Heat shock fusion protein-based immunotherapy for treatment of cervical intraepithelial neoplasia III
Heat shock fusion protein-based immunotherapy for treatment of cervical intraepithelial neoplasia III
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DOI：
10.1016/j.ygyno.2007.04.038
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发表时间：
2007-09-01
影响因子：
4.7
通讯作者：
Runowicz, Carolyn D.
中科院分区：
文献类型：
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作者：
Einstein, Mark H.;Kadish, Anna S.;Runowicz, Carolyn D.
目标。SGN-00101 （HspE7, Nventa, San Diego， CA）是一种新型治疗性疫苗，由含有与HPV 16 ET全序列共价连接的牛M卡介苗热休克蛋白（Hsp65）的融合蛋白组成。该试验旨在评估HspE7在CIN iii型女性中的疗效和毒性。活检证实CIN III型的HIV（-）妇女是合格的。累积了两个队列；一个队列确定疗效，第二个队列有较长的随访期，以提高试验的准确性，以估计反应率。每名患者每月接受500 μ g HspE7皮下接种3次，然后在队列I中每月进行1个月的阴道镜随访，在队列2中延长观察期（2个月）。所有患者随后接受LEEP或宫颈锥活检。完全病理反应（pCR）被定义为没有CIN或CIN I的证据（只有HPV改变）。部分缓解（PR）定义为阴道镜下病变缩小50%。每次就诊时取宫颈阴道灌洗液样本，用MY09/MY11型HPV pcr进行HPV分型。对72例患者进行了登记和筛选，其中64例符合条件。58名患者完成了试验并可评估（队列1中31名，队列2中27名）。两个队列之间没有明显的流行病学或HPV类型差异，因此将反应合并进行分析。在58例可评估的患者中，13例（22.5%）有pCR；32例（55%）有PR， 11例（19%）病情稳定。队列2中有2例（3.5%）患者患有微创性疾病，并被定义为进行性疾病。58名患者中有33名（57%）在接种疫苗前或随后的就诊中感染了HPV 16。与未感染HPV 16的妇女相比，感染HPV 16的妇女的回归无显著差异（88%对70%；p=0.12）。与未接受过治疗的患者相比，既往LEEP或消融治疗CIN的女性完全缓解的可能性高2.7倍，尽管差异无统计学意义（95% Cl比率：0.95-6.19,p=0.10）。在细胞水平上，局部炎症和反应之间存在显著关联；病变炎症程度较低与HspE7反应相关（使用Wilcoxon秩和检验p=0.04）。HspE7似乎在CIN III型女性中表现出活性，并且符合有效性的先验假设；然而，尚不清楚这种反应是由于自然回归还是治疗效果。HspE7靶向HPV 16 E7癌蛋白，对感染16型以外HPV的患者有效，提示交叉反应性。需要更大规模的随机对照试验来更好地确定疗效，并确定最有可能从免疫治疗中受益的妇女亚群。(c) 2007爱思唯尔公司版权所有。
Objectives. SGN-00101 (HspE7, Nventa, San Diego, CA) is a novel therapeutic vaccine consisting of a fusion protein containing an M bovis BCG heat shock protein (Hsp65) covalently linked to the entire sequence of HPV 16 ET This trial was designed to evaluate the efficacy and toxicities of HspE7 in women with CIN III.Methods. HIV (-) women with biopsy-proven CIN III were eligible. Two cohorts were accrued; one cohort to establish efficacy and a second cohort with a longer follow-up period to improve the precision of the trial to estimate response rates. Each patient underwent 3 monthly subcutaneous vaccinations with 500 mu g of HspE7 followed by monthly colposcopic follow-up for I month in cohort I and an extended observation period (2 months) in cohort 2. All patients then underwent a LEEP or cone biopsy of the cervix. A complete pathologic response (pCR) was defined as no evidence of CIN or CIN I (only HPV changes). A partial response (PR) was defined as colposcopic lesion regression of > 50% in size. Cervicovaginal lavage samples were obtained at each visit for HPV typing using MY09/MY11 HPV PCR.Results. Seventy-two patients were registered and screened, of whom 64 were eligible. Fifty-eight patients completed the trial and were evaluable (31 in cohort 1, 27 in cohort 2). There were no significant epidemiologic or HPV type differences between the 2 cohorts so responses were combined for analysis. Of the 58 evaluable patients, 13 (22.5%) had a pCR; 32 (55%) had a PR and 11 (19%) had stable disease. Two (3.5%) patients in cohort 2 had microinvasive disease and were defined as progressive disease. Thirty-three of 58 (57%) of the patients were infected with HPV 16 prior to vaccination or in subsequent visits. There was no significant difference in regression in women infected with HPV 16 compared to those without HPV 16 infection (88% vs. 70%; p=0.12). Women who had a previous LEEP or ablation for CIN were 2.7 times more likely to have a complete response compared to patients without previous treatment, although the difference was not statistically significant (95% Cl for rate ratio: 0.95-6.19, p=0.10). At a cellular level, there was a significant association between local inflammation and response; lower grade of lesional inflammation correlated with a response to HspE7 (p=0.04 using Wilcoxon rank sum test).Conclusions. HspE7 appeared to demonstrate activity in women with CIN III and met a priori assumptions for efficacy; however, it is unclear whether this response was due to natural regression rather than treatment effect. HspE7, which targets the HPV 16 E7 oncoprotein, had efficacy in patients infected with HPV types other than 16, suggesting cross-reactivity. A larger randomized, controlled trial is needed to better define efficacy and to identify subsets of women most likely to benefit from immunotherapy. (c) 2007 Elsevier Inc. All rights reserved.