An international research team has developed a novel approach to enhance CAR-T cell therapy for B-cell Acute Lymphoblastic Leukemia (B-ALL) by creating a decoy mechanism that prevents cancer cells from deactivating immune responses. The promising preclinical results, published in the journal 'Blood', demonstrate improved anti-leukemia effectiveness and could potentially address the high relapse rates currently seen in CAR-T therapy.
B-ALL, the most common childhood cancer representing 35% of pediatric cancer cases, is an aggressive form of blood cancer that can affect people of all ages. While CAR-T cell therapy has significantly improved outcomes for many patients, more than 50% still experience relapse, leaving them with limited treatment options.
Uncovering the Immune Evasion Mechanism
Researchers from the Josep Carreras Leukaemia Research Institute and the Hospital Universitario 12 de Octubre – Spanish National Cancer Research Center (CNIO) discovered that B-ALL tumors exploit the body's natural immune checkpoint pathways to evade attack from CAR-T cells.
The team identified that relapsed leukemia cells express unusually high levels of galectin-9, a ligand that interacts with the TIM-3 receptor on CAR-T cells. This interaction effectively "turns off" the CAR-T cells, allowing cancer to persist despite the presence of the engineered immune cells.
"Although in the preclinical stage, this research is a first step toward improving treatments for B-ALL patients," the authors noted. "The goal is to enhance the effectiveness of CAR-T therapy and reduce relapses."
The TIM-3 Decoy Solution
To counter this immune evasion strategy, the researchers developed a soluble version of the TIM-3 protein that acts as a decoy. This innovative approach blocks the galectin-9/TIM-3 interaction without directly signaling the CAR-T cells to cease their immune activity.
In CAR-T therapy, T-lymphocytes are extracted from a patient's blood, genetically modified in the laboratory to recognize specific cancer markers, and then reintroduced into the patient's body. The modified approach involves engineering these CAR-T cells to also secrete the TIM-3 decoy.
Laboratory tests using genetically modified mice with human B-ALL cells showed promising results. The CAR-T cells engineered to secrete the TIM-3 decoy demonstrated improved anti-leukemia effectiveness and maintained longer persistence in the body compared to standard CAR-T cells.
Future Implications and Research Direction
This research represents an important advancement in addressing two major challenges in current CAR-T treatments: effectiveness and relapse rates. The approach could potentially lead to the development of "armored CAR-T cells" with enhanced capabilities against cancer.
Beyond B-ALL, researchers suggest this strategy could expand the potential of CAR-T therapy to treat solid tumors, which have historically been more resistant to immunotherapy approaches.
The international study was led by Aïda Falgàs, Rodrigo Lázaro-Gorines, and Samanta Romina Zanetti, under the supervision of Pablo Menéndez, Clara Bueno, and Luis Álvarez-Vallina. The collaboration included researchers from Salamanca University, Hospital Clinic, and other Spanish and European research institutions.
As this research progresses from preclinical models toward potential clinical applications, it offers new hope for improving outcomes in patients with B-ALL and potentially other cancers that currently have limited treatment options.
