A new CAR-T-cell therapy that tricks the tumor could increase treatment efficiency in B-cell Acute Lymphoblastic Leukemia

B-cell Acute Lymphoblastic Leukaemia (B-ALL) is a life-threatening and highly aggressive form of blood cancer. It is the most common childhood cancer, making up 35% of paediatric 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 effectiveness.

One of the major challenges in treating B-cell Acute Lymphoblastic Leukaemia (B-ALL) 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 tumour and immune cells, including CAR-T cells.

It turns out that B-ALL tumours may take advantage of the body's natural defence 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, tumours can hijack this system to avoid being attacked by the immune system

CAR-T cells ‘turned off’ by the tumour

In the case of B-ALL, researchers discovered that relapsed leukaemia 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 tumour seems to use this interaction to "turn off" the CAR-T cells, allowing the cancer to persist.

To address this problem, researchers tested an innovative approach: they 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 tumour from turning off the CAR-T cells, without directly signalling 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-leukaemia 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 "armoured CAR-T cells" and expanding the potential of CAR-T therapy to treat solid tumours in the future.

This international study has been led by researchers from the Josep Carreras Leukaemia Research Institute and the Hospital Universitario 12 de Octubre – Spanish National Cancer Research Centre (CNIO), in collaboration with Salamanca University, Hospital Clinic, and other Spanish and European research institutions. The research team was led by Aïda Falgàs, Rodrigo Lázaro-Gorines and Samanta Romina Zanetti, under the supervision of Pablo Menéndez, Clara Bueno, and Luis Álvarez-Vallina.

This research has been partly funded by the Generalitat de Catalunya, the Spanish Ministry of Science, Innovation and Universities and the European Union through the Next Generation programme. Private initiatives have also funded the research team, among which the Josep Carreras Foundation, Obra Social La Caixa, the Spanish Association Against Cancer, Unoentrecienmil Foundation, Cris Cancer Foundation and Fundación FERO.

Reference Article:

“A TIM-3-Fc decoy secreted by engineered T cells improves CD19 CAR-T cell therapy in B-cell acute lymphoblastic leukemia”

Falgàs A, Lázaro-Gorines R, Zanetti SR, Rubio-Pérez L, Martinez-Moreno A, Vinyoles M, Guerrero-Murillo M, Fernandez-Fuentes N, Roca-Ho H, Tirado N, Panisello C, Velasco-Hernandez T, Mayado A, Pérez-Pons A, Genesca E, Ribera JM, Ribera J, Camos M, Ramírez-Orellana M, Anguita E, Ballerini P, Fuster JL, Juan M, González-Navarro EAA, Locatelli F, Stam RWW, Querol S, Velasco P, Ortiz-Maldonado V, Martínez-Cibrian N, Delgado J, Orfao A, Alvarez-Vallina L, Bueno C, Menendez P. Blood. 2025 Mar 16:blood.2024025440. https://doi.org/10.1182/blood.2024025440