Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas.
Christopher W MountRobbie G MajznerShree SundareshEvan P ArnoldMeena KadapakkamSamuel HaileLouai LabaniehEsther HullemanPamelyn J WooSkyler P RietbergHannes VogelMichelle MonjeCrystal L MackallPublished in: Nature medicine (2018)
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 malignancies7-10, and recent results suggest benefit in central nervous system malignancies11-13. 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 trials15-17. 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.
Keyphrases
- high grade
- low grade
- spinal cord
- clinical trial
- induced apoptosis
- cancer therapy
- cell cycle arrest
- endothelial cells
- type diabetes
- spinal cord injury
- traumatic brain injury
- single cell
- dna methylation
- metabolic syndrome
- drug delivery
- skeletal muscle
- wild type
- randomized controlled trial
- cerebrospinal fluid
- stem cells
- gene expression
- bone marrow
- inflammatory response
- cell proliferation
- cell death
- mesenchymal stem cells
- signaling pathway
- deep brain stimulation
- lps induced
- high fat diet induced
- blood brain barrier