Human VH-based chimeric antigen receptor T cells targeting glypican 3 eliminate tumors in preclinical models of HCC.
| Title: | Human VH-based chimeric antigen receptor T cells targeting glypican 3 eliminate tumors in preclinical models of HCC. |
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| Authors: | Kolluri, Aarti, Dan Li, Nan Li, Zhijian Duan, Roberts, Lewis R., Ho, Mitchell |
| Source: | Hepatology Communications; Feb2023, Vol. 7 Issue 2, p1-13, 13p |
| Subject Terms: | GLYPICANS, CHIMERIC antigen receptors, TRANSMEMBRANE domains, ANIMAL models in research, T cells |
| Abstract: | Background and Aims: Efficacy of chimeric antigen receptor (CAR) T cells for treating solid tumors, including HCC, remains a challenge. Nanobodies are emerging building blocks of CAR T cells due to their small size and high expression. Membrane proximal sites have been shown as attractive epitopes of CAR T cells. However, current CAR formats are not tailored toward nanobodies or targeting membrane distal epitopes. Approach and Results: Using hYP7 Fv (membrane proximal) and HN3 VH nanobody (membrane distal) as GPC3 targeting elements, we sought to determine how hinges and transmembrane portions of varying structures and sizes affect CAR T-cell function. We generated multiple permutations of CAR T cells containing CD8, CD28, IgG4, and Fc domains. We show that engineered HN3 CAR T cells can be improved by 2 independent, synergistic changes in the hinge and transmembrane domains. The T cells expressing the HN3 CAR which contains the hinge region of IgG4 and the CD28 transmembrane domain (HN3-IgG4H-CD28TM) exhibited high cytotoxic activity and caused complete HCC tumor eradication in immunodeficient mice. HN3-IgG4H-CD28TM CAR T cells were enriched for cytotoxic-memory CD8+ T cells and NFAT signals, and reduced ß catenin levels in HCC cells. Conclusion: Our findings indicate that altering the hinge and transmembrane domains of a nanobody-based CAR targeting a distal GPC3 epitope, in contrast to a membrane proximal epitope, lead to robust T-cell signaling and induce swift and durable eradication of HCC tumors. [ABSTRACT FROM AUTHOR] |
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| Database: | Complementary Index |
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| Items | – Name: Title Label: Title Group: Ti Data: Human VH-based chimeric antigen receptor T cells targeting glypican 3 eliminate tumors in preclinical models of HCC. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Kolluri%2C+Aarti%22">Kolluri, Aarti</searchLink><br /><searchLink fieldCode="AR" term="%22Dan+Li%22">Dan Li</searchLink><br /><searchLink fieldCode="AR" term="%22Nan+Li%22">Nan Li</searchLink><br /><searchLink fieldCode="AR" term="%22Zhijian+Duan%22">Zhijian Duan</searchLink><br /><searchLink fieldCode="AR" term="%22Roberts%2C+Lewis+R%2E%22">Roberts, Lewis R.</searchLink><br /><searchLink fieldCode="AR" term="%22Ho%2C+Mitchell%22">Ho, Mitchell</searchLink> – Name: TitleSource Label: Source Group: Src Data: Hepatology Communications; Feb2023, Vol. 7 Issue 2, p1-13, 13p – Name: Subject Label: Subject Terms Group: Su Data: <searchLink fieldCode="DE" term="%22GLYPICANS%22">GLYPICANS</searchLink><br /><searchLink fieldCode="DE" term="%22CHIMERIC+antigen+receptors%22">CHIMERIC antigen receptors</searchLink><br /><searchLink fieldCode="DE" term="%22TRANSMEMBRANE+domains%22">TRANSMEMBRANE domains</searchLink><br /><searchLink fieldCode="DE" term="%22ANIMAL+models+in+research%22">ANIMAL models in research</searchLink><br /><searchLink fieldCode="DE" term="%22T+cells%22">T cells</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Background and Aims: Efficacy of chimeric antigen receptor (CAR) T cells for treating solid tumors, including HCC, remains a challenge. Nanobodies are emerging building blocks of CAR T cells due to their small size and high expression. Membrane proximal sites have been shown as attractive epitopes of CAR T cells. However, current CAR formats are not tailored toward nanobodies or targeting membrane distal epitopes. Approach and Results: Using hYP7 Fv (membrane proximal) and HN3 VH nanobody (membrane distal) as GPC3 targeting elements, we sought to determine how hinges and transmembrane portions of varying structures and sizes affect CAR T-cell function. We generated multiple permutations of CAR T cells containing CD8, CD28, IgG4, and Fc domains. We show that engineered HN3 CAR T cells can be improved by 2 independent, synergistic changes in the hinge and transmembrane domains. The T cells expressing the HN3 CAR which contains the hinge region of IgG4 and the CD28 transmembrane domain (HN3-IgG4H-CD28TM) exhibited high cytotoxic activity and caused complete HCC tumor eradication in immunodeficient mice. HN3-IgG4H-CD28TM CAR T cells were enriched for cytotoxic-memory CD8+ T cells and NFAT signals, and reduced ß catenin levels in HCC cells. Conclusion: Our findings indicate that altering the hinge and transmembrane domains of a nanobody-based CAR targeting a distal GPC3 epitope, in contrast to a membrane proximal epitope, lead to robust T-cell signaling and induce swift and durable eradication of HCC tumors. [ABSTRACT FROM AUTHOR] – Name: Abstract Label: Group: Ab Data: <i>Copyright of Hepatology Communications is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1097/HC9.0000000000000022 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 13 StartPage: 1 Subjects: – SubjectFull: GLYPICANS Type: general – SubjectFull: CHIMERIC antigen receptors Type: general – SubjectFull: TRANSMEMBRANE domains Type: general – SubjectFull: ANIMAL models in research Type: general – SubjectFull: T cells Type: general Titles: – TitleFull: Human VH-based chimeric antigen receptor T cells targeting glypican 3 eliminate tumors in preclinical models of HCC. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Kolluri, Aarti – PersonEntity: Name: NameFull: Dan Li – PersonEntity: Name: NameFull: Nan Li – PersonEntity: Name: NameFull: Zhijian Duan – PersonEntity: Name: NameFull: Roberts, Lewis R. – PersonEntity: Name: NameFull: Ho, Mitchell IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 02 Text: Feb2023 Type: published Y: 2023 Identifiers: – Type: issn-print Value: 2471254X Numbering: – Type: volume Value: 7 – Type: issue Value: 2 Titles: – TitleFull: Hepatology Communications Type: main |
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