• Kei Kawana, Katsuyuki Adachi, Satoko Kojima, Ayumi Taguchi, Kensuke Tomio, Aki Yamashita, Haruka Nishida, Kazunori Nagasaka, Takahide Arimoto, Terufumi Yokoyama, Osamu Wada-Hiraike, Katsutoshi Oda, Tomomitsu Sewaki, Yutaka Osuga, and Tomoyuki Fujii.
• Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Electronic address: kkawana-tky@umin.org.
• Vaccine. 2014 Oct 29; 32 (47): 6233-9.

BackgroundCervical intraepithelial neoplasia grade 3 (CIN3) is a mucosal precancerous lesion caused by high-risk human papillomavirus (HPV). Induction of immunological clearance of CIN3 by targeting HPV antigens is a promising strategy for CIN3 therapy. No successful HPV therapeutic vaccine has been developed.MethodsWe evaluated the safety and clinical efficacy of an attenuated Lactobacillus casei expressing modified full-length HPV16 E7 protein in patients with HPV16-associated CIN3. Ten patients were vaccinated orally during dose optimization studies (1, 2, 4, or 6 capsules/day) at weeks 1, 2, 4, and 8 (Step 1). Seven additional participants were only tested using the optimized vaccine formulation (Step 2), giving a total of 10 patients who received optimized vaccination. Cervical lymphocytes (CxLs) and peripheral blood mononuclear cells (PBMCs) were collected and E7 specific interferon-γ-producing cells were counted (E7 cell-mediated immune responses: E7-CMI) by ELISPOT assay. All patients were re-evaluated 9 weeks after initial vaccine exposure using cytology and biopsy to assess pathological efficacy.ResultsNo patient experienced an adverse event. E7-CMI in both CxLs and PBMCs was negligible at baseline. All patients using 4-6 capsules/day showed increased E7-CMI in CxLs, whereas patients using 1-2 capsules/day did not. No patient demonstrated an increase in E7-CMI in their PBMCs. In comparison between patients of cohorts, E7-CMI at week 9 (9 wk) in patients on 4 capsules/day was significantly higher than those in patients on 1, 2, or 6 capsules/day. Most patients (70%) taking the optimized dose experienced a pathological down-grade to CIN2 at week 9 of treatment. E7-CMI in CxLs correlated directly with the pathological down-grade.ConclusionsOral administration of an E7-expressing Lactobacillus-based vaccine can elicit E7-specific mucosal immunity in the uterine cervical lesions. We are the first to report a correlation between mucosal E7-CMI in the cervix and clinical response after immunotherapy in human mucosal neoplasia.Copyright © 2014 Elsevier Ltd. All rights reserved.

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