CAR T-cell therapy tricks cancer cells with decoy, increases treatment efficiency in B-cell acute lymphoblastic leukemia

by The Spanish National Cancer Research Centre

A new CAR-T-cell therapy that tricks the tumor could increase treatment efficiency in B-cell Acute Lymphoblastic LeukemiaGalectin-9 impairs CAR19-T cells. (A) Cartoon depicting the in vitro experimental design of co749 cultures of CAR19-T cells with B-ALL cells. (B) Expression levels of TIM-3 in CAR19-T cells (left panel) and galectin-9 in CAR19-T cell-resistant B-ALL cells (right panel) determined by FACS after 24 h of CAR-T cell:B-ALL co-culture. (C, D) Apoptosis assay (Annexin-V/7-AAD) and T-cell proliferation measured by an eFluor 670 retention assay, after incubation of CAR19-T cells with or without rhGalectin-9 (1 μg/mL) for 48 h. Left panels show representative FACS profiles. Right panels show average data. Credit: Blood Journal (2025). DOI: 10.1182/blood.2024025440

B-cell acute lymphoblastic leukemia (B-ALL) is a life-threatening and highly aggressive form of blood cancer. It is the most common childhood cancer, making up 35% of pediatric cancer cases, but it can affect people of any age. CAR T-cell therapy has significantly improved outcomes for B-ALL patients, but relapse still occurs in over 50% of cases, leaving many with limited treatment options. Ongoing research aims to address this challenge and improve CAR T therapy’s effectiveness.

One of the major challenges in treating B-cell acute lymphoblastic leukemia with CAR T-cell therapy is relapse. A key issue that researchers are investigating is why CAR T cells, which are a living medicine, sometimes fail to respond to cancer cells, even in their presence. A promising lead has emerged from examining the interaction between the tumor and immune cells, including CAR T cells.

The findings are published in the Blood Journal.

It turns out that B-ALL tumors may take advantage of the body’s natural defense mechanisms, specifically the immune checkpoint pathways. These pathways usually act as “off switches,” telling immune cells to stop attacking once the infection or threat has been cleared. However, tumors can hijack this system to avoid being attacked by the immune system.

Car T cells ‘turned off’ by the tumor

In CAR T therapy, T-lymphocytes are extracted from the patient’s blood to be treated and modified in the laboratory, so that they can specifically recognize and target cancer cells. Once modified, T-lymphocytes are reintroduced into the patient’s body.

In the case of B-ALL, researchers discovered that relapsed leukemia cells have unusually high levels of galectin-9, a ligand that is part of the immune checkpoint system. On the other hand, CAR T cells express high levels of TIM-3, a receptor that normally interacts with galectin-9 to suppress immune activity. The tumor seems to use this interaction to “turn off” the CAR T cells, allowing the cancer to persist.

To address this problem, researchers created a TIM-3 decoy, a soluble version of the TIM-3 protein, that could block the ligand-receptor interaction. The idea was that this decoy would prevent the tumor from turning off the CAR T cells, without directly signaling them to stop their immune activity.

In laboratory tests using genetically modified mice with human B-ALL cells, the results were promising. CAR T cells engineered to secrete the TIM-3 decoy showed improved anti-leukemia effectiveness and long-term persistence.

Although still in the preclinical stage, this research marks an important first step toward improving treatments for B-ALL patients. The goal is to enhance the effectiveness of CAR T therapy and reduce relapses, two major challenges faced by patients undergoing current CAR T treatments. This approach could also pave the way for developing “armored CAR T cells” and expanding the potential of CAR T therapy to treat solid tumors in the future.

More information: Aïda Falgàs et al, A TIM-3-Fc decoy secreted by engineered T cells improves CD19 CAR-T cell therapy in B-cell acute lymphoblastic leukemia, Blood Journal (2025). DOI: 10.1182/blood.2024025440

Journal information:Blood

Provided by The Spanish National Cancer Research Centre


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