治疗人乳头瘤病毒16型在HIV阳性男性肛管上皮内瘤变的疫苗治疗
Therapeutic Vaccination against Human Papillomavirus Type 16 for the Treatment of Anal Intraepithelial Neoplasia in HIV+ Men.
发表日期:2023 Aug 04
作者:
Karien C M Gosens, Sjoerd H van der Burg, Marij J P Welters, Sanne Boekestijn, Nikki M Loof, Wim G V Quint, Carel J M van Noesel, Allard C van der Wal, Olivier Richel, Wilhelmus J T A Krebber, Cornelis J M Melief, Henry J C de Vries, Jan M Prins
来源:
Immunity & Ageing
摘要:
HIV阳性男同性恋人群中肛门癌发病率上升。对其前驱病变高度肛门上皮内瘤变(HGAIN)的治疗选择不足。在本阶段I-II剂量寻找研究中,我们评估了人乳头瘤病毒16型(HPV16)合成长肽疫苗(SLP-HPV-01®)在HPV16阳性HGAIN患者中的安全性和疗效。每个剂量水平的10名患者经皮下注射SLP-HPV-01®疫苗,间隔三周,共有四个剂量方案(1-5-10;5-10-20;10-20-40和40-40-40-40毫克)。每个剂量组中有五名患者亦皮下注射1µg/kg聚乙二醇干扰素-α-2b。主要终点为3、6和12个月时的安全性和HGAIN的退化情况。在134名患者中,81名(60%)HGAIN患者为HPV16阴性,符合条件的为53名患者,剔除了13名患者后剩下40名患者。疫苗耐受性良好,其中1名患者出现全身性皮疹。最高剂量水平产生了最强的免疫反应。在IFN-α组中没有显示出更强的反应迹象。经过18个月的随访,38名意向治疗患者中有8人完全临床和组织反应(CR),还有一人部分反应(PR),总计9人(23.7%)。在最高剂量水平下,临床反应为4/10(40%)。在临床反应者中检测到更强的免疫反应。最高剂量水平是安全的、具有免疫原性,并与HPV16引起病变的临床反应相关。然而,由于大多数HGAIN是由其他HPV类型引起的,进一步研究应致力于全HPV预防或治疗HGAIN。
Anal cancer is increasing in HIV-positive men who have sex with men (MSM). Treatment options for its precursor, high-grade anal intraepithelial neoplasia (HGAIN), are suboptimal. In this phase I-II dose-finding study we assessed the safety and efficacy of the human papillomavirus type 16 (HPV16) synthetic long peptide vaccine (SLP-HPV-01®) in HIV-positive MSM with HPV16-positive HGAIN.Four dosage schedules (1-5-10; 5-10-20; 10-20-40 and 40-40-40-40 mg) of SLP-HPV-01® were administered intradermally with a three-week interval in 10 patients per dose level. In each dose group, five patients also received 1 µg/kg pegylated interferon-alpha-2b subcutaneously. Primary endpoints were safety and regression of HGAIN at 3,6 and 12 months.Eighty-one of 134 screened patients (60%) had HPV16-negative HGAIN lesions, leaving 53 eligible patients. Thirteen patients were excluded, leaving 40 men. The vaccine was well tolerated. One patient developed a generalized rash. The highest dosage level induced the strongest immune responses. There was no indication for stronger reactivity in the IFN-α groups. Up to 18 months of follow-up, 8/38 intention-to-treat patients had a complete clinical and histological response (CR) and one had a partial response (PR) (in total 9/38, 23.7%). At the highest dosage level the clinical response was 4/10 (40%). Stronger immune responses were detected among clinical responders.The highest dose level is safe, immunogenic and associated with clinical responses to HPV16-induced lesions. However, as the majority of HGAIN is caused by the other HPV types, further studies should aim at pan-HPV vaccination to prevent or treat HGAIN.