Kawana Kei, Adachi Katsuyuki, Kojima Satoko, Taguchi Ayumi, Tomio Kensuke, Yamashita Aki, Nishida Haruka, Nagasaka Kazunori, Arimoto Takahide, Yokoyama Terufumi, Wada-Hiraike Osamu, Oda Katsutoshi, Sewaki Tomomitsu, Osuga Yutaka, Fujii Tomoyuki
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Vaccine. 2014 Oct 29;32(47):6233-9. doi: 10.1016/j.vaccine.2014.09.020. Epub 2014 Sep 22.
Cervical 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.
We 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.
No 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.
Oral 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.
宫颈上皮内瘤变3级（CIN3）是一种由高危型人乳头瘤病毒（HPV）引起的黏膜癌前病变。通过靶向HPV抗原诱导CIN3的免疫清除是一种有前景的CIN3治疗策略。目前尚未开发出成功的HPV治疗性疫苗。
我们评估了一种表达修饰的全长HPV16 E7蛋白的减毒干酪乳杆菌在HPV16相关CIN3患者中的安全性和临床疗效。在第1、2、4和8周（步骤1）的剂量优化研究（每天1、2、4或6粒胶囊）期间，10名患者口服疫苗。另外7名参与者仅使用优化后的疫苗制剂进行测试（步骤2），共有10名患者接受了优化后的疫苗接种。收集宫颈淋巴细胞（CxLs）和外周血单核细胞（PBMCs），并通过ELISPOT测定法计数产生E7特异性干扰素-γ的细胞（E七细胞介导的免疫反应：E7-CMI）。在初次疫苗接种后9周，所有患者均通过细胞学和活检进行重新评估，以评估病理疗效。
没有患者出现不良事件。基线时，CxLs和PBMCs中的E7-CMI均可忽略不计。所有每天服用4-6粒胶囊的患者CxLs中的E7-CMI均增加，而每天服用1-2粒胶囊的患者则没有。没有患者的PBMCs中E7-CMI增加。在队列患者之间的比较中，每天服用4粒胶囊的患者在第9周（9 wk）时的E7-CMI显著高于每天服用1、2或6粒胶囊的患者。大多数服用优化剂量的患者（70%）在治疗第9周时病理分级降至CIN2。CxLs中的E7-CMI与病理分级下降直接相关。
口服表达E7的基于乳酸杆菌的疫苗可在子宫颈病变中引发E7特异性黏膜免疫。我们首次报道了宫颈黏膜E7-CMI与人类黏膜肿瘤免疫治疗后的临床反应之间的相关性。
