A Phase I trial assessing the safety and tolerability of a therapeutic DNA vaccination against HPV16 and HPV18 E6/E7 oncogenes after chemoradiation for cervical cancer.

作者：Hasan, Yasmin^*; Furtado, Larissa; Tergas, Ana; Lee, Nita; Brooks, Rebecca; McCall, Anne; Golden, Daniel; Jolly, Shruti; Fleming, Gini; Morrow, Matthew; Kraynyak, Kimberly; Sylvester, Albert; Arif, Fauzia; Levin, Matt; Schwartz, David; Boyer, Jean; Skolnik, Jeffrey; Esser, Mark; Kumar, Rakesh; Bagarazzi, Mark; Weichselbaum, Ralph; Spiotto, Michael

来源：Int J Radiat Oncol Biol Phys, 2020.

DOI：10.1016/j.ijrobp.2020.02.031

• Cancer of Cervix
• Chemoradiotherapy
• DNA
• Human papillomavirus 16
• Human papillomavirus 18
• Immunotherapy
• Vaccines

PURPOSE: This study assessed the safety and tolerability of therapeutic immunization against the HPV viral oncoproteins E6 and E7 in cervical cancer patients following chemoradiation. EXPERIMENTAL DESIGN: MEDI0457 (INO-3112) is a DNA-based vaccine targeting E6 and E7 of HPV-16/18 that is co-injected with an IL-12 plasmid followed by electroporation with the CELLECTRA(R) 5P device. Two to 4 weeks following chemoradiation, patients with newly diagnosed stage IB1-IVA (Cohort 1) or persistent/recurrent (Cohort 2) cervical cancers were treated with four 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-gamma (IFNgamma), ELISA for antibody responses and multiplexed immunofluorescence for immune cells in cervical biopsy specimens. RESULTS: 10 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. 8 of 10 patients had detectable cellular and/or humoral immune responses against HPV antigens following chemoradiation and vaccination: 6/10 patients generated anti-HPV antibody responses and 6/10 patients generated IFNgamma 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 and/or recurrent cervical cancers supporting further investigation into combining tumor-specific vaccines with radiotherapy.

• 单位
  new; university of chicago; The University of Chicago; Columbia University Medical Center