Sanne Samuels1, A Marijne Heeren2, Henry J M A A Zijlmans1, Marij J P Welters3, Joost H van den Berg4, Daisy Philips5, Pia Kvistborg5, Ilina Ehsan3, Suzy M E Scholl6, Bastiaan Nuijen7, Ton N M Schumacher5, Marc van Beurden1, Ekaterina S Jordanova1, John B A G Haanen5,8, Sjoerd H van der Burg3, Gemma G Kenter9. 1. Department of Gynecology, Center for Gynecologic Oncology Amsterdam, P.O. Box 90203, 1006 BE, Amsterdam, The Netherlands. 2. Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. 3. Department of Clinical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. 4. Amsterdam Biotherapeutics Unit (AmBTU), Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. 5. Department of Immunology, Netherlands Cancer Institute, Antoni van Leeuwenhoek, P.O. Box 90203, 1006 BE, Amsterdam, The Netherlands. 6. Department of Medical Oncology, Institut Curie, 25 Rue d'Ulm, 75005, Paris, France. 7. Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Antoni van Leeuwenhoek, P.O. Box 90203, 1006 BE, Amsterdam, The Netherlands. 8. Department of Medical Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek, P.O. Box 90203, 1006 BE, Amsterdam, The Netherlands. 9. Department of Gynecology, Center for Gynecologic Oncology Amsterdam, P.O. Box 90203, 1006 BE, Amsterdam, The Netherlands. g.kenter@nki.nl.
Abstract
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.
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.
Entities:
Keywords:
DNA vaccine; HPV; Immunogenicity; Immunotherapy; Safety; VIN
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