Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1,2,3,4,5 are aggressive and universally fatal pediatric brain cancers6. Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7,8,9,10, and recent results suggest benefit in central nervous system malignancies11,12,13. 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 domain14 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 trials15,16,17. 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.
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We thank the following for generously providing cell cultures: A. Moore (University of Queensland) and C. Jones (Institute of Cancer Research) for QCTB R059, R. Seeger (Children's Hospital Los Angeles) for CHLA136, 255, C. Khanna (National Cancer Institute) for MG63-3 and L. Helman (Children's Hospital Los Angeles) for EW8 and TC32.
This work was supported by a Stand Up To Cancer–St. Baldrick’s–National Cancer Institute Pediatric Dream Team Translational Cancer Research Grant (C.L.M.). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. C.L.M is a member of the Parker Institute for Cancer Immunotherapy, which supports the Stanford University Cancer Immunotherapy Program. The authors gratefully acknowledge support from the National Institute of Neurological Disorders and Stroke (F31NS098554 to C.W.M. and R01NS092597 to M.M.), Abbie’s Army Foundation (M.M.), Unravel Pediatric Cancer (M.M.), Maiy’s Miracle Foundation (E.P.A.), Stella S. Jones Foundation (M.M.), McKenna Claire Foundation (M.M.), Alex’s Lemonade Stand Foundation (M.M.), Izzy's Infantry Foundation (M.M.), The Cure Starts Now Foundation and DIPG Collaborative (M.M.), Lyla Nsouli Foundation (M.M.), Declan Gloster Memorial Fund (M.M.), N8 Foundation (M.M.), Fly a Kite Foundation (M.M.), Liwei Wang Research Fund (M.M.), Virginia and D.K. Ludwig Fund for Cancer Research (M.M. and C.L.M.), Sam Jeffers Foundation (M.M.), Michael Mosier DEFEAT DIPG Foundation (M.M.), ChadTough Foundation (M.M.), Reller Family Research Fund, Child Health Research Institute at Stanford and SPARK program (M.M.) and the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases (M.M.).