FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4286298907> ?p ?o ?g. }

• W4286298907 endingPage "e14521" @default.
• W4286298907 startingPage "e14521" @default.
• W4286298907 abstract "e14521 Background: Hepatocellular carcinoma (HCC), the fourth leading cause of cancer-related deaths worldwide, is amenable to immunotherapies that target glypican-3 (GPC3), a protein expressed by over 75% of HCCs but not by healthy tissues. The invariant natural killer T cells (NKTs) prevent HCC tumorogenesis through interactions with the gut microbiome in mice, and the presence of tumor-infiltrating NKTs is associated with improved clinical outcomes. We previously tested GPC3-specific chimeric antigen receptors (CARs) and selected a receptor with both CD28 and 41BB costimulatory endodomains based on its ability to mediate superior antitumor activity of transduced NKTs in vivo. Co-expression of interleukin-15 (IL15), a cytokine that supports NKT expansion and persistence, with the chosen GPC3-CAR further enhanced this activity. GPC3-CAR NKTs co-expressing IL15 (15.GPC3-CAR) overexpressed the Basic Leucine Zipper ATF-Like Transcription Factor 3 (BATF3), a member of the AP-1 family. Since AP-1 family proteins are master regulators of cell survival and proliferation, we hypothesized that overexpressing BATF3 in GPC3-CAR NKTs (BATF3.GPC3-CAR) will lead to superior expansion, persistence, and antitumor activity compared to 15.GPC3-CAR NKTs. Methods: We used RNAseq and flow cytometry to define the transcriptomic and phenotypic characteristics, respectively, of BATF3-overexpressing NKTs at baseline and after tumor cell killing in co-culture. We also used co-culture assays to evaluate the ability of BATF3- or IL15-expressing NKTs to proliferate, produce effector cytokines, and kill tumor cells after multiple rounds of exposure. Finally, we evaluated the ability of BATF3.GPC3-CAR and IL15.GPC3-CAR NKTs to expand, persist, and target tumors in an HCC xenograft murine model. Results: BATF3 overexpression in NKTs induced significant differences in gene expression profiles compared to a GFP control at baseline (DEGs up: 20; down: 26, p < 0.01) and after tumor cell killing (DEGs up: 19; down: 32; p < 0.01; fold change > 2 or < 0.5, respectively) corresponding to enrichment of gene sets related to metabolic fitness. Importantly, CD62L+ NKTs, which have enhanced antitumor properties, were enriched in BATF3-expressing NKTs (27.6% vs 8.2%, p < 0.05, versus GFP control). Further, BATF3 significantly enhanced NKT proliferation (area under the curve of absolute NKT cell counts: 5x10 11 vs 1.1x10 11 , p = 0.001; fold expansion: 6.12x10 4 vs 1.2x10 4 , p = 0.001, versus IL15 NKTs). Finally, BATF3.GPC3-CAR NKTs induced long-term tumor control and significantly improved survival of HCC xenograft-bearing mice compared to 15.GPC3-CAR NKTs (p = 0.0002, Mantel-Cox analysis). Conclusions: BATF3.GPC3-CAR NKTs induce robust antitumor activity in pre-clinical models of HCC. These results provide a foundation for evaluating BATF3.GPC3-CAR NKTs in patients with relapsed/refractory HCC." @default.
• W4286298907 created "2022-07-21" @default.
• W4286298907 creator A5003039585 @default.
• W4286298907 creator A5005099413 @default.
• W4286298907 creator A5016553017 @default.
• W4286298907 creator A5021334593 @default.
• W4286298907 creator A5024963763 @default.
• W4286298907 creator A5034619275 @default.
• W4286298907 creator A5064986621 @default.
• W4286298907 creator A5065127545 @default.
• W4286298907 creator A5070484157 @default.
• W4286298907 creator A5085626597 @default.
• W4286298907 creator A5085646513 @default.
• W4286298907 date "2022-06-01" @default.
