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-  2019 

Anti-GD2 CAR T cells could prove transformative for H3-K27M+ diffuse midline gliomas

DOI: 10.21037/24141

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Abstract:

Diffuse intrinsic pontine glioma (DIPG)-derived primary cultures and other diffuse midline glioma (DMG)-ones were served for screening of surface antigen expression and gene expression analysis of responsible glycosyltransferases. Disialoganglioside GD2 was widely and highly expressed in H3-K27M-mutant (H3-K27M+) glioma cells. Relevant glycosyltransferase genes underwent up-regulation as analyzed by quantitative reverse transcription polymerase chain reaction (RT-qPCR). As well known, gliomas are generally very malignant and resistant to any current therapies (1). Especially, DIPG are aggressive and universally fatal, and hard to even mitigate the symptoms, since it is difficult to dissect tumor tissues from surrounding normal ones because of its site of occurrence and invasive natures (2). Palliative radiation therapy has been performed, resulting in minimal improvement of the patients’ life. Chimeric antigen receptor (CAR)-expressing T cells have shown impressive effects on B cell malignancies. Thus, effects of anti-GD2 CAR T cells incorporating a 4-1BBz costimulatory domain were examined by adding to cultured tumor cells, and adoptive transfer into NSG mice bearing orthotopically-generated DMGs (3). Anti-GD2 CAR T cells demonstrated robust GD2-dependent cytokine release and killing of DMG cells in the in vitro system. For patient-derived H3-K27M+ DMG orthotopic xenografts, i.e., injection of anti-GD2 CAR T cells resulted in excellent effects to eliminate GD2-positive tumor cells, and to extend survival times of mice. Anti-GD2 CAR T cell administration was tolerated in the majority of mice bearing orthotopic xenografts, while peritumoral neuroinflammation during the acute phase of antitumor activity sometimes induced lethality of mice. Consequently, this novel approach should be very promising and could prove transformative for the lethal childhood cancers, provided that careful monitoring and aggressive neurointensive care management are prepared. Here, great significances of this study and some concerns to be solved before being applied in the clinical fields have been proposed

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