Mount et al. utilized patient-derived xenograft murine models of three subtypes (pons, thalamus, and spinal cord) of diffuse midline gliomas with H3-K27M+ mutations to demonstrate the potent antitumor effects of GD2 CAR T cell therapy. The K27M mutation in histone H3 increased expression of ganglioside synthesis enzymes, providing high levels of target antigen expression, desirable for CAR therapy. Lethal “on target, on tumor” neuroinflammation in this precarious anatomical site dictate a cautious approach in entry to human trials.

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 GD2(lo) 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.

Author Info: (1) Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA. Medical Scientist Training Program, Stanford University, Stanford, CA, USA. Neurosciences Program, Stanford University

Author Info: (1) Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA. Medical Scientist Training Program, Stanford University, Stanford, CA, USA. Neurosciences Program, Stanford University, Stanford, CA, USA. (2) Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (3) Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA. (4) Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA. (5) Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (6) Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (7) Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Department of Bioengineering, Stanford University, Stanford, CA, USA. (8) Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands. (9) Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA. (10) Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (11) Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. (12) Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA. mmonje@stanford.edu. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. mmonje@stanford.edu. Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA. mmonje@stanford.edu. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. mmonje@stanford.edu. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. mmonje@stanford.edu. Stanford Institute for Stem Cell and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. mmonje@stanford.edu. (13) Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.

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