Dataset Information

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

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-?B 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 T_H1 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.

SUBMITTER: Rammensee HG

PROVIDER: S-EPMC6858783 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Rammensee Hans-Georg HG Wiesmüller Karl-Heinz KH Chandran P Anoop PA Zelba Henning H Rusch Elisa E Gouttefangeas Cécile C Kowalewski Daniel J DJ Di Marco Moreno M Haen Sebastian P SP Walz Juliane S JS Gloria Yamel Cardona YC Bödder Johanna J Schertel Jill-Marie JM Tunger Antje A Müller Luise L Kießler Maximilian M Wehner Rebekka R Schmitz Marc M Jakobi Meike M Schneiderhan-Marra Nicole N Klein Reinhild R Laske Karoline K Artzner Kerstin K Backert Linus L Schuster Heiko H Schwenck Johannes J Weber Alexander N R ANR Pichler Bernd J BJ Kneilling Manfred M la Fougère Christian C Forchhammer Stephan S Metzler Gisela G Bauer Jürgen J Weide Benjamin B Schippert Wilfried W Stevanović Stefan S Löffler Markus W MW

Journal for immunotherapy of cancer 20191115 1

<h4>Background</h4>We previously showed that the bacterial lipopeptide Pam<sub>3</sub>Cys-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<sup>+</sup> T cells in mice, when covalently coupled to a synthetic peptide.<h4>Case presentation</h4>We now designed a new water-soluble synthetic Pam<sub>3</sub>Cys-derivative, named XS15 and characterized it in vitro by a TLR2 NF-κB luciferase reporter assay. Further, ...[more]

PMID: 31730025

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Project description:BackgroundAmplivant is a molecularly optimized Toll-like receptor 2 ligand that can be covalently conjugated to tumor peptide antigens. In preclinical models, amplivant-adjuvanted synthetic long peptides (SLPs) strongly enhanced antigen presentation by dendritic cells, T cell priming and induction of effective antitumor responses. The current study is a first-in-human trial to investigate safety and immunogenicity of amplivant conjugated to human papillomavirus (HPV) 16-SLP.MethodsA dose escalation phase I vaccination trial was performed in 25 patients treated for HPV16 positive (pre-)malignant lesions. Amplivant was conjugated to two SLPs derived from the two most immunodominant regions of the HPV16 E6 oncoprotein. The vaccine, containing a mix of these two conjugates in watery solution without any other formulation, was injected intradermally three times with a 3-week interval in four dose groups (1, 5, 20 or 50 µg per conjugated peptide). Safety data were collected during the study. Peptide-specific T cell immune responses were determined in blood samples taken before, during and after vaccination using complementary immunological assays.ResultsToxicity after three amplivant-conjugated HPV16-SLP vaccinations was limited to grade 1 or 2, observed as predominantly mild skin inflammation at the vaccination site and sometimes mild flu-like symptoms. Adverse events varied from none in the lowest dose group to mild/moderate vaccine-related inflammation in all patients and flu-like symptoms in three out of seven patients in the highest dose group, after at least one injection. In the lowest dose group, vaccine-induced T cell responses were observed in the blood of three out of six vaccinated persons. In the highest dose group, all patients displayed a strong HPV16-specific T cell response after vaccination. These HPV16-specific T cell responses lasted until the end of the trial.ConclusionsAmplivant-conjugated SLPs can safely be used as an intradermal therapeutic vaccine to induce robust HPV16-specific T cell immunity in patients previously treated for HPV16 positive (pre-) malignancies. Increased vaccine dose was associated with a higher number of mild adverse events and with stronger systemic T cell immunity.Trial registration numbersNCT02821494 and 2014-000658-12.

Dataset Information

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

Background

Case presentation

Conclusion

Publications

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

Similar Datasets

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