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

Sanne Samuels, A. Marijne Heeren, Henry J.M.A.A. Zijlmans, Marij J.P. Welters, Joost H. van den Berg, Daisy Philips, Pia Kvistborg, Ilina Ehsan, Suzy M.E. Scholl, Bastiaan Nuijen, Ton N.M. Schumacher, Marc van Beurden, Ekaterina S. Jordanova, John B.A.G. Haanen, Sjoerd H. van der Burg, Gemma G. Kenter

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)1163-1173
Number of pages11
JournalCancer Immunology, Immunotherapy
Volume66
Issue number9
DOIs
Publication statusPublished - 1 Sep 2017

Cite this

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. / HPV16 E7 DNA tattooing : safety, immunogenicity, and clinical response in patients with HPV-positive vulvar intraepithelial neoplasia. In: Cancer Immunology, Immunotherapy. 2017 ; Vol. 66, No. 9. pp. 1163-1173.
@article{00214e23776349f79aa403ac537d31d4,
title = "HPV16 E7 DNA tattooing: safety, immunogenicity, and clinical response in patients with HPV-positive vulvar intraepithelial neoplasia",
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.",
keywords = "DNA vaccine, HPV, Immunogenicity, Immunotherapy, Safety, VIN",
author = "Sanne Samuels and {Marijne Heeren}, A. and Zijlmans, {Henry J.M.A.A.} and Welters, {Marij J.P.} and {van den Berg}, {Joost H.} and Daisy Philips and Pia Kvistborg and Ilina Ehsan and Scholl, {Suzy M.E.} and Bastiaan Nuijen and Schumacher, {Ton N.M.} and {van Beurden}, Marc and Jordanova, {Ekaterina S.} and Haanen, {John B.A.G.} and {van der Burg}, {Sjoerd H.} and Kenter, {Gemma G.}",
year = "2017",
month = "9",
day = "1",
doi = "10.1007/s00262-017-2006-y",
language = "English",
volume = "66",
pages = "1163--1173",
journal = "Cancer Immunology and Immunotherapy",
issn = "0340-7004",
publisher = "Springer Science and Business Media Deutschland GmbH",
number = "9",

}

Samuels, S, Marijne Heeren, A, Zijlmans, HJMAA, Welters, MJP, van den Berg, JH, Philips, D, Kvistborg, P, Ehsan, I, Scholl, SME, Nuijen, B, Schumacher, TNM, van Beurden, M, Jordanova, ES, Haanen, JBAG, van der Burg, SH & Kenter, GG 2017, 'HPV16 E7 DNA tattooing: safety, immunogenicity, and clinical response in patients with HPV-positive vulvar intraepithelial neoplasia' Cancer Immunology, Immunotherapy, vol. 66, no. 9, pp. 1163-1173. https://doi.org/10.1007/s00262-017-2006-y

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

In: Cancer Immunology, Immunotherapy, Vol. 66, No. 9, 01.09.2017, p. 1163-1173.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - HPV16 E7 DNA tattooing

T2 - safety, immunogenicity, and clinical response in patients with HPV-positive vulvar intraepithelial neoplasia

AU - Samuels, Sanne

AU - Marijne Heeren, A.

AU - Zijlmans, Henry J.M.A.A.

AU - Welters, Marij J.P.

AU - van den Berg, Joost H.

AU - Philips, Daisy

AU - Kvistborg, Pia

AU - Ehsan, Ilina

AU - Scholl, Suzy M.E.

AU - Nuijen, Bastiaan

AU - Schumacher, Ton N.M.

AU - van Beurden, Marc

AU - Jordanova, Ekaterina S.

AU - Haanen, John B.A.G.

AU - van der Burg, Sjoerd H.

AU - Kenter, Gemma G.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - 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.

AB - 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.

KW - DNA vaccine

KW - HPV

KW - Immunogenicity

KW - Immunotherapy

KW - Safety

KW - VIN

UR - http://www.scopus.com/inward/record.url?scp=85018279038&partnerID=8YFLogxK

U2 - 10.1007/s00262-017-2006-y

DO - 10.1007/s00262-017-2006-y

M3 - Article

VL - 66

SP - 1163

EP - 1173

JO - Cancer Immunology and Immunotherapy

JF - Cancer Immunology and Immunotherapy

SN - 0340-7004

IS - 9

ER -