Human papillomavirus type 16 viral load is decreased following a therapeutic vaccination.
Human papillomavirus type 16 viral load is decreased following a therapeutic vaccination.
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DOI：
10.1007/s00262-016-1821-x
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发表时间：
2016-05
期刊：
影响因子：
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通讯作者：
Nakagawa M
中科院分区：
文献类型：
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作者：
Coleman HN;Greenfield WW;Stratton SL;Vaughn R;Kieber A;Moerman-Herzog AM;Spencer HJ;Hitt WC;Quick CM;Hutchins LF;Mackintosh SG;Edmondson RD;Erickson SW;Nakagawa M
在I期临床试验的剂量递增阶段中，其中六名受试者各自以50、100、250和500μg/肽剂量接种PepCan，50μg剂量显示出最佳的组织学消退率。另外10例受试者在最终给药期以该剂量接种疫苗。与剂量递增阶段一样，未观察到剂量限制性毒性。总体而言，50μg剂量组（7/14）和100μg剂量组（3/6）的组织学消退率为50%，总体为45%（14/31）。在入组时检测到HPV 16型（HPV 16）的受试者中，有3例受试者在接种疫苗后变得不可检测，9例受试者在入组和退出时检测到HPV 16感染，病毒载量显著降低（p=0.008）。免疫分析显示，接种疫苗后1型辅助性T细胞增加（2次和4次接种后分别为p=0.02和p=0.0004）。2型辅助性T细胞最初在2次疫苗接种后增加（p=0.01），但在4次疫苗接种后下降至基线水平以下，但并不显着。组织学应答者的接种前调节性T细胞水平显著低于非应答者（p=0.03）。检测血浆用于多重细胞因子/趋化因子分析和进行PBMC蛋白质组学分析的可行性，以在未来潜在地鉴定生物标志物。虽然这些分析是可行的，但需要注意采血后血液样本的处理时间。由于已证明PepCan具有足够的安全性，II期临床试验的入组已经开放。
In the dose-escalation phase of a Phase I clinical trial in which six subjects each were vaccinated with PepCan at the 50, 100, 250, and 500μg per peptide dose, the 50μg dose showed the best histological regression rate. Ten additional subjects were vaccinated at this dose in the final dose phase. As with the dose-escalation phase, no dose-limiting toxicities were observed. Overall, the histological regression rates were 50% at the 50μg dose (7 of 14) and 100μg dose (3 of 6), and 45% overall (14 of 31). Of subjects in whom HPV type 16 (HPV 16) was detected at entry, it became undetectable in 3 subjects after vaccination, and the viral loads significantly decreased in 9 subjects in whom HPV 16 infection was detected at entry and exit (p=0.008). Immune profiling revealed increased T-helper type 1 cells after vaccinations (p=0.02 and p=0.0004 after 2 and 4 vaccinations respectively). T-helper type 2 cells initially increased after 2 vaccinations (p=0.01), but decreased below the baseline level after 4 vaccinations although not significantly. Pre-vaccination regulatory T-cell levels were significantly lower in histological responders compared to non-responders (p=0.03). Feasibility of testing plasma for multiplex cytokine/chemokine analysis and of performing proteomic analysis of PBMCs was examined for potentially identifying biomarkers in the future. While these analyses are feasible to perform, attention needs to be given to how soon the blood samples would be processed after phlebotomy. As sufficient safety of PepCan has been demonstrated, enrollment for the Phase II clinical trial has been opened.