RT Journal Article
SR Electronic
T1 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
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e005016
DO 10.1136/jitc-2022-005016
VO 10
IS 10
A1 Frank M Speetjens
A1 Marij J P Welters
A1 Marije Slingerland
A1 Mariette I E van Poelgeest
A1 Peggy J de Vos van Steenwijk
A1 Inge Roozen
A1 Sanne Boekestijn
A1 Nikki M Loof
A1 Gijs G Zom
A1 A Rob P M Valentijn
A1 Willem-Jan Krebber
A1 Nico J Meeuwenoord
A1 Catharina A H Janssen
A1 Cornelis J M Melief
A1 Gijs A van der Marel
A1 Dmitri V Filippov
A1 Sjoerd H van der Burg
A1 Hans Gelderblom
A1 Ferry Ossendorp
YR 2022
UL http://jitc.bmj.com/content/10/10/e005016.abstract
AB Background 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.Methods 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.Results 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.Conclusions 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.Trial registration numbers NCT02821494 and 2014-000658-12.Data are available on reasonable request.