Anti-GD2 CAR T Cells Are Potent in H3-K27M⁺ Diffuse Midline Gliomas

Chimeric antigen receptor (CAR) T-cell therapies have exhibited efficacy against pediatric hematologic malignancies and adult glioblastoma, but it is unclear whether CAR T cells are a potential therapy for patients with pediatric central nervous system malignancies. To identify potential CAR T-cell targets, Mount, Majzner, and colleagues established patient-derived cultures of diffuse intrinsic pontine gliomas (DIPG), which are highly aggressive pediatric brain tumors. Screening of the patient-derived DIPG cultures with a cell surface antigen–targeting panel showed that the disialoganglioside GD2, which is being evaluated as an immunotherapeutic target in other cancers, was highly and specifically expressed in H3-K27M⁺ DIPGs compared to wild-type H3 DIPG or pediatric high-grade glioma (HGG). Anti-GD2 CAR T cells exhibited cytotoxicity against H3-K27M⁺ DIPGs but not GD2-negative patient-derived DIPG cells in vitro; consistent with these findings, anti-GD2 CAR T-cell therapy reduced orthotopic H3-K27M⁺ DIPG growth and significantly increased survival of a highly aggressive patient-derived DIPG, SU-DIPG-13P*, xenograft in vivo. Further, anti-GD2 CAR T-cell therapy resulted in eradication of SU-DIPG-13P* xenografts and was accompanied by inflammatory infiltration of the parenchyma, meninges, and ventricles with no evidence of neuronal toxicity. Anti-GD2 CAR T-cell therapy was efficacious against orthotopic patient-derived pediatric H3-K27M⁺ spinal cord diffuse midline glioma (DMG) xenografts without toxicity; however, anti-GD2 CAR T cells induced tumor clearance and significant toxicity in mice harboring orthotopic patient-derived pediatric H3-K27M⁺ thalamic DMG xenografts potentially due to ventricular compression and herniation. Taken together, these results identify GD2 as an immunotherapeutic target for patients with pediatric H3-K27M⁺ DMGs, and provide evidence that the toxicity of inflammation-induced edema is significantly dependent upon neuroanatomic location.

Mount CM, Majzner RG, Sundaresh S, Arnold EP, Kadapakkam M, Haile S, et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M⁺ diffuse midline gliomas. Nature Med 2018 Apr 16 [Epub ahead of print].

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