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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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1093\/neuonc\/noab300","type":"journal-article","created":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T20:28:07Z","timestamp":1640723287000},"page":"1150-1163","source":"Crossref","is-referenced-by-count":65,"title":["Dual IGF1R\/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant"],"prefix":"10.1093","volume":"24","author":[{"given":"Emmanuel","family":"de Billy","sequence":"first","affiliation":[{"name":"Department of Onco-hematology, Gene and Cell Therapy, Bambino Ges\u00f9 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