Abstract CT209: Safety, efficacy and immunogenicity of VB10.16, a therapeutic DNA vaccine targeting human papillomavirus (HPV) 16 E6 and E7 proteins for high grade cervical intraepithelial neoplasia (CIN 2/3): 6-month data from an exploratory open-label phase I/2a trial
Authors: Hillemanns Peter , Petry Karl Ulrich , Woelber Linn , Böhmer Gerd , Stubsrud Elisabeth , Skjørestad Irene , Schjetne Karoline , Fredriksen Agnete , Axelsen Mads 
Published: August 2019

Abstract
BACKGROUND: Persistent HPV infection can lead to high-grade squamous intraepithelial lesions (HSIL) in cervical cells; current treatments are exclusively ablative which can lead to long-term reproductive morbidity. VB10.16, an investigational immunotherapy designed to treat precancers and cancers induced by HPV16, is a highly potent DNA plasmid vaccine with intrinsic adjuvant effect designed for efficient delivery of antigens E6 and E7 from HPV16 to elicit strong immune responses. Here we explored in a first in human clinical study the safety/tolerability, immunogenicity and efficacy of VB10.16 in patients with HPV16+ CIN 2/3.
METHODS: Safety, efficacy and immunogenicity of VB10.16 were assessed in patients with HPV16+ associated CIN2/3 in an exploratory open-label phase I/2a study. 16 patients were enrolled and treated in the dosing phase to assess two different vaccination schedules (week 0, 3, 6 or week 0, 4, 12) and 17 patients completed four injections with VB10.16 in the subsequent expansion cohort (dosed week 0, 3, 6 and 16). VB10.16 is delivered i.m. using the needle-free PharmaJet™ Stratis injector device. The trial is registered at ClinicalTrials.gov (NCT02529930).
RESULTS: Vaccinations were well tolerated. The AEs were mainly mild to moderate and related to the injection site. No SAEs or DLTs were reported. A strong HPV16-specific T cell response (IFN-γ ELISpot) was observed correlating with lesion size regression. Mean T cell response was stronger in patients dosed with shorter intervals. Mean peak response was observed at week 24 when a boost vaccination was administrated in week 16. Flow cytometric analysis revealed the induction of HPV16-specific CD8(+) T cells. Interim analysis of 17 patients in the Expansion cohort 8 weeks after last dose (week 24), demonstrated regression in lesion size in 14 patients and in lesion grade (CIN1/0) in 8 patients. 15 patients were assessed as responders (PR/CR) by investigator. Patients not achieving CIN1/0 at week 24 had persistent other high-risk HPV infections or locally upregulated PD-L1 which might be induced by the strong immune response elicited by the vaccine.
CONCLUSION: We report strongly encouraging phase 1/2a safety, tolerability, and immunogenicity results for a therapeutic HPV16 DNA plasmid vaccine VB10.16. These data demonstrate that VB10.16 is capable of eliciting CD8+ T cells and driving robust immune responses to antigens from HPV16 contributing to elimination of HPV16-infected cells, subsequent regression in lesion size and grade in treated CIN2/3 patients. Up-regulation of PD-L1 argues for the rationale for investigating the combination of checkpoint inhibitors with VB10.16 in HPV16-associated cancers in future trials.
Citation Format: Peter Hillemanns, Karl Ulrich Petry, Linn Woelber, Gerd Böhmer, Elisabeth Stubsrud, Irene Skjørestad, Karoline Schjetne, Agnete Fredriksen, Mads Axelsen. Safety, efficacy and immunogenicity of VB10.16, a therapeutic DNA vaccine targeting human papillomavirus (HPV) 16 E6 and E7 proteins for high grade cervical intraepithelial neoplasia (CIN 2/3): 6-month data from an exploratory open-label phase I/2a trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT209.