Intradermal vaccination of HPV-16 E6 synthetic peptides conjugated to an optimized Toll-like receptor 2 ligand shows safety and potent T cell immunogenicity in patients with HPV-16 positive (pre-)malignant lesions
| Autor: | Speetjens, F.M., Welters, M.J.P., Slingerland, M., Poelgeest, M.I.E. van, Steenwijk, P.J.D. van, Roozen, I., Boekestijn, S., Loof, N.M., Zom, G.G., Valentijn, A.R.P.M., Krebber, W.J., Meeuwenoord, N.J., Janssen, C.A.H., Melief, C.J.M., Marel, G.A. van der, Filippov, D.V., Burg, S.H. van der, Gelderblom, H., Ossendorp, F. |
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| Přispěvatelé: | Obstetrie & Gynaecologie, MUMC+: MA Medische Staf Obstetrie Gynaecologie (9), RS: GROW - R2 - Basic and Translational Cancer Biology |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Inflammation
Pharmacology Human papillomavirus 16 Cancer Research Immunodominant Epitopes T-Lymphocytes Papillomavirus Infections Vaccination Immunology Uterine Cervical Neoplasms Ligands Cancer Vaccines Toll-Like Receptor 2 Oncology Inflammation/drug therapy Humans Molecular Medicine Immunology and Allergy Female Papillomavirus Vaccines Peptides |
| Zdroj: | Journal for ImmunoTherapy of Cancer, 10(10):e005016. BMJ PUBLISHING GROUP Journal for ImmunoTherapy of Cancer, 10(10). BMJ PUBLISHING GROUP Journal for ImmunoTherapy of Cancer, 10(10):e005016. BioMed Central Ltd |
| ISSN: | 0282-1494 2051-1426 |
| Popis: | 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 numbersNCT02821494and 2014-000658-12. |
| Databáze: | OpenAIRE |
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