Targeting EGFRvIII and CD47-SIRPα: A New CAR-T Strategy for Glioblastoma Treatment
Review contributed by: PhD candidate Eugenio Contreras Castillo (one of the 2024 ICIS-Pfizer Trainee Award Winners for Most Promising Research Presentations at Cytokines 2024), Department of Cell Biology Institute of Cellular Physiology (IFC), National Autonomous University of Mexico (UNAM) 8RHF+62 Mexico City
Glioblastoma, with a median survival of only 15 months, urgently requires more effective treatments. CAR-T cell therapies have been successful in blood cancers, but solid tumors like glioblastoma present unique challenges. Nearly 70% of glioblastomas express the EGFRvIII antigen, making it a key target for CAR-T therapy. However, while anti-EGFRvIII CAR-T cells have shown initial safety and efficacy in trials, they have not yet achieved long-lasting responses. A significant barrier is the tumor’s immunosuppressive microenvironment, particularly the “don’t eat me” signal via the CD47-SIRPα axis, which inhibits the phagocytic activity of glioma-associated microglia and macrophages.
Researchers at the University of Basel have developed a fourth-generation CAR-T therapy, anti-EGFRvIII-SGRP CAR-T, that not only targets EGFRvIII but also secretes SIRPγ to block CD47. In glioblastoma models, this dual-target approach has improved survival and long-term tumor control compared to traditional CAR-T therapies by reprogramming microglia for greater phagocytic activity. This strategy has also shown promise in lymphoma, with anti-CD19-SGRP CAR-T outperforming standard anti-CD19 CAR-T. Developing strategies that overcome the immunosuppressive tumor microenvironment holds tremendous potential for advancing effective cancer therapies.