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

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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.
Originele taal-2Engels
Pagina's (van-tot)572-579
TijdschriftNature medicine
Volume24
Nummer van het tijdschrift5
DOI's
StatusGepubliceerd - mei 2018

Vingerafdruk

Duik in de onderzoeksthema's van 'Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M + diffuse midline gliomas'. Samen vormen ze een unieke vingerafdruk.

Citeer dit