• W4286298907 modified "2023-10-16" @default.
• W4286298907 title "Glypican-3-specific CAR-NKT cells overexpressing BATF3 mediate potent antitumor activity against hepatocellular carcinoma." @default.
• W4286298907 doi "https://doi.org/10.1200/jco.2022.40.16_suppl.e14521" @default.
• W4286298907 hasPublicationYear "2022" @default.
• W4286298907 type Work @default.
• W4286298907 citedByCount "1" @default.
• W4286298907 countsByYear W42862989072022 @default.
• W4286298907 crossrefType "journal-article" @default.
• W4286298907 hasAuthorship W4286298907A5003039585 @default.
• W4286298907 hasAuthorship W4286298907A5005099413 @default.
• W4286298907 hasAuthorship W4286298907A5016553017 @default.
• W4286298907 hasAuthorship W4286298907A5021334593 @default.
• W4286298907 hasAuthorship W4286298907A5024963763 @default.
• W4286298907 hasAuthorship W4286298907A5034619275 @default.
• W4286298907 hasAuthorship W4286298907A5064986621 @default.
• W4286298907 hasAuthorship W4286298907A5065127545 @default.
• W4286298907 hasAuthorship W4286298907A5070484157 @default.
• W4286298907 hasAuthorship W4286298907A5085626597 @default.
• W4286298907 hasAuthorship W4286298907A5085646513 @default.
• W4286298907 hasConcept C154317977 @default.
• W4286298907 hasConcept C202751555 @default.
• W4286298907 hasConcept C203014093 @default.
• W4286298907 hasConcept C2777701055 @default.
• W4286298907 hasConcept C2778690821 @default.
• W4286298907 hasConcept C2778867473 @default.
• W4286298907 hasConcept C3875195 @default.
• W4286298907 hasConcept C502942594 @default.
• W4286298907 hasConcept C55493867 @default.
• W4286298907 hasConcept C71924100 @default.
• W4286298907 hasConcept C86803240 @default.
• W4286298907 hasConcept C8891405 @default.
• W4286298907 hasConceptScore W4286298907C154317977 @default.
• W4286298907 hasConceptScore W4286298907C202751555 @default.
• W4286298907 hasConceptScore W4286298907C203014093 @default.
• W4286298907 hasConceptScore W4286298907C2777701055 @default.
• W4286298907 hasConceptScore W4286298907C2778690821 @default.
• W4286298907 hasConceptScore W4286298907C2778867473 @default.
• W4286298907 hasConceptScore W4286298907C3875195 @default.
• W4286298907 hasConceptScore W4286298907C502942594 @default.
• W4286298907 hasConceptScore W4286298907C55493867 @default.
• W4286298907 hasConceptScore W4286298907C71924100 @default.
• W4286298907 hasConceptScore W4286298907C86803240 @default.
• W4286298907 hasConceptScore W4286298907C8891405 @default.
• W4286298907 hasIssue "16_suppl" @default.
• W4286298907 hasLocation W42862989071 @default.
• W4286298907 hasOpenAccess W4286298907 @default.
• W4286298907 hasPrimaryLocation W42862989071 @default.
• W4286298907 hasRelatedWork W2046089611 @default.
• W4286298907 hasRelatedWork W2120341761 @default.
• W4286298907 hasRelatedWork W3021024241 @default.
• W4286298907 hasRelatedWork W3027210704 @default.
• W4286298907 hasRelatedWork W3083637057 @default.
• W4286298907 hasRelatedWork W3160193319 @default.
• W4286298907 hasRelatedWork W3194618061 @default.
• W4286298907 hasRelatedWork W3212282404 @default.
• W4286298907 hasRelatedWork W4226082485 @default.
• W4286298907 hasRelatedWork W4375856453 @default.
• W4286298907 hasVolume "40" @default.
• W4286298907 isParatext "false" @default.
• W4286298907 isRetracted "false" @default.
• W4286298907 workType "article" @default.