Research: Brain Tumor and Immune Cell Engineering
Tumors arising in the brain are notoriously hard to treat. Intensive research in the last decade provided in depth characterization of the molecular profile of high grade gliomas, but unfortunately no impactful novel therapies. We contributed to immune based therapies for gliomas, especially in the identification of overexpressed cell surface markers of GBM in vivo and with the development multiepitopic vaccinations using synthetic peptides. We had the opportunity to translate our research into the clinic in an early phase trial where 19 patients with newly diagnosed GBM tumors were treated with the IMA950 peptide vaccine. We were able to demonstrate safety and immunogenicity. This endeavour led to another ambitious phase I trial using a personalized vaccination approach adapted to each patient’s tumor molecular profile.
Our next endeavour is to develop improved chimeric antigen receptor (CAR)-T cell approaches for glioma for the development of successful translational programs. T-cell engineering allows the construction of cell products harboring a high-affinity single-chain fragment variable (scFv) specific for a target of interest, fused to domains necessary for full activation and costimulation. CAR-T cell therapy in the context of brain tumors is promising because glioma is a good example of how specific improvements in trafficking, persistence, and resistance to the immunosuppressive factors related to the TME will be especially critical for success of engineered cellular therapies. We are fortunate to benefit from the generous support of the ISREC Foundation and to be part of the newly formed Swiss Cancer Center Léman (SCCL) which brings together fundamental, translational and clinical cancer research experts from Geneva and Lausanne. The SCCL federates skills and ressources at the cutting edge of the fight against cancer and allows us to integrate our efforts in a wide multidisciplinary community."
- Oncolytic Viruses as a Platform for the Treatment of Malignant Brain Tumors. Sostoa J, Dutoit V, Migliorini D. Int J Mol Sci. 2020 Oct 9;21(20):7449. doi: 10.3390/ijms21207449. PMID: 33050329
- Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies. Parker KR, Migliorini D, Perkey E, Yost KE, Bhaduri A, Bagga P, Haris M, Wilson NE, Liu F, Gabunia K, Scholler J, Montine TJ, Bhoj VG, Reddy R, Mohan S, Maillard I, Kriegstein AR, June CH, Chang HY, Posey AD Jr, Satpathy AT. Cell. 2020 Oct 1;183(1):126-142.e17. doi: 10.1016/j.cell.2020.08.022. Epub 2020 Sep 21. PMID: 32961131
- An Experimentally Defined Hypoxia Gene Signature in Glioblastoma and Its Modulation by Metformin. Calvo Tardón M, Marinari E, Migliorini D, Bes V, Tankov S, Charrier E, McKee TA, Dutoit V, Dietrich PY, Cosset E, Walker PR. Biology (Basel). 2020 Sep 2;9(9):264. doi: 10.3390/biology9090264. PMID: 32887267
- Impact of Radiochemotherapy on Immune Cell Subtypes in High-Grade Glioma Patients. Dutoit V, Philippin G, Widmer V, Marinari E, Vuilleumier A, Migliorini D, Schaller K, Dietrich PY. Front Oncol. 2020 Feb 14;10:89. doi: 10.3389/fonc.2020.00089. eCollection 2020. PMID: 32117743