TY - JOUR
T1 - A Phase 1 Trial Assessing the Safety and Tolerability of a Therapeutic DNA Vaccination Against HPV16 and HPV18 E6/E7 Oncogenes After Chemoradiation for Cervical Cancer
AU - Hasan, Yasmin
AU - Furtado, Larissa
AU - Tergas, Ana
AU - Lee, Nita
AU - Brooks, Rebecca
AU - McCall, Anne
AU - Golden, Daniel
AU - Jolly, Shruti
AU - Fleming, Gini
AU - Morrow, Matthew
AU - Kraynyak, Kimberly
AU - Sylvester, Albert
AU - Arif, Fauzia
AU - Levin, Matt
AU - Schwartz, David
AU - Boyer, Jean
AU - Skolnik, Jeffrey
AU - Esser, Mark
AU - Kumar, Rakesh
AU - Bagarazzi, Mark
AU - Weichselbaum, Ralph
AU - Spiotto, Michael
N1 - Funding Information:
Research support was provided by Inovio Pharmaceuticals, Inc and AstraZeneca ; the Burroughs Wellcome Career Award for Medical Scientists 1010964 (M.T.S.); and the National Institutes of Health / National Institute of Dental and Craniofacial Research R01DE027445-01 (M.T.S.). This work was supported in part by a grant for the National Institutes of Health R01DE027445-01 (M.T.S) and the Virginia and D.K. Ludwig Fund for Cancer Research (R.R.W and M.T.S).
Funding Information:
Research support was provided by Inovio Pharmaceuticals, Inc and AstraZeneca; the Burroughs Wellcome Career Award for Medical Scientists 1010964 (M.T.S.); and the National Institutes of Health/National Institute of Dental and Craniofacial Research R01DE027445-01 (M.T.S.). This work was supported in part by a grant for the National Institutes of Health R01DE027445-01 (M.T.S) and the Virginia and D.K. Ludwig Fund for Cancer Research (R.R.W and M.T.S). Disclosures: M.T.E. and R.K. are employees of and own stock in AstraZeneca. J.B., K.K., M.M., J.S., and A.S. are employees of Inovio Pharmaceuticals and own shares or have been awarded stock options in the company. M.B. owns stock in Inovio Pharmaceuticals. D.G. reports grants from Inovio Pharmaceuticals, Inc, and grants from AstraZeneca, during the conduct of the study. S.J. reports other from Inovio, during the conduct of the study. G.F. reports other from Corcept Therapeutics, AbbVie, Genentech, Tesaro, Syndax, Forty Seven, Iovance, Syros, Astex, Marck, Wolters Kluwer, and Sermonix and personal fees from Vaniam Group, during the conduct of the study.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - Purpose: This study assessed the safety and tolerability of therapeutic immunization against the human papillomavirus (HPV) viral oncoproteins E6 and E7 in patients with cervical cancer after chemoradiation. Methods and Materials: MEDI0457 (INO-3112) is a DNA-based vaccine targeting E6 and E7 of HPV-16/18 that is coinjected with an IL-12 plasmid followed by electroporation with the CELLECTRA 5P device. At 2 to 4 weeks after chemoradiation, patients with newly diagnosed stage IB1-IVA (cohort 1) or persistent/recurrent (cohort 2) cervical cancers were treated with 4 immunizations of MEDI0457 every 4 weeks. The primary endpoints were incidence of adverse events and injection site reactions. Immune responses against HPV antigens were measured by ELISpot for interferon-γ (IFNγ), enzyme-linked immunosorbent assay for antibody responses and multiplexed immunofluorescence for immune cells in cervical biopsy specimens. Results: Ten patients (cohort 1, n = 7; cohort 2, n = 3) with HPV16 (n = 7) or HPV18 (n = 3) cervical cancers received MEDI0457 after chemoradiation. Treatment-related adverse events were all grade 1, primarily related to the injection site. Eight of 10 patients had detectable cellular or humoral immune responses against HPV antigens after chemoradiation and vaccination: 6 of 10 patients generated anti-HPV antibody responses and 6 of 10 patients generated IFNγ-producing T cell responses. At the completion of chemoradiation and vaccination, cervical biopsy specimens had detectable CD8+ T cells and decreased PD-1+CD8+, PD-L1+CD8+, and PD-L1+CD68+ subpopulations. All patients cleared detectable HPV DNA in cervical biopsies by completion of chemoradiation and vaccination. Conclusions: Adjuvant MEDI0457 is safe and well tolerated after chemoradiation for locally advanced or recurrent cervical cancers, supporting further investigation into combining tumor-specific vaccines with radiation therapy.
AB - Purpose: This study assessed the safety and tolerability of therapeutic immunization against the human papillomavirus (HPV) viral oncoproteins E6 and E7 in patients with cervical cancer after chemoradiation. Methods and Materials: MEDI0457 (INO-3112) is a DNA-based vaccine targeting E6 and E7 of HPV-16/18 that is coinjected with an IL-12 plasmid followed by electroporation with the CELLECTRA 5P device. At 2 to 4 weeks after chemoradiation, patients with newly diagnosed stage IB1-IVA (cohort 1) or persistent/recurrent (cohort 2) cervical cancers were treated with 4 immunizations of MEDI0457 every 4 weeks. The primary endpoints were incidence of adverse events and injection site reactions. Immune responses against HPV antigens were measured by ELISpot for interferon-γ (IFNγ), enzyme-linked immunosorbent assay for antibody responses and multiplexed immunofluorescence for immune cells in cervical biopsy specimens. Results: Ten patients (cohort 1, n = 7; cohort 2, n = 3) with HPV16 (n = 7) or HPV18 (n = 3) cervical cancers received MEDI0457 after chemoradiation. Treatment-related adverse events were all grade 1, primarily related to the injection site. Eight of 10 patients had detectable cellular or humoral immune responses against HPV antigens after chemoradiation and vaccination: 6 of 10 patients generated anti-HPV antibody responses and 6 of 10 patients generated IFNγ-producing T cell responses. At the completion of chemoradiation and vaccination, cervical biopsy specimens had detectable CD8+ T cells and decreased PD-1+CD8+, PD-L1+CD8+, and PD-L1+CD68+ subpopulations. All patients cleared detectable HPV DNA in cervical biopsies by completion of chemoradiation and vaccination. Conclusions: Adjuvant MEDI0457 is safe and well tolerated after chemoradiation for locally advanced or recurrent cervical cancers, supporting further investigation into combining tumor-specific vaccines with radiation therapy.
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U2 - 10.1016/j.ijrobp.2020.02.031
DO - 10.1016/j.ijrobp.2020.02.031
M3 - Article
C2 - 32151670
AN - SCOPUS:85086069181
SN - 0360-3016
VL - 107
SP - 487
EP - 498
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
IS - 3
ER -