dc.contributor.author | de Billy, E | |
dc.contributor.author | Pellegrino, M | |
dc.contributor.author | Orlando, D | |
dc.contributor.author | Pericoli, G | |
dc.contributor.author | Ferretti, R | |
dc.contributor.author | Businaro, P | |
dc.contributor.author | Ajmone-Cat, MA | |
dc.contributor.author | Rossi, S | |
dc.contributor.author | Petrilli, LL | |
dc.contributor.author | Maestro, N | |
dc.contributor.author | Diomedi-Camassei, F | |
dc.contributor.author | Pezzullo, M | |
dc.contributor.author | De Stefanis, C | |
dc.contributor.author | Bencivenga, P | |
dc.contributor.author | Palma, A | |
dc.contributor.author | Rota, R | |
dc.contributor.author | Del Bufalo, F | |
dc.contributor.author | Massimi, L | |
dc.contributor.author | Weber, G | |
dc.contributor.author | Jones, C | |
dc.contributor.author | Carai, A | |
dc.contributor.author | Caruso, S | |
dc.contributor.author | De Angelis, B | |
dc.contributor.author | Caruana, I | |
dc.contributor.author | Quintarelli, C | |
dc.contributor.author | Mastronuzzi, A | |
dc.contributor.author | Locatelli, F | |
dc.contributor.author | Vinci, M | |
dc.date.accessioned | 2022-03-22T09:39:37Z | |
dc.date.available | 2022-03-22T09:39:37Z | |
dc.date.issued | 2022-07-01 | |
dc.identifier.citation | Neuro-oncology, 2021 | |
dc.identifier.issn | 1522-8517 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5045 | |
dc.identifier.eissn | 1523-5866 | |
dc.identifier.eissn | 1523-5866 | |
dc.identifier.doi | 10.1093/neuonc/noab300 | |
dc.identifier.doi | 10.1093/neuonc/noab300 | |
dc.description.abstract | BACKGROUND: Diffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy. METHODS: Immunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function. RESULTS: GD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo. CONCLUSION: Our study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG. | |
dc.format | Print-Electronic | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | OXFORD UNIV PRESS INC | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc/4.0/ | |
dc.title | Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-12-29 | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1093/neuonc/noab300 | |
rioxxterms.licenseref.startdate | 2021-12-29 | |
dc.relation.isPartOf | Neuro-oncology | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team | |
pubs.publication-status | Published | |
pubs.embargo.terms | Not known | |
icr.researchteam | Glioma Team | |
dc.contributor.icrauthor | Jones, Chris | |