학술논문
Redirector of Vaccine-induced Effector Responses (RoVER) for specific killing of cellular targets.
Document Type
Academic Journal
Author
Konrad CV; Department of Clinical Medicine, Aarhus University, Aarhus C, 8000, Denmark; Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, 8200, Denmark.; Iversen EF; Department of Clinical Medicine, Aarhus University, Aarhus C, 8000, Denmark.; Gunst JD; Department of Clinical Medicine, Aarhus University, Aarhus C, 8000, Denmark; Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, 8200, Denmark.; Monrad I; Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, 8200, Denmark.; Holleufer A; Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, 8000, Denmark.; Hartmann R; Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, 8000, Denmark.; Østergaard LJ; Department of Clinical Medicine, Aarhus University, Aarhus C, 8000, Denmark; Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, 8200, Denmark.; Søgaard OS; Department of Clinical Medicine, Aarhus University, Aarhus C, 8000, Denmark; Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, 8200, Denmark.; Schleimann MH; Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, 8200, Denmark.; Tolstrup M; Department of Clinical Medicine, Aarhus University, Aarhus C, 8000, Denmark; Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, 8200, Denmark. Electronic address: marttols@rm.dk.
Source
Publisher: Elsevier B.V Country of Publication: Netherlands NLM ID: 101647039 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2352-3964 (Electronic) Linking ISSN: 23523964 NLM ISO Abbreviation: EBioMedicine Subsets: MEDLINE
Subject
Language
English
Abstract
Background: In individuals with malignancy or HIV-1 infection, antigen-specific cytotoxic T lymphocytes (CTLs) often display an exhausted phenotype with impaired capacity to eliminate the disease. Existing cell-based immunotherapy strategies are often limited by the requirement for adoptive transfer of CTLs. We have developed an immunotherapy technology in which potent CTL responses are generated in vivo by vaccination and redirected to eliminate target cells using a bispecific Redirector of Vaccine-induced Effector Responses (RoVER).
Methods: Following Yellow fever (YF) 17D vaccination of 51 healthy volunteers (NCT04083430), single-epitope YF-specific CTL responses were quantified by tetramer staining and multi-parameter flow cytometry. RoVER-mediated redirection of YF-specific CTLs to kill antigen-expressing Raji-Env cells, autologous CD19+ B cells or CD4+ T cells infected in vitro with a full-length HIV-1-eGFP was assessed in cell killing assays. Moreover, secreted IFN-γ, granzyme B, and TNF-α were analyzed by mesoscale multiplex assays.
Findings: YF-17D vaccination induced strong epitope-specific CTL responses in the study participants. In cell killing assays, RoVER-mediated redirection of YF-specific CTLs to autologous CD19+ B cells or HIV-1-infected CD4+ cells resulted in 58% and 53% killing at effector to target ratio 1:1, respectively.
Interpretation: We have developed an immunotherapy technology in which epitope-specific CTLs induced by vaccination can be redirected to kill antigen-expressing target cells by RoVER linking. The RoVER technology is highly specific and can be adapted to recognize various cell surface antigens. Importantly, this technology obviates the need for adoptive transfer of CTLs.
Funding: This work was funded by the Novo Nordisk Foundation (Hallas Møller NNF10OC0054577).
Competing Interests: Declaration of interests The authors declare no competing interests. CVK, JDG, MHS and MT are listed as inventors on a patent application filed by Aarhus University.
(Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
Methods: Following Yellow fever (YF) 17D vaccination of 51 healthy volunteers (NCT04083430), single-epitope YF-specific CTL responses were quantified by tetramer staining and multi-parameter flow cytometry. RoVER-mediated redirection of YF-specific CTLs to kill antigen-expressing Raji-Env cells, autologous CD19+ B cells or CD4+ T cells infected in vitro with a full-length HIV-1-eGFP was assessed in cell killing assays. Moreover, secreted IFN-γ, granzyme B, and TNF-α were analyzed by mesoscale multiplex assays.
Findings: YF-17D vaccination induced strong epitope-specific CTL responses in the study participants. In cell killing assays, RoVER-mediated redirection of YF-specific CTLs to autologous CD19+ B cells or HIV-1-infected CD4+ cells resulted in 58% and 53% killing at effector to target ratio 1:1, respectively.
Interpretation: We have developed an immunotherapy technology in which epitope-specific CTLs induced by vaccination can be redirected to kill antigen-expressing target cells by RoVER linking. The RoVER technology is highly specific and can be adapted to recognize various cell surface antigens. Importantly, this technology obviates the need for adoptive transfer of CTLs.
Funding: This work was funded by the Novo Nordisk Foundation (Hallas Møller NNF10OC0054577).
Competing Interests: Declaration of interests The authors declare no competing interests. CVK, JDG, MHS and MT are listed as inventors on a patent application filed by Aarhus University.
(Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)