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Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas letter
- Source :
- Nature Medicine, 24(5), 572-579. Nature Publishing Group, Mount, C W, Majzner, R G, Sundaresh, S, Arnold, E P, Kadapakkam, M, Haile, S, Labanieh, L, Hulleman, E, Woo, P J, Rietberg, S P, Vogel, H, Monje, M & Mackall, C L 2018, ' Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas letter ', Nature Medicine, vol. 24, no. 5, pp. 572-579 . https://doi.org/10.1038/s41591-018-0006-x
- Publication Year :
- 2018
-
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.
- Subjects :
- 0301 basic medicine
business.industry
medicine.medical_treatment
Central nervous system
General Medicine
medicine.disease
General Biochemistry, Genetics and Molecular Biology
Chimeric antigen receptor
In vitro
3. Good health
03 medical and health sciences
030104 developmental biology
medicine.anatomical_structure
Cytokine
Glioma
medicine
Systemic administration
Cancer research
business
Neuroinflammation
B cell
Subjects
Details
- Language :
- English
- ISSN :
- 10788956
- Database :
- OpenAIRE
- Journal :
- Nature Medicine, 24(5), 572-579. Nature Publishing Group, Mount, C W, Majzner, R G, Sundaresh, S, Arnold, E P, Kadapakkam, M, Haile, S, Labanieh, L, Hulleman, E, Woo, P J, Rietberg, S P, Vogel, H, Monje, M & Mackall, C L 2018, ' Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas letter ', Nature Medicine, vol. 24, no. 5, pp. 572-579 . https://doi.org/10.1038/s41591-018-0006-x
- Accession number :
- edsair.doi.dedup.....5d4031bb143fa2278be3f21ea578efb4