Transgenic CD8αβ co-receptor rescues endogenous TCR function in TCR-transgenic virus-specific T cells.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_FD8350547BA6
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Transgenic CD8αβ co-receptor rescues endogenous TCR function in TCR-transgenic virus-specific T cells.
Journal
Journal for immunotherapy of cancer
Author(s)
Bajwa G., Lanz I., Cardenas M., Brenner M.K., Arber C.
ISSN
2051-1426 (Electronic)
ISSN-L
2051-1426
Publication state
Published
Issued date
11/2020
Peer-reviewed
Oui
Volume
8
Number
2
Pages
e001487
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Genetically engineered virus-specific T cells (VSTs) are a platform for adoptive cell therapy after allogeneic hematopoietic stem cell transplantation. However, redirection to a tumor-associated antigen by the introduction of a transgenic T-cell receptor (TCR) reduces anti-viral activity, thereby impeding the possibility of preventing or treating two distinct complications-malignant relapse and viral infection-with a single cell therapy product. Availability of CD8αβ co-receptor molecules can significantly impact class I restricted T-cell activation, and thus, we interrogated whether transgenic CD8αβ improves anti-viral activity mediated by native VSTs with or without a co-expressed transgenic TCR (TCR8).
Our existing clinical VST manufacturing platform was adapted and validated to engineer TCR+ or TCR8+ VSTs targeting cytomegalovirus and Epstein-Barr virus. Simultaneous anti-viral and anti-tumor function of engineered VSTs was assessed in vitro and in vivo. We used pentamer staining, interferon (IFN)-γ enzyme-linked immunospot (ELISpot), intracellular cytokine staining (ICS), cytotoxicity assays, co-cultures, and cytokine secretion assays for the in vitro characterization. The in vivo anti-tumor function was assessed in a leukemia xenograft mouse model.
Both transgenic CD8αβ alone and TCR8 had significant impact on the anti-viral function of engineered VSTs, and TCR8+ VSTs had comparable anti-viral activity as non-engineered VSTs as determined by IFN-γ ELISpot, ICS and cytotoxicity assays. TCR8-engineered VSTs had improved anti-tumor function and greater effector cytokine production in vitro, as well as enhanced anti-tumor function against leukemia xenografts in mice.
Incorporation of transgenic CD8αβ into vectors for TCR-targetable antigens preserves anti-viral activity of TCR transgenic VSTs while simultaneously supporting tumor-directed activity mediated by a transgenic TCR. Our approach may provide clinical benefit in preventing and treating viral infections and malignant relapse post-transplant.
Keywords
adoptive, antigen, cell engineering, immunotherapy, receptors
Pubmed
Web of science
Open Access
Yes
Create date
22/11/2020 11:58
Last modification date
30/04/2021 6:16
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