{"doi":"10.1136/jitc-2022-005016","title":"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","abstract":"<jats:sec>\n                  <jats:title>Background</jats:title>\n                  <jats:p>Amplivant 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.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Methods</jats:title>\n                  <jats:p>A 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.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Results</jats:title>\n                  <jats:p>Toxicity 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.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions</jats:title>\n                  <jats:p>Amplivant-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.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Trial registration numbers</jats:title>\n                  <jats:p>\n                     <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02821494\">NCT02821494</jats:ext-link> and 2014-000658-12.</jats:p>\n               </jats:sec>","journal":"Journal for ImmunoTherapy of Cancer","year":2022,"id":657160,"datarank":0.9351348415043206,"base_score":3.6635616461296463,"endowment":3.6635616461296463,"self_citation_contribution":0.5495342469194471,"citation_network_contribution":0.3856005945848735,"self_endowment_contribution":0.5495342469194471,"citer_contribution":0.3856005945848735,"corpus_percentile":null,"corpus_rank":null,"citation_count":38,"citer_count":33,"citers_with_citation_signal":27,"citers_with_endowment":27,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1688240,"name":"Marij J P Welters","orcid":null,"position":1,"is_corresponding":false},{"id":1715467,"name":"Marije Slingerland","orcid":null,"position":2,"is_corresponding":false},{"id":1715469,"name":"Mariette I E van Poelgeest","orcid":null,"position":3,"is_corresponding":false},{"id":1715472,"name":"Peggy J de Vos van Steenwijk","orcid":null,"position":4,"is_corresponding":false},{"id":1715474,"name":"Inge Roozen","orcid":null,"position":5,"is_corresponding":false},{"id":1715476,"name":"Sanne Boekestijn","orcid":null,"position":6,"is_corresponding":false},{"id":1715478,"name":"Nikki M Loof","orcid":null,"position":7,"is_corresponding":false},{"id":1715479,"name":"Gijs G Zom","orcid":null,"position":8,"is_corresponding":false},{"id":1715480,"name":"A Rob P M Valentijn","orcid":null,"position":9,"is_corresponding":false},{"id":1715481,"name":"Willem-Jan Krebber","orcid":null,"position":10,"is_corresponding":false},{"id":1715482,"name":"Nico J Meeuwenoord","orcid":null,"position":11,"is_corresponding":false},{"id":1715483,"name":"Catharina A H Janssen","orcid":null,"position":12,"is_corresponding":false},{"id":1715484,"name":"Cornelis J M Melief","orcid":null,"position":13,"is_corresponding":false},{"id":1715485,"name":"Gijs A van der Marel","orcid":null,"position":14,"is_corresponding":false},{"id":1715486,"name":"Dmitri V Filippov","orcid":null,"position":15,"is_corresponding":false},{"id":1715487,"name":"Sjoerd H van der Burg","orcid":null,"position":16,"is_corresponding":false},{"id":260049,"name":"Hans Gelderblom","orcid":"0000-0001-9270-8636","position":17,"is_corresponding":false},{"id":1715488,"name":"Ferry Ossendorp","orcid":null,"position":18,"is_corresponding":false},{"id":1715456,"name":"Frank M Speetjens","orcid":"0000-0003-2065-9593","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"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","abstract":"<jats:sec>\n                  <jats:title>Background</jats:title>\n                  <jats:p>Amplivant 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.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Methods</jats:title>\n                  <jats:p>A 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.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Results</jats:title>\n                  <jats:p>Toxicity 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.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions</jats:title>\n                  <jats:p>Amplivant-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.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Trial registration numbers</jats:title>\n                  <jats:p>\n                     <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02821494\">NCT02821494</jats:ext-link> and 2014-000658-12.</jats:p>\n               </jats:sec>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"36261215","pmcid":"PMC9582304","openalex_id":null,"authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":null,"license":"http://creativecommons.org/licenses/by-nc/4.0/","oa_locations":[{"url":"https://syndication.highwire.org/content/doi/10.1136/jitc-2022-005016","host_type":"publisher"},{"url":"https://europepmc.org/articles/PMC9582304","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC9582304?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":[],"mesh_terms":["T-Lymphocytes","Humans","Papillomavirus Infections","Inflammation","Peptides","Immunodominant Epitopes","Ligands","Uterine Cervical Neoplasms","Female","Toll-Like Receptor 2","Human papillomavirus 16","Papillomavirus Vaccines"],"keywords":["Immunotherapy","Vaccination","Adjuvants, Immunologic","Immunogenicity, Vaccine"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"eudract"},{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-11T23:55:57.692905Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}