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dc.contributor.authorde Billy, E
dc.contributor.authorPellegrino, M
dc.contributor.authorOrlando, D
dc.contributor.authorPericoli, G
dc.contributor.authorFerretti, R
dc.contributor.authorBusinaro, P
dc.contributor.authorAjmone-Cat, MA
dc.contributor.authorRossi, S
dc.contributor.authorPetrilli, LL
dc.contributor.authorMaestro, N
dc.contributor.authorDiomedi-Camassei, F
dc.contributor.authorPezzullo, M
dc.contributor.authorDe Stefanis, C
dc.contributor.authorBencivenga, P
dc.contributor.authorPalma, A
dc.contributor.authorRota, R
dc.contributor.authorDel Bufalo, F
dc.contributor.authorMassimi, L
dc.contributor.authorWeber, G
dc.contributor.authorJones, C
dc.contributor.authorCarai, A
dc.contributor.authorCaruso, S
dc.contributor.authorDe Angelis, B
dc.contributor.authorCaruana, I
dc.contributor.authorQuintarelli, C
dc.contributor.authorMastronuzzi, A
dc.contributor.authorLocatelli, F
dc.contributor.authorVinci, M
dc.identifier.citationNeuro-oncology, 2021en_US
dc.description.abstract<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.en_US
dc.titleDual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant.en_US
dc.typeJournal Article
pubs.notesNot knownen_US
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.embargo.termsNot knownen_US
icr.researchteamGlioma Team
dc.contributor.icrauthorJones, Chrisen_US

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