A new synthetic toll-like receptor 1/2 ligand is an efficient adjuvant for peptide vaccination in a human volunteer

Journal for ImmunoTherapy of Cancer

Manfred Kneilling¹  Johannes Schwenck¹  Bernd J. Pichler¹  Benjamin Weide²  Jürgen Bauer²  Stephan Forchhammer²  Gisela Metzler²  Wilfried Schippert²  Sebastian P. Haen³  Hans-Georg Rammensee³  P. Anoop Chandran³  Linus Backert³  Elisa Rusch³  Henning Zelba³  Johanna Bödder³  Alexander N. R. Weber³  Stefan Stevanović³  Heiko Schuster³  Daniel J. Kowalewski³  Cécile Gouttefangeas³  Yamel Cardona Gloria³  Kerstin Artzner³  Juliane S. Walz³  Markus W. Löffler³  Karoline Laske³  Moreno Di Marco³  Reinhild Klein⁴  Karl-Heinz Wiesmüller⁵  Jill-Marie Schertel⁶  Rebekka Wehner⁶  Antje Tunger⁶  Maximilian Kießler⁶  Marc Schmitz⁶  Luise Müller⁶  Christian la Fougère⁷  Meike Jakobi⁸  Nicole Schneiderhan-Marra⁸ 

[1] Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen;Department of Dermatology, University Hospital of Tübingen;Department of Immunology, Institute for Cell Biology, University of Tübingen;Department of Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University Hospital of Tübingen;EMC microcollections GmbH;Faculty of Medicine Carl Gustav Carus, Institute of Immunology, Technische Universität Dresden;German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) partner site Tübingen;NMI Natural and Medical Sciences Institute at the University of Tübingen;

关键词: Adjuvant;    Lipopeptide;    TLR1/2 ligand;    Immunotherapy;    Vaccines;   

DOI  :  10.1186/s40425-019-0796-5

来源: DOAJ

【 摘 要 】

Abstract Background We previously showed that the bacterial lipopeptide Pam3Cys-Ser-Ser, meanwhile established as a toll-like receptor (TLR) 1/2 ligand, acts as a strong adjuvant for the induction of virus specific CD8+ T cells in mice, when covalently coupled to a synthetic peptide. Case presentation We now designed a new water-soluble synthetic Pam3Cys-derivative, named XS15 and characterized it in vitro by a TLR2 NF-κB luciferase reporter assay. Further, the capacity of XS15 to activate immune cells and stimulate peptide-specific CD8+ T and NK cells by 6-sulfo LacNAc+ monocytes was assessed by flow cytometry as well as cytokine induction using immunoassays. The induction of a functional immune response after vaccination of a volunteer with viral peptides was assessed by ELISpot assay and flow cytometry in peripheral blood cells and infiltrating cells at the vaccination site, as well as by immunohistochemistry and imaging. XS15 induced strong ex vivo CD8+ and TH1 CD4+ responses in a human volunteer upon a single injection of XS15 mixed to uncoupled peptides in a water-in-oil emulsion (Montanide™ ISA51 VG). A granuloma formed locally at the injection site containing highly activated functional CD4+ and CD8+ effector memory T cells. The total number of vaccine peptide-specific functional T cells was experimentally assessed and estimated to be 3.0 × 105 in the granuloma and 20.5 × 106 in peripheral blood. Conclusion Thus, in one volunteer we show a granuloma forming by peptides combined with an efficient adjuvant in a water-in-oil-emulsion, inducing antigen specific T cells detectable in circulation and at the vaccination site, after one single vaccination only. The ex vivo T cell responses in peripheral blood were detectable for more than one year and could be strongly boosted by a second vaccination. Hence, XS15 is a promising adjuvant candidate for peptide vaccination, in particular for tumor peptide vaccines in a personalized setting.

【 授权许可】

Unknown