UNIGE Scientists Develop Dual-Target CAR-T Cell Therapy for Treatment-Resistant Glioblastoma
核心洞察
Scientists at the University of Geneva and Geneva University Hospital (搜索) have engineered CAR-T cells (搜索) targeting both PTPRZ1 (搜索) and Tenascin-C (搜索) proteins to overcome glioblastoma (搜索)'s resistance to standard immunotherapies.
The dual-target approach demonstrated enhanced efficacy in mouse models by triggering inflammatory reactions that destroy cancer cells while avoiding damage to healthy tissue.
Researchers overcame CAR-T cell exhaustion by identifying and counteracting three markers of cell fatigue, significantly prolonging therapeutic effectiveness in preclinical studies.
Scientists at the University of Geneva (UNIGE) and Geneva University Hospital (搜索) (HUG) have developed a breakthrough CAR-T cell therapy capable of destroying glioblastoma (搜索) cells, potentially offering new hope for patients with one of the deadliest forms of brain cancer (搜索). The innovative dual-target approach has shown promising results in animal models and is expected to enter human clinical trials within a year.
Addressing Glioblastoma's Unique Immunotherapy Resistance
Glioblastoma (搜索) presents a formidable challenge in oncology, with a five-year survival rate of less than 5 percent. Unlike melanoma (搜索) or certain lung cancers that respond to standard immunotherapies, glioblastoma contains very few T cells—the immune system's primary cancer-fighting cells.
"However, glioblastoma (搜索) is unique in that it contains very few T cells, the immune cells that are able to recognise cancer cells and destroy them," explains Valérie Dutoit, a researcher in the Department of Medicine and the Translational Research Centre in Onco-Haematology (CRTOH) at the UNIGE Faculty of Medicine. "This is why glioblastoma, unlike melanoma (搜索) or certain lung cancers, for example, does not respond to standard immunotherapies. Our approach is therefore to provide the patient with the missing T cells by generating them in the laboratory."
Dual-Target Strategy Enhances Therapeutic Precision
The research team's approach builds upon their previous identification of PTPRZ1 (搜索), a marker present on the surface of certain tumor cells. However, Professor Denis Migliorini, head of the neuro-oncology unit at HUG, recognized the limitations of single-target therapy.
"In a previous study, we identified an important target, the PTPRZ1 (搜索) marker, which is present on the surface of certain tumour cells. However, attacking glioblastoma (搜索) on a single target is not enough to avoid the risk of relapse," says Migliorini.
The team has now strengthened their therapeutic arsenal by adding Tenascin-C (搜索) (TNC (搜索)) as a complementary target. This protein forms part of the extracellular matrix—described as a "jelly" in which tumor cells are immersed. By engineering CAR-T cells (搜索) to target Tenascin-C, the researchers trigger inflammatory reactions that induce death in the cells producing it.
"Furthermore, we have been able to demonstrate that CAR-T cells (搜索) are capable of locally destroying cancer cells that do not produce Tenascin-C (搜索), which amplifies their activity without any risk of deleterious effects on healthy cells," Migliorini explains.
Overcoming CAR-T Cell Exhaustion
A major obstacle in CAR-T therapies has been the rapid exhaustion of engineered cells, which limits their therapeutic impact. The UNIGE team addressed this challenge by identifying three specific markers of cell exhaustion and developing methods to counteract their activity.
"By identifying three markers of cell exhaustion and counteracting their activity, we were able to significantly prolong the efficacy of CAR-T cells (搜索) in mice with glioblastoma (搜索) used as models of the human disease," reports Dutoit.
Clinical Translation on the Horizon
With strong preclinical results demonstrating enhanced efficacy and prolonged activity, the researchers are preparing to advance their dual-target CAR-T approach into human clinical trials. The trial, expected to begin within a year in Geneva and Lausanne, will focus on tailoring CAR-T cells (搜索) to individual patients to maximize therapeutic coverage across the heterogeneous tumor environment.
The production process involves collecting T cells from the patient's blood, genetically modifying them in the laboratory to recognize tumor-specific proteins, and then re-injecting them. This personalized approach aims to generate immune cells capable of targeting multiple markers simultaneously, potentially reaching as many cancer cells as possible despite glioblastoma (搜索)'s characteristic cellular heterogeneity.