Engineering T cell states for pediatric solid tumor immunotherapy via systematic analysis of endogenous and novel synthetic gene programs

• Applicant: Dr. Laura Moser
• Subject Area: Hematology, Oncology ; Pediatric and Adolescent Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572299126

CAR-T cell therapy (Chimeric-Antigen-Receptor), which uses a patient’s own genetically modified immune cells to fight cancer, has shown remarkable success in treating certain blood cancers. However, it has not yet been effective for solid tumors. Cancers like rhabdomyosarcoma, neuroblastoma, and osteosarcoma – the most common non-brain solid tumors in children – remain very difficult to treat and new therapeutic strategies are urgently needed. One reason for the limited success of CAR-T cells in solid tumors may be the lack of appropriate model systems. Unlike blood cancers, solid tumors form dense 3D structures and create a suppressive environment that impairs immune cell activity. Most current studies rely on 2D models and test only a few genetic changes at a time. In addition, most studies use T cells from healthy adults, which does not reflect the situation of children with cancer, whose immune systems are frequently weakened by intensive treatment. This project aims to improve CAR-T cell therapy for pediatric solid tumors by systematically testing genetic changes that may enhance T cell function – using 3D tumor models that more accurately mimic the complex environment of solid tumors. i) Advanced gene editing techniques will be used to test over 400 genetic modifications – previously shown to enhance T cell function – in parallel, to identify those that most effectively improve CAR-T activity in 3D tumor models. ii) In addition, new, synthetic genes created by combining elements of natural genes known to regulate T cell behavior will be explored. These constructs may help reprogram T cells into more functional states and increase their resistance to tumor-induced suppression. iii) Finally, CAR-T cells generated from pediatric patients will be compared to those from healthy donors to examine dysfunctional programs in patient cells and assess which genetic changes can reverse them. By using clinically relevant models and systematically evaluating both known and novel genetic modifications, this project aims to discover new strategies to improve CAR-T cell therapy for children with neuroblastoma and sarcoma.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Ansuman Satpathy, Ph.D.