Combined treatment approach with GD2-CAR T cells and immune checkpoint inhibitors for high-risk neuroblastoma

• Applicant: Professorin Dr. Judith Feucht
• Subject Area: Pediatric and Adolescent Medicine ; Hematology, Oncology ; Immunology
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 317745709

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Despite recent therapeutic advances, the outcome in patients with high-risk (HR) NB remains poor. Novel immunotherapeutic approaches, such as chimeric antigen receptor (CAR) therapy, have shown impressive results in chemorefractory leukemia. CAR T cells are genetically modified T cells that acquire specificity for selected cell surface antigens. Despite success in B-cell malignancies, CAR therapy still faces several challenges in solid tumors. Due to the poorly immunogenic tumor entity and multiple immune escape mechanisms developed by NB, antitumor immune responses are hampered in the highly immunosuppressive tumor microenvironment (TM). Thus, there is a strong medical need to develop CAR therapies designed to overcome the TM of HR NB. Therefore, the aim of this project is to focus on mechanisms to enhance the function of GD2-specific CARs through costimulation mediated by advanced CAR design and combined treatment approaches with antibodies against inhibitory signals in xenograft mouse models of NB. Engineered co-stimulation has a profound impact on CAR T-cell persistence and function. It has now been demonstrated that CD19-directed CAR T cells with a configuration using the signaling domains CD28 and CD3z as well as co-expression of 4-1BB ligand (CD1928z-41BBL) lead to superior tumor eradication. Enhanced antitumor activity is associated with 4-1BBL-mediated trans-costimulation and induction of T-cell type I interferon (IFN-I) by the transcription factor IRF7. Until now, it has not been investigated if these findings can be used to enhance antitumor activity of CAR T cells against solid tumors. To address this question, I will evaluate the impact of structural conformations of co-stimulatory signaling domains on GD2-CAR T-cell function. I will generate different GD2-CAR configurations, including GD22z-41BBL, to provide optimal co-stimulatory support and analyze functional activity in vitro and in a NB engrafted mouse model in vivo. Furthermore, I will investigate combined treatment of GD2-CAR T cells with monoclonal antibodies targeting T-cell inhibitory molecules - referred to as checkpoint inhibitors - in order to overcome NB-mediated inhibition. Finally, I will evaluate functional relevance of molecular mechanisms underlying improved antitumor activity with regards to IRF7/IFNß-signaling. This project aims at the development of a potent immunotherapeutic treatment approach to increase cure rates in HR NB.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Michel Sadelain, Ph.D.