Project description
Combining CAR T cells and targeted therapy for childhood brain tumours
Diffuse midline gliomas are devastating childhood brain tumours with a median survival of under 12 months and no effective treatments beyond palliative radiotherapy. CAR T cell immunotherapy has shown promise but remains limited by the protective blood brain barrier and the tumour’s immunosuppressive environment. With the support of the Marie Skłodowska-Curie Actions programme, the ONCAR-TRAIL project will combine engineered CAR T cells with a targeted drug that sensitises tumour cells to immune-mediated killing. Researchers will develop CAR T cells capable of locally delivering a cancer cell-killing protein restricted to tumour tissue. They will investigate how this combination reprogrammes immune cells within the tumour microenvironment. The approach aims to enhance therapeutic efficacy against these aggressive paediatric brain tumours.
Objective
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), are fatal pediatric brain tumors with median survival under 12 months, and current therapy is limited to palliative radiotherapy.
Chimeric antigen receptor (CAR) T cells are a promising immunotherapy, but responses in DMG remain incomplete due to blood-brain barrier (BBB) restriction and an immunosuppressive tumor microenvironment (TME). At Seattle Children’s Hospital, I contributed to the development of B7-H3 CAR T cells in the BrainChild-03 trial (NCT04185038), which showed tolerability in children but highlighted the urgent need for combinatorial approaches.
ONC206, an imipridone tested in the PNOC-023 trial (NCT04732065), crosses the BBB and primes DMG cells for apoptosis by disrupting mitochondrial respiration and upregulating death receptor 5 (DR5). B7-H3 CAR T cells combined with ONC206 improved efficacy but underscored the need for additional synergistic strategies. TRAIL, the natural ligand of DR5, induces apoptosis and can reprogram macrophages toward an anti-tumor phenotype. However, its poor stability and pharmacokinetics limit systemic delivery.
To address these barriers, ONCAR-TRAIL combines local TRAIL delivery with ONC206 and aims to:
1. develop and test TRAIL-expressing B7-H3 CAR T cells in patient-derived models and orthotopic xenografts, with an inducible GD2-SynNotch circuit restricting TRAIL expression to GD2⁺ DMG cells;
2. assess how ONC206/TRAIL repolarize human macrophages using phenotypic, transcriptomic, and metabolic analyses, with exploratory in vivo studies corroborating macrophage shift and tumor apoptosis.
ONCAR-TRAIL combines my CAR T expertise with the resources of the Universities of Zurich and Geneva. Enhancing CAR T cell efficacy and modulating the DMG TME provide a framework for novel translational therapies against DMG through Pediatric Neuro-Oncology Consortium, the Diffuse Midline Glioma-ACT initiative, and the Children’s Brain Tumor Network.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
This project's classification has been human-validated.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
This project's classification has been human-validated.
Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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Call for proposal
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(opens in new window) HORIZON-MSCA-2025-PF
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8006 Zurich
Switzerland
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