Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas letter

Christopher W. Mount, Robbie G. Majzner, Shree Sundaresh, Evan P. Arnold, Meena Kadapakkam, Samuel Haile, Louai Labanieh, Esther Hulleman, Pamelyn J. Woo, Skyler P. Rietberg, Hannes Vogel, Michelle Monje, Crystal L. Mackall

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M) 1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies 7-10, and recent results suggest benefit in central nervous system malignancies 11-13 . Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2. Anti-GD2 CAR T cells incorporating a 4-1BBz costimulatory domain 14 demonstrated robust antigen-dependent cytokine generation and killing of DMG cells in vitro. In five independent patient-derived H3-K27M+ DMG orthotopic xenograft models, systemic administration of GD2-targeted CAR T cells cleared engrafted tumors except for a small number of residual GD2lo glioma cells. To date, GD2-targeted CAR T cells have been well tolerated in clinical trials 15-17 . Although GD2-targeted CAR T cell administration was tolerated in the majority of mice bearing orthotopic xenografts, peritumoral neuroinflammation during the acute phase of antitumor activity resulted in hydrocephalus that was lethal in a fraction of animals. Given the precarious neuroanatomical location of midline gliomas, careful monitoring and aggressive neurointensive care management will be required for human translation. With a cautious multidisciplinary clinical approach, GD2-targeted CAR T cell therapy for H3-K27M+ diffuse gliomas of pons, thalamus and spinal cord could prove transformative for these lethal childhood cancers.
Original languageEnglish
Pages (from-to)572-579
JournalNature Medicine
Volume24
Issue number5
DOIs
Publication statusPublished - 2018

Cite this

Mount, C. W., Majzner, R. G., Sundaresh, S., Arnold, E. P., Kadapakkam, M., Haile, S., ... Mackall, C. L. (2018). Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas letter. Nature Medicine, 24(5), 572-579. https://doi.org/10.1038/s41591-018-0006-x