A phase 1, single centre, open label, escalating dose study to assess the safety, tolerability and immunogenicity of a therapeutic human papillomavirus (HPV) DNA vaccine (AMV002) for HPV-associated head and neck cancer (HNC)

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Abstract

Background

We conducted a phase 1 dose escalation study (ACTRN12618000140257 registered on 30/01/2018) to evaluate the safety, tolerability and immunogenicity of a therapeutic human papillomavirus (HPV) DNA vaccine (AMV002) in subjects previously treated for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC).

Methods

Eligible subjects had to have no evidence of recurrent and/or metastatic disease at least 12 weeks following the completion of treatment. Three dosing cohorts each consisted of four subjects: group 1: 0.25 mg/dose, group 2: 1 mg/dose, group 3: 4 mg/dose. AMV002 was delivered intradermally on days 0, 28 and 56. Incidence and severity of treatment-emergent adverse events (TEAE) including local reaction at the injection site, and vaccination compliance were recorded. T cell and antibody responses to HPV16 E6 and E7 were measured by interferon gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay and enzyme-linked immunosorbent assay (ELISA).

Results

All subjects completed the vaccination programme and experienced mild discomfort at the injection site(s). Pre-immunisation, cell-mediated responses to HPV16 E6 and E7 were evident in all subjects, and E7-specific antibodies were detected in 11 (91.7%), reflecting previous exposure to HPV. Post-vaccination, 10 of 12 (83.3%) subjects responded to one or more of the E6 and/or E7 peptide pools, while 2 (16.7%) did not show additional vaccine-induced cell-mediated responses. Vaccination resulted in a ≥ 4-fold increase in anti-HPV16 E7 antibody titre in one subject in group 3.

Conclusions

AMV002 was well tolerated at all dose levels and resulted in enhanced specific immunity to virus-derived tumour-associated antigens in subjects previously treated for HPV-associated OPSCC.

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Abbreviations

ELISA:

Enzyme-linked immunosorbent assay

ELISpot:

Enzyme-linked immunosorbent spot

HPV:

Human papillomavirus

HNC:

Head and neck cancer

IFNγ:

Interferon gamma

OPSCC:

Oropharyngeal squamous cell carcinoma

PBMC:

Peripheral blood mononuclear cells

TEAE:

Treatment emergent adverse events

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Acknowledgements

We thank all patients participating in this study and complying with the protocol. We thank the Queensland Head and Neck Cancer Centre. We thank all relevant staff from the clinical trials unit of the Princess Alexandra Hospital who were involved in carrying out the clinical trial. We thank Clinical Network Services for compiling and analysing data. We thank the staff of TetraQ for the conduction of humoral immunology assays. We also thank Caroline Cooper from Pathology Queensland at the Princess Alexandra Hospital and staff of the Immunohistochemistry Laboratory, Tissue Pathology and Diagnostic Oncology at the Royal Prince Alfred Hospital in Camperdown, NSW, for conducting the RNAscope assay.

Funding

This study was funded by Admedus Vaccines Pty Ltd, Advance Queensland Ignite Ideas Fund and Jingang Medicine (Australia) Pty Ltd. Assay development and the vaccine technologies used in this study was in part supported by Queensland Government development grants, and by funding from the National Health and Medical Research Council of Australia.

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Affiliations

Authors

Contributions

SVP, IHF and NF conceptualised the study and acquired funding. SVP recruited patients and oversaw the delivery of the vaccine. SVP verified all clinical data entered onto the case research forms. HYL, MMcG, RL and BP were involved in identifying and recruiting patients to the trial. HYL and MMcG also provided assistance in clinical oversight during the delivery of the vaccine and entering of clinical data. WPW, MB, YX and SH were involved in data curation. JC, WPW and IHF formally analysed data. WPW, YX and SH performed experiments and collected data. WPW and YX developed and designed the methodology. WPW, MB, NF and SVP managed and coordinated trial execution. IHF, SVP and NF supervised the trial execution. JC prepared data visualisation and presentation. JC and WPW prepared the original draft of the manuscript. JC, WPW, IHF and SVP revised and edited the manuscript.

Corresponding author

Correspondence to Sandro V. Porceddu.

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Conflict of interest

We have read the journal’s policy and the authors of this manuscript have the following competing interests: WPW, YX and NF are employees of the company that funded the study. WPW, YX and NF hold share options. IHF is a board member of the company that funded the study, is a consultant to the company, is an inventor on the patent US 2011/0287039 A1, “Expression system for modulating an immune response” and WO 02/083181 A1, “Novel compositions and uses” which have been assigned to the company. IHF also holds share options in the company and is a minority shareholder (< 0.01% of the company shares). JC is a consultant to the company that funded the study. SVP reports personal fees from UpToDate, Merck, Celgene and Merck Sharpe & Dome. RL reports honoraria for speaking at symposia at Roche, Merck Serono and Ipsen, holds positions on advisory boards of Roche, Sanofi Aventis, Merck Sharpe & Dohme and Ipsen, and receives financial support for attending symposia and educational programmes at Ipsen and Novartis. We confirm that these commercial affiliations do not alter our adherence to the journals policies on sharing data and materials.

Ethical approval

This clinical trial was approved by the Metro South Hospital and Health Service Human Research Ethics Committee.

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All subjects gave written informed consent for use of their material for research and publication.

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All relevant data are within the paper and its Supporting Information files.

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Chandra, J., Woo, W.P., Finlayson, N. et al. A phase 1, single centre, open label, escalating dose study to assess the safety, tolerability and immunogenicity of a therapeutic human papillomavirus (HPV) DNA vaccine (AMV002) for HPV-associated head and neck cancer (HNC). Cancer Immunol Immunother 70, 743–753 (2021). https://doi.org/10.1007/s00262-020-02720-7

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Keywords

  • Human papillomavirus
  • Head and neck cancer
  • Oropharyngeal squamous cell carcinoma
  • Immunotherapy
  • DNA vaccine
  • HPV E6 and E7 oncoproteins