Envelope-Specific Adaptive Immunity following Transplantation of Hematopoietic Stem Cells Modified with VSV-G Lentivirus
Current approaches for hematopoietic stem cell gene therapy typically involve lentiviral gene transfer in tandem with a conditioning regimen to aid stem cell engraftment. Although many pseudotyped envelopes have the capacity to be immunogenic due to their viral origins, thus far immune responses aga...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2020-12-01
|
Series: | Molecular Therapy: Methods & Clinical Development |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050120302060 |
id |
doaj-17e9f17e8b7b4e7394f2b7ba11cb9f15 |
---|---|
record_format |
Article |
spelling |
doaj-17e9f17e8b7b4e7394f2b7ba11cb9f152020-12-11T04:21:58ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012020-12-0119438446Envelope-Specific Adaptive Immunity following Transplantation of Hematopoietic Stem Cells Modified with VSV-G LentivirusBlake J. Rust0Pamela S. Becker1Devikha Chandrasekaran2Sara P. Kubek3Christopher W. Peterson4Jennifer E. Adair5Hans-Peter Kiem6Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 91911, USAStem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 91911, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USAStem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 91911, USAStem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 91911, USAStem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 91911, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USAStem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 91911, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USAStem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 91911, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA; Corresponding author: Hans-Peter Kiem, Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mail Stop D1-100, PO Box 19024, Seattle, WA 98109-1024, USA.Current approaches for hematopoietic stem cell gene therapy typically involve lentiviral gene transfer in tandem with a conditioning regimen to aid stem cell engraftment. Although many pseudotyped envelopes have the capacity to be immunogenic due to their viral origins, thus far immune responses against the most common envelope, vesicular stomatitis virus glycoprotein G (VSV-G), have not been reported in hematopoietic stem cell gene therapy trials. Herein, we report on two Fanconi anemia patients who underwent autologous transplantation of a lineage-depleted, gene-modified hematopoietic stem cell product without conditioning. We observed the induction of robust VSV-G-specific immunity, consistent with low/undetectable gene marking in both patients. Upon further interrogation, adaptive immune mechanisms directed against VSV-G were detected following transplantation in both patients, including increased VSV-G-specific T cell responses, anti-VSV-G immunoglobulin G (IgG), and cytotoxic responses that can specifically kill VSV-G-expressing target cell lines. A proportion of healthy controls also displayed preexisting VSV-G-specific CD4+ and CD8+ T cell responses, as well as VSV-G-specific IgG. Taken together, these data show that VSV-G-pseudotyped lentiviral vectors have the ability to elicit interfering adaptive immune responses in the context of certain hematopoietic stem cell transplantation settings.http://www.sciencedirect.com/science/article/pii/S2329050120302060adaptive immunityVSV-G envelopevector pseudotypelentivirustransplantgene therapy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Blake J. Rust Pamela S. Becker Devikha Chandrasekaran Sara P. Kubek Christopher W. Peterson Jennifer E. Adair Hans-Peter Kiem |
spellingShingle |
Blake J. Rust Pamela S. Becker Devikha Chandrasekaran Sara P. Kubek Christopher W. Peterson Jennifer E. Adair Hans-Peter Kiem Envelope-Specific Adaptive Immunity following Transplantation of Hematopoietic Stem Cells Modified with VSV-G Lentivirus Molecular Therapy: Methods & Clinical Development adaptive immunity VSV-G envelope vector pseudotype lentivirus transplant gene therapy |
author_facet |
Blake J. Rust Pamela S. Becker Devikha Chandrasekaran Sara P. Kubek Christopher W. Peterson Jennifer E. Adair Hans-Peter Kiem |
author_sort |
Blake J. Rust |
title |
Envelope-Specific Adaptive Immunity following Transplantation of Hematopoietic Stem Cells Modified with VSV-G Lentivirus |
title_short |
Envelope-Specific Adaptive Immunity following Transplantation of Hematopoietic Stem Cells Modified with VSV-G Lentivirus |
title_full |
Envelope-Specific Adaptive Immunity following Transplantation of Hematopoietic Stem Cells Modified with VSV-G Lentivirus |
title_fullStr |
Envelope-Specific Adaptive Immunity following Transplantation of Hematopoietic Stem Cells Modified with VSV-G Lentivirus |
title_full_unstemmed |
Envelope-Specific Adaptive Immunity following Transplantation of Hematopoietic Stem Cells Modified with VSV-G Lentivirus |
title_sort |
envelope-specific adaptive immunity following transplantation of hematopoietic stem cells modified with vsv-g lentivirus |
publisher |
Elsevier |
series |
Molecular Therapy: Methods & Clinical Development |
issn |
2329-0501 |
publishDate |
2020-12-01 |
description |
Current approaches for hematopoietic stem cell gene therapy typically involve lentiviral gene transfer in tandem with a conditioning regimen to aid stem cell engraftment. Although many pseudotyped envelopes have the capacity to be immunogenic due to their viral origins, thus far immune responses against the most common envelope, vesicular stomatitis virus glycoprotein G (VSV-G), have not been reported in hematopoietic stem cell gene therapy trials. Herein, we report on two Fanconi anemia patients who underwent autologous transplantation of a lineage-depleted, gene-modified hematopoietic stem cell product without conditioning. We observed the induction of robust VSV-G-specific immunity, consistent with low/undetectable gene marking in both patients. Upon further interrogation, adaptive immune mechanisms directed against VSV-G were detected following transplantation in both patients, including increased VSV-G-specific T cell responses, anti-VSV-G immunoglobulin G (IgG), and cytotoxic responses that can specifically kill VSV-G-expressing target cell lines. A proportion of healthy controls also displayed preexisting VSV-G-specific CD4+ and CD8+ T cell responses, as well as VSV-G-specific IgG. Taken together, these data show that VSV-G-pseudotyped lentiviral vectors have the ability to elicit interfering adaptive immune responses in the context of certain hematopoietic stem cell transplantation settings. |
topic |
adaptive immunity VSV-G envelope vector pseudotype lentivirus transplant gene therapy |
url |
http://www.sciencedirect.com/science/article/pii/S2329050120302060 |
work_keys_str_mv |
AT blakejrust envelopespecificadaptiveimmunityfollowingtransplantationofhematopoieticstemcellsmodifiedwithvsvglentivirus AT pamelasbecker envelopespecificadaptiveimmunityfollowingtransplantationofhematopoieticstemcellsmodifiedwithvsvglentivirus AT devikhachandrasekaran envelopespecificadaptiveimmunityfollowingtransplantationofhematopoieticstemcellsmodifiedwithvsvglentivirus AT sarapkubek envelopespecificadaptiveimmunityfollowingtransplantationofhematopoieticstemcellsmodifiedwithvsvglentivirus AT christopherwpeterson envelopespecificadaptiveimmunityfollowingtransplantationofhematopoieticstemcellsmodifiedwithvsvglentivirus AT jennifereadair envelopespecificadaptiveimmunityfollowingtransplantationofhematopoieticstemcellsmodifiedwithvsvglentivirus AT hanspeterkiem envelopespecificadaptiveimmunityfollowingtransplantationofhematopoieticstemcellsmodifiedwithvsvglentivirus |
_version_ |
1724386873102565376 |