Browsing by Subject "Gangliosides"
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Item Open Access GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas.(Nature, 2022-03) Majzner, Robbie G; Ramakrishna, Sneha; Yeom, Kristen W; Patel, Shabnum; Chinnasamy, Harshini; Schultz, Liora M; Richards, Rebecca M; Jiang, Li; Barsan, Valentin; Mancusi, Rebecca; Geraghty, Anna C; Good, Zinaida; Mochizuki, Aaron Y; Gillespie, Shawn M; Toland, Angus Martin Shaw; Mahdi, Jasia; Reschke, Agnes; Nie, Esther H; Chau, Isabelle J; Rotiroti, Maria Caterina; Mount, Christopher W; Baggott, Christina; Mavroukakis, Sharon; Egeler, Emily; Moon, Jennifer; Erickson, Courtney; Green, Sean; Kunicki, Michael; Fujimoto, Michelle; Ehlinger, Zach; Reynolds, Warren; Kurra, Sreevidya; Warren, Katherine E; Prabhu, Snehit; Vogel, Hannes; Rasmussen, Lindsey; Cornell, Timothy T; Partap, Sonia; Fisher, Paul G; Campen, Cynthia J; Filbin, Mariella G; Grant, Gerald; Sahaf, Bita; Davis, Kara L; Feldman, Steven A; Mackall, Crystal L; Monje, MichelleDiffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system1. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 106 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly3. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.Item Open Access Multiple phenotypic changes in mice after knockout of the B3gnt5 gene, encoding Lc3 synthase--a key enzyme in lacto-neolacto ganglioside synthesis.(BMC Dev Biol, 2010-11-18) Kuan, Chien-Tsun; Chang, Jinli; Mansson, Jan-Eric; Li, Jianjun; Pegram, Charles; Fredman, Pam; McLendon, Roger E; Bigner, Darell DBACKGROUND: Ganglioside biosynthesis occurs through a multi-enzymatic pathway which at the lactosylceramide step is branched into several biosynthetic series. Lc3 synthase utilizes a variety of galactose-terminated glycolipids as acceptors by establishing a glycosidic bond in the beta-1,3-linkage to GlcNaAc to extend the lacto- and neolacto-series gangliosides. In order to examine the lacto-series ganglioside functions in mice, we used gene knockout technology to generate Lc3 synthase gene B3gnt5-deficient mice by two different strategies and compared the phenotypes of the two null mouse groups with each other and with their wild-type counterparts. RESULTS: B3gnt5 gene knockout mutant mice appeared normal in the embryonic stage and, if they survived delivery, remained normal during early life. However, about 9% developed early-stage growth retardation, 11% died postnatally in less than 2 months, and adults tended to die in 5-15 months, demonstrating splenomegaly and notably enlarged lymph nodes. Without lacto-neolacto series gangliosides, both homozygous and heterozygous mice gradually displayed fur loss or obesity, and breeding mice demonstrated reproductive defects. Furthermore, B3gnt5 gene knockout disrupted the functional integrity of B cells, as manifested by a decrease in B-cell numbers in the spleen, germinal center disappearance, and less efficiency to proliferate in hybridoma fusion. CONCLUSIONS: These novel results demonstrate unequivocally that lacto-neolacto series gangliosides are essential to multiple physiological functions, especially the control of reproductive output, and spleen B-cell abnormality. We also report the generation of anti-IgG response against the lacto-series gangliosides 3'-isoLM1 and 3',6'-isoLD1.