HPV16 E7 DNA tattooing: safety, immunogenicity, and clinical response in patients with HPV-positive vulvar intraepithelial neoplasia

• Published in: Cancer Immunology, Immunotherapy Vol. 66; no. 9; pp. 1163 - 1173
• Main Authors: Samuels, Sanne, Marijne Heeren, A., Zijlmans, Henry J. M. A. A., Welters, Marij J. P., van den Berg, Joost H., Philips, Daisy, Kvistborg, Pia, Ehsan, Ilina, Scholl, Suzy M. E., Nuijen, Bastiaan, Schumacher, Ton N. M., van Beurden, Marc, Jordanova, Ekaterina S., Haanen, John B. A. G., van der Burg, Sjoerd H., Kenter, Gemma G.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2017; Springer Nature B.V
• Subjects: Adult; Animal models; Cancer Research; CD4 antigen; CD8 antigen; CTLA-4 protein; Deoxyribonucleic acid; DNA; DNA - genetics; DNA vaccines; Enzyme-linked immunosorbent assay; Female; Flow cytometry; Human papillomavirus 16 - genetics; Humans; Immune response; Immunogenicity; Immunology; Immunotherapy; Interleukin 2; Lymphocytes T; Medicine; Medicine & Public Health; Middle Aged; Oncogene Proteins, Viral - immunology; Oncology; Original; Original Article; PD-1 protein; Peptides; Tattoos; Tumor necrosis factor; Vaccination; Vaccines; Vaccines, DNA - immunology; Vulvar Neoplasms - genetics; Vulvar Neoplasms - therapy; DNA vaccine; VIN; Safety; Immunogenicity; Immunotherapy; HPV
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-017-2006-y

Background
Usual type vulvar intraepithelial neoplasia (uVIN) is caused by HPV, predominantly type 16. Several forms of HPV immunotherapy have been studied, however, clinical results could be improved. A novel intradermal administration route, termed DNA tattooing, is superior in animal models, and was tested for the first time in humans with a HPV16 E7 DNA vaccine (TTFC-E7SH).
Methods
The trial was designed to test safety, immunogenicity, and clinical response of TTFC-E7SH in twelve HPV16
+
uVIN patients. Patients received six vaccinations via DNA tattooing. The first six patients received 0.2 mg TTFC-E7SH and the next six 2 mg TTFC-E7SH. Vaccine-specific T-cell immunity was evaluated by IFNγ-ELISPOT and multiparametric flow cytometry.
Results
Only grade I-II adverse events were observed upon TTFC-E7SH vaccination. The ELISPOT analysis showed in 4/12 patients a response to the peptide pool containing shuffled E7 peptides. Multiparametric flow cytometry showed low CD4
+
and/or CD8
+
T-cell responses as measured by increased expression of PD-1 (4/12 in both), CTLA-4 (2/12 and 3/12), CD107a (5/12 and 4/12), or the production of IFNγ (2/12 and 1/12), IL-2 (3/12 and 4/12), TNFα (2/12 and 1/12), and MIP1β (3/12 and 6/12). At 3 months follow-up, no clinical response was observed in any of the twelve vaccinated patients.
Conclusion
DNA tattoo vaccination was shown to be safe. A low vaccine-induced immune response and no clinical response were observed in uVIN patients after TTFC-E7SH DNA tattoo vaccination. Therefore, a new phase I/II trial with an improved DNA vaccine format is currently in development for patients with uVIN.