FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2914304825> ?p ?o ?g. }

• W2914304825 abstract "Glioblastoma (GBM) is the most common type of primary brain tumor, with the standard therapy only modestly improving the prognosis, highlighting the necessity to develop advanced treatments. We and others have established the platform to potentiate immune response against GBMs using chimeric antigen receptor (CAR) engineered T-cells. Specifically, we have shown that intracranial administration of CAR T-cells can be well tolerated in patients with recurrent GBMs, together with some early clinical evidence of antitumor response. However, CAR T-cell therapy against GBMs is complicated by the inter- and intratumoral heterogeneity, while the single-targeting therapies only respond to a subset of tumor cells. The development of new CAR therapy would thus aim for targeting a wider range of tumor cells and bypassing antigen escape. Here, we took an approach different from conventional strategies of tumor antigen discovery, exploiting the tumor-binding potential of a natural peptide to develop CAR T-cells that broadly target GBMs. Chlorotoxin (CLTX) is a 36-amino acid peptide with demonstrated GBM-binding capability. Inspired by the utilization of CLTX in GBM tumor imaging, we used a fluorescence-conjugated CLTX to screen the freshly-dispersed primary GBM cells and patient-derived GBM neurospheres, and found that CLTX binding was more homogeneous than the expression of other GBM-associated antigens including EGFR, HER2 and IL13Rα2. Although CLTX has limited inhibitory effect on GBM growth, its broad binding to GBM cells illustrates the potential to be conjugated with a cytotoxic agent. Therefore, we generated CAR T-cells bearing CLTX as the antigen targeting domain. CLTX-CAR T-cells were able to get activated after stimulating with GBM cells, as indicated by their degranulation, cytokine production and immuno-synapse formation. Modification of CAR constructs revealed that CLTX-CAR T-cells with CD28 costimulatory signal exhibited potent effector activity, while the 4-1BB costimulation resulted in inadequate CAR activation. In both in vitro and in vivo models, CLTX-CAR T-cells effectively eliminated GBM cells and tumors, including the ones with no/low expression of EGFR, HER2 and IL13Rα2. Importantly, CLTX peptide exhibited negligible binding to a panel of normal cells from neural and other tissues, and CLTX-CAR T-cells showed no off-target effect against normal organs in tumor-bearing mouse models. Screening on patient-derived GBM neurospheres, we discovered that the expression of metalloproteinase (MMP)-2 on targeT-cells was correlated with the effector function of CLTX-CAR T-cells. Further, the antitumor function of CLTX-CAR T-cells was severely diminished against GBMs with MMP-2 knockdown. Consistent with the cytotoxicity of CLTX-CAR T-cells, MMP-2 expression was also present in a subgroup of GBM cells with undetectable levels of EGFR, HER2 and IL13Rα2 expression. Our results demonstrate for the first time that a peptide toxin can be successfully used as the tumor targeting domain of a CAR, which eliminates GBMs with high efficiency and selectivity. The CLTX-CAR has the potential to limit GBM heterogeneity and compensate current CAR T-cell therapies against solid tumors. Citation Format: Dongrui Wang, Vanessa Jonsson, Sarah Wright, Wen-Chung Chang, Xin Yang, Renate Starr, Alfonso Brito, Brenda Aguilar, Aniee Sarkissian, Lihong Weng, Stephen J Forman, Michael E Barish, Christine E. Brown. Chlorotoxin redirects T-cells for specific and effective targeting against glioblastomas [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A045." @default.
• W2914304825 created "2019-02-21" @default.
• W2914304825 creator A5006450343 @default.
• W2914304825 creator A5010868067 @default.
• W2914304825 creator A5012025508 @default.
• W2914304825 creator A5017277322 @default.
• W2914304825 creator A5028928234 @default.
• W2914304825 creator A5032461204 @default.
• W2914304825 creator A5039374832 @default.
• W2914304825 creator A5039825744 @default.
• W2914304825 creator A5039968122 @default.
• W2914304825 creator A5048566863 @default.
• W2914304825 creator A5056204407 @default.
• W2914304825 creator A5061976329 @default.
• W2914304825 creator A5079918856 @default.
• W2914304825 date "2019-02-01" @default.
• W2914304825 modified "2023-09-27" @default.
• W2914304825 title "Abstract A045: Chlorotoxin redirects T-cells for specific and effective targeting against glioblastomas" @default.
• W2914304825 doi "https://doi.org/10.1158/2326-6074.cricimteatiaacr18-a045" @default.
