Department of Obstetrics and Gynecology, Nihon University School of Medicine, Tokyo, Japan.
Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
JNCI Cancer Spectr. 2023 Oct 31;7(6). doi: 10.1093/jncics/pkad101.
Although many human papillomavirus (HPV)-targeted therapeutic vaccines have been examined for efficacy in clinical trials, none have been translated into clinical use. These previous agents were mostly administered by intramuscular or subcutaneous injection to induce systemic immunity. We investigated the safety and therapeutic efficacy of an HPV-16 E7-expressing lacticaseibacillus-based oral vaccine.
In a double-blind, placebo-controlled, randomized trial, a total of 165 patients with HPV-16-positive high-grade cervical intraepithelial neoplasia 2 and 3 were assigned to orally administered placebo or low, intermediate, or high doses of IGMKK16E7 (lacticaseibacillus paracasei expressing cell surface, full-length HPV-16 E7). In the 4 groups, IGMKK16E7 or placebo was administered orally at weeks 1, 2, 4, and 8 postenrollment. The primary outcomes included histopathological regression and IGMKK16E7 safety.
In per-protocol analyses, histopathological regression to normal (complete response) occurred in 13 (31.7%) of 41 high-dose recipients and in 5 (12.5%) of 40 placebo recipients (rate difference = 19.2, 95% confidence interval [CI] = 0.5 to 37.8). In patients positive for HPV-16 only, the clinical response rate was 40.0% (12 of 30) in high-dose recipients and 11.5% (3 of 26) in recipients of placebo (rate difference = 28.5, 95% CI = 4.3 to 50.0). There was no difference in adverse events that occurred in the high-dose and placebo groups (P = .83). The number of HPV-16 E7-specific interferon-γ producing cells within peripheral blood increased with level of response (stable disease, partial, and complete responses; P = .004). The regression to normal (complete response) rates among recipients with high levels of immune response were increased in a dose-dependent manner.
This trial demonstrates safety of IGMKK16E7 and its efficacy against HPV-16-positive cervical intraepithelial neoplasia 2 and 3. IGMKK16E7 is the first oral immunotherapeutic vaccine to show antineoplastic effects.
jRCT2031190034.
尽管已有许多针对人类乳头瘤病毒（HPV）的治疗性疫苗在临床试验中被评估了疗效，但没有一种疫苗被转化为临床应用。这些先前的药物主要通过肌肉内或皮下注射给药，以诱导全身免疫。我们研究了一种表达 HPV-16 E7 的乳杆菌基口服疫苗的安全性和治疗效果。
在一项双盲、安慰剂对照、随机试验中，共有 165 名 HPV-16 阳性的高级别宫颈上皮内瘤变 2 和 3 患者被分配接受口服安慰剂或低、中、高剂量的 IGMKK16E7（表达细胞表面全长 HPV-16 E7 的副干酪乳杆菌）。在这 4 组中，IGMKK16E7 或安慰剂分别在入组后 1、2、4 和 8 周时口服给药。主要结局包括组织病理学消退和 IGMKK16E7 的安全性。
在符合方案分析中，在 41 名高剂量组中，有 13 名（31.7%）患者的组织病理学完全缓解（完全反应），而在 40 名安慰剂组中，有 5 名（12.5%）患者（反应率差异=19.2，95%置信区间[CI]为 0.5 至 37.8）。在 HPV-16 阳性的患者中，高剂量组的临床反应率为 40.0%（30 名患者中的 12 名），安慰剂组的临床反应率为 11.5%（26 名患者中的 3 名）（反应率差异=28.5，95%CI 为 4.3 至 50.0）。高剂量组和安慰剂组的不良事件发生率无差异（P=0.83）。外周血中 HPV-16 E7 特异性干扰素-γ产生细胞的数量随反应水平而增加（稳定疾病、部分反应和完全反应；P=0.004）。在剂量依赖性方式下，具有高免疫反应水平的患者的正常（完全反应）回归率增加。
本试验证明了 IGMKK16E7 的安全性及其对 HPV-16 阳性的宫颈上皮内瘤变 2 和 3 的疗效。IGMKK16E7 是首个显示抗肿瘤作用的口服免疫治疗疫苗。
jRCT2031190034。
