chemotherapy further boosts the therapeutic effect, especially against cancer cells with antigen-negative "escapees".

"Our FACE platform is composed of an endogenous protein and polymer derivatives approved by the United States Food and Drug Administration, and it can be prepared through a simple and scalable process," said Wei Wei, corresponding author of the study and a professor at the Chinese Academy of Sciences' Institute of Process Engineering, highlighting the method's clinical translation potential.

"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," Wei added.

Ma Guanghui, an author of the study and an academician of the Chinese Academy of Sciences at the Institute of Process Engineering, said the FACE platform was validated in multiple mouse models and human patient samples, demonstrating "its broad applicability across multiple leukemia subtypes and treatment-resistant settings". To further support clinical translation, Ma said the team 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 "a promising translational approach" to improving responsiveness against leukemia and other blood cancers. They emphasized that the strategy's lack of additional genetic engineering could allow it to be implemented in a wide variety of clinical settings and highlighted its potential to combat the variability of leukemia antigens.

limenghan@chinadaily.com.cn