• W2914304825 hasPublicationYear "2019" @default.
• W2914304825 type Work @default.
• W2914304825 sameAs 2914304825 @default.
• W2914304825 citedByCount "0" @default.
• W2914304825 crossrefType "proceedings-article" @default.
• W2914304825 hasAuthorship W2914304825A5006450343 @default.
• W2914304825 hasAuthorship W2914304825A5010868067 @default.
• W2914304825 hasAuthorship W2914304825A5012025508 @default.
• W2914304825 hasAuthorship W2914304825A5017277322 @default.
• W2914304825 hasAuthorship W2914304825A5028928234 @default.
• W2914304825 hasAuthorship W2914304825A5032461204 @default.
• W2914304825 hasAuthorship W2914304825A5039374832 @default.
• W2914304825 hasAuthorship W2914304825A5039825744 @default.
• W2914304825 hasAuthorship W2914304825A5039968122 @default.
• W2914304825 hasAuthorship W2914304825A5048566863 @default.
• W2914304825 hasAuthorship W2914304825A5056204407 @default.
• W2914304825 hasAuthorship W2914304825A5061976329 @default.
• W2914304825 hasAuthorship W2914304825A5079918856 @default.
• W2914304825 hasConcept C121608353 @default.
• W2914304825 hasConcept C123012128 @default.
• W2914304825 hasConcept C126322002 @default.
• W2914304825 hasConcept C147483822 @default.
• W2914304825 hasConcept C154317977 @default.
• W2914304825 hasConcept C162746124 @default.
• W2914304825 hasConcept C185592680 @default.
• W2914304825 hasConcept C202751555 @default.
• W2914304825 hasConcept C203014093 @default.
• W2914304825 hasConcept C20875687 @default.
• W2914304825 hasConcept C2776662205 @default.
• W2914304825 hasConcept C2777701055 @default.
• W2914304825 hasConcept C2781230642 @default.
• W2914304825 hasConcept C3875195 @default.
• W2914304825 hasConcept C502942594 @default.
• W2914304825 hasConcept C55493867 @default.
• W2914304825 hasConcept C71924100 @default.
• W2914304825 hasConcept C8891405 @default.
• W2914304825 hasConceptScore W2914304825C121608353 @default.
• W2914304825 hasConceptScore W2914304825C123012128 @default.
• W2914304825 hasConceptScore W2914304825C126322002 @default.
• W2914304825 hasConceptScore W2914304825C147483822 @default.
• W2914304825 hasConceptScore W2914304825C154317977 @default.
• W2914304825 hasConceptScore W2914304825C162746124 @default.
• W2914304825 hasConceptScore W2914304825C185592680 @default.
• W2914304825 hasConceptScore W2914304825C202751555 @default.
• W2914304825 hasConceptScore W2914304825C203014093 @default.
• W2914304825 hasConceptScore W2914304825C20875687 @default.
• W2914304825 hasConceptScore W2914304825C2776662205 @default.
• W2914304825 hasConceptScore W2914304825C2777701055 @default.
• W2914304825 hasConceptScore W2914304825C2781230642 @default.
• W2914304825 hasConceptScore W2914304825C3875195 @default.
• W2914304825 hasConceptScore W2914304825C502942594 @default.
• W2914304825 hasConceptScore W2914304825C55493867 @default.
• W2914304825 hasConceptScore W2914304825C71924100 @default.
• W2914304825 hasConceptScore W2914304825C8891405 @default.
• W2914304825 hasLocation W29143048251 @default.
• W2914304825 hasOpenAccess W2914304825 @default.
• W2914304825 hasPrimaryLocation W29143048251 @default.
• W2914304825 hasRelatedWork W2020590412 @default.
• W2914304825 hasRelatedWork W203177496 @default.
• W2914304825 hasRelatedWork W2064357373 @default.
• W2914304825 hasRelatedWork W2285466634 @default.
• W2914304825 hasRelatedWork W2413922971 @default.
• W2914304825 hasRelatedWork W2761773593 @default.
• W2914304825 hasRelatedWork W2791145324 @default.
• W2914304825 hasRelatedWork W2914304825 @default.
• W2914304825 hasRelatedWork W4224119345 @default.
• W2914304825 hasRelatedWork W4229455221 @default.
• W2914304825 isParatext "false" @default.
• W2914304825 isRetracted "false" @default.
• W2914304825 magId "2914304825" @default.
• W2914304825 workType "article" @default.