Department of Obstetrics and Gynecology, Nihon University School of Medicine, Tokyo, Japan.
Department of Functional Morphology, Nihon University School of Medicine, Tokyo, Japan.
JNCI Cancer Spectr. 2024 Nov 1;8(6). doi: 10.1093/jncics/pkae091.
Although therapeutic human papillomavirus vaccines could offer a noninvasive treatment for patients with cervical intraepithelial neoplasia, none has been clinically implemented. Oral administration of the therapeutic human papillomavirus vaccine IGMKK16E7 results in the histological regression of human papillomavirus 16-positive cervical intraepithelial neoplasia 2/3 to normal (complete response). We investigated biomarkers that could predict complete response after oral administration of IGMKK16E7.
Forty-two patients administered high-dose oral IGMKK16E7 in a phase I/II trial were included. Cervix-exfoliated cells were collected before vaccine administration. Gene expression of CD4, CD8, FOXP3, programmed cell death 1 protein, CTLA4, CD103, CD28, CD80, CD86, and programmed cell death 1 ligand 1 in the cells was measured by quantitative reverse transcriptase-polymerase chain reaction. Receiver operating characteristic curve analysis and Mann-Whitney tests were used to explore potential biomarkers. Pearson correlation coefficient analysis was used to correlate gene expression profiles with clinical outcome.
The only predictive biomarker of vaccine response for which receiver operating characteristic curve analysis showed significant diagnostic performance with histological complete response was CD86 (area under the curve = 0.71, 95% confidence interval = 0.53 to 0.88, P = .020). Patients with complete response had significantly lower CD86 expression (CD86-low) than patients with no complete response (P = .035). The complete response rates for CD86-low and CD86-high patients were 50% and 19%, respectively, and CD86-low patients had a significantly higher complete response rate (P = .047). Compared with all patients, the CD86-low group had a 1.5-fold increase in the complete response rate. Gene expression of CD86 and CTLA4 showed the strongest positive correlation with clinical outcomes in the incomplete response group (P < .001).
Low expression of CD86 in exfoliated cervical cells can be used as a pretreatment biomarker to predict histological complete response after IGMKK16E7 administration.
尽管治疗性人乳头瘤病毒疫苗可为宫颈上皮内瘤变患者提供一种非侵入性的治疗方法，但目前尚无临床应用。口服治疗性人乳头瘤病毒疫苗 IGMKK16E7 可使人乳头瘤病毒 16 阳性的宫颈上皮内瘤变 2/3 组织学消退至正常（完全缓解）。我们研究了可预测口服 IGMKK16E7 后完全缓解的生物标志物。
纳入了在 I 期/II 期试验中接受高剂量口服 IGMKK16E7 的 42 例患者。在疫苗接种前采集宫颈脱落细胞。通过定量逆转录-聚合酶链反应测量细胞中 CD4、CD8、FOXP3、程序性细胞死亡 1 蛋白、CTLA4、CD103、CD28、CD80、CD86 和程序性细胞死亡 1 配体 1 的基因表达。采用受试者工作特征曲线分析和曼-惠特尼检验来探索潜在的生物标志物。采用 Pearson 相关系数分析将基因表达谱与临床结果相关联。
仅 CD86 的受试者工作特征曲线分析显示与组织学完全缓解有显著诊断性能的预测疫苗反应的生物标志物（曲线下面积=0.71，95%置信区间=0.53 至 0.88，P=0.020）。完全缓解的患者 CD86 表达明显较低（CD86 低），而非完全缓解的患者（P=0.035）。CD86 低和 CD86 高的患者完全缓解率分别为 50%和 19%，CD86 低的患者完全缓解率明显更高（P=0.047）。与所有患者相比，CD86 低组的完全缓解率增加了 1.5 倍。在不完全缓解组中，CD86 和 CTLA4 的基因表达与临床结果呈最强的正相关（P<0.001）。
宫颈脱落细胞中 CD86 的低表达可用作 IGMKK16E7 给药后组织学完全缓解的预测生物标志物。
