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Alpharetroviral self-inactivating vectors produced by a superinfection-resistant stable packaging cell line allow genetic modification of primary human T lymphocytes.
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2016 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 97, 97-109 p.Article in journal (Refereed) Published
Abstract [en]

Primary human T lymphocytes represent an important cell population for adoptive immunotherapies, including chimeric-antigen and T-cell receptor applications, as they have the capability to eliminate non-self, virus-infected and tumor cells. Given the increasing numbers of clinical immunotherapy applications, the development of an optimal vector platform for genetic T lymphocyte engineering, which allows cost-effective high-quality vector productions, remains a critical goal. Alpharetroviral self-inactivating vectors (ARV) have several advantages compared to other vector platforms, including a more random genomic integration pattern and reduced likelihood for inducing aberrant splicing of integrated proviruses. We developed an ARV platform for the transduction of primary human T lymphocytes. We demonstrated functional transgene transfer using the clinically relevant herpes-simplex-virus thymidine kinase variant TK.007. Proof-of-concept of alpharetroviral-mediated T-lymphocyte engineering was shown in vitro and in a humanized transplantation model in vivo. Furthermore, we established a stable, human alpharetroviral packaging cell line in which we deleted the entry receptor (SLC1A5) for RD114/TR-pseudotyped ARVs to prevent superinfection and enhance genomic integrity of the packaging cell line and viral particles. We showed that superinfection can be entirely prevented, while maintaining high recombinant virus titers. Taken together, this resulted in an improved production platform representing an economic strategy for translating the promising features of ARVs for therapeutic T-lymphocyte engineering.

Place, publisher, year, edition, pages
Elsevier, 2016. Vol. 97, 97-109 p.
Keyword [en]
Alpharetroviral SIN vector, CRISPR-Cas9, Immunotherapy, Stable packaging cell line, Superinfection, TK007
National Category
Microbiology Immunology in the medical area
Research subject
Immunology; Genetics; Microbiology
Identifiers
URN: urn:nbn:se:umu:diva-133870DOI: 10.1016/j.biomaterials.2016.04.019ISI: 000377735800009PubMedID: 27162078OAI: oai:DiVA.org:umu-133870DiVA: diva2:1089487
Available from: 2017-04-19 Created: 2017-04-19 Last updated: 2017-05-08Bibliographically approved

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Charpentier, Emmanuelle
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CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
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  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
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