Purpose: We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator versus imiquimod plus a 9-valent human papillomavirus (HPV) vaccine (9vHPV) versus clinical surveillance in cervical intraepithelial neoplasia (CIN2/3) patients. Patients and Methods: We randomly allocated 133 patients with untreated CIN2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (Arm B) or imiquimod plus a 9vHPV (Arm C) versus clinical surveillance (Arm A). The main outcome was efficacy, defined as histologic regression to CIN1 or less. Secondary outcomes were HPV clearance and tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and posttreatment by flow cytometry among study arms. Results: Of the 114 evaluable patients 77% and 23% harbored CIN2 and CIN3, respectively. Regression to CIN1 or less was observed in 95% of patients in the imiquimod group (Arm B) compared with 79% in the control/surveillance (Arm A); P = 0.043 and 84% in the imiquimod+9vHPV group (Arm C; P = 0.384 vs. Arm A). Neither of the treatment-arm differences from Arm A reached the prespecified α = 0.025 significance level. No significant differences were noted in the secondary outcome of rate of HPV clearance. The number of tissue-resident memory CD4/CD8 T cells in cytobrush samples demonstrated a >5-fold increase in Arm B/imiquimod when compared with Arm A/surveillance (P < 0.01). In contrast, there was no significant difference in T-cell responses among participants in Arm C when compared with Arm A. Imiquimod treatment was well tolerated. Conclusions: Although imiquimod induced a higher regression to CIN1 or less and significant increases in CD4/CD8 T cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trials with imiquimod targeting CIN3 patients are warranted.

中文翻译：

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咪喹莫特联合或不联合 9 价 HPV 疫苗与高级别癌前宫颈病变患者观察的随机 II 期试验 (NCT02864147)

目的：我们报告了咪喹莫特（一种局部免疫反应调节剂）与咪喹莫特加 9 价人乳头瘤病毒 (HPV) 疫苗 (9vHPV) 的随机 II 期试验对比宫颈上皮内瘤变 (CIN2/3) 患者临床监测的结果。患者和方法：我们将 133 名未经治疗的 CIN2/3 患者按相同比例随机分配至 4 个月的自用阴道栓剂治疗组，其中包含咪喹莫特（B 组）或咪喹莫特加 9vHPV（C 组）与临床监测（A 组） ）。主要结果是疗效，定义为组织学回归至 CIN1 或更低。次要结果是 HPV 清除率和耐受性。探索性目标包括通过流式细胞术比较研究组之间基线、研究中期和治疗后的宫颈 CD4/CD8 T 细胞浸润情况。结果：在 114 名可评估患者中，77% 和 23% 分别患有 CIN2 和 CIN3。咪喹莫特组（B 组）中有 95% 的患者回归到 CIN1 或更低，而对照组/监测组（A 组）的这一比例为 79%；咪喹莫特+9vHPV 组的 P = 0.043 和 84%（C 组；相对于 A 组，P = 0.384）。治疗组与 A 组的差异均未达到预先指定的 α = 0.025 显着性水平。 HPV 清除率的次要结果没有显着差异。细胞刷样品中组织驻留记忆CD4/CD8 T细胞的数量证明，与A组/监视相比，B组/咪喹莫特增加了＞5倍(P＜0.01)。相比之下，与 A 组相比，C 组参与者的 T 细胞反应没有显着差异。咪喹莫特治疗的耐受性良好。结论：虽然咪喹莫特诱导 CIN1 或更低的回归，并且浸润宫颈的 CD4/CD8 T 细胞显着增加，但它没有达到其预先设定的疗效统计结果。在这项前瞻性试验的监测组中观察到的回归率高于预期。未来需要针对 CIN3 患者开展咪喹莫特临床试验。