Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA.
Lyndhurst Clinical Research, Winston-Salem, NC 27103, USA.
Sci Transl Med. 2012 Oct 10;4(155):155ra138. doi: 10.1126/scitranslmed.3004414.
Despite the development of highly effective prophylactic vaccines against human papillomavirus (HPV) serotypes 16 and 18, prevention of cervical dysplasia and cancer in women infected with high-risk HPV serotypes remains an unmet medical need. We report encouraging phase 1 safety, tolerability, and immunogenicity results for a therapeutic HPV16/18 candidate vaccine, VGX-3100, delivered by in vivo electroporation (EP). Eighteen women previously treated for cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) received a three-dose (intramuscular) regimen of highly engineered plasmid DNA encoding HPV16 and HPV18 E6/E7 antigens followed by EP in a dose escalation study (0.3, 1, and 3 mg per plasmid). Immunization was well tolerated with reports of mild injection site reactions and no study-related serious or grade 3 and 4 adverse events. No dose-limiting toxicity was noted, and pain was assessed by visual analog scale, with average scores decreasing from 6.2/10 to 1.4 within 10 min. Average peak interferon-γ enzyme-linked immunospot magnitudes were highest in the 3 mg cohort in comparison to the 0.3 and 1 mg cohorts, suggesting a trend toward a dose effect. Flow cytometric analysis revealed the induction of HPV-specific CD8(+) T cells that efficiently loaded granzyme B and perforin and exhibited full cytolytic functionality in all cohorts. These data indicate that VGX-3100 is capable of driving robust immune responses to antigens from high-risk HPV serotypes and could contribute to elimination of HPV-infected cells and subsequent regression of the dysplastic process.
尽管已经开发出针对人乳头瘤病毒（HPV）血清型 16 和 18 的高效预防性疫苗，但预防感染高危 HPV 血清型的女性宫颈癌前病变和癌症仍然是一个未满足的医疗需求。我们报告了一种治疗性 HPV16/18 候选疫苗 VGX-3100 的令人鼓舞的 1 期安全性、耐受性和免疫原性结果，该疫苗通过体内电穿孔（EP）递送。18 名先前因宫颈上皮内瘤变 2 级或 3 级（CIN2/3）而接受治疗的女性接受了三剂（肌肉内）高工程化质粒 DNA 方案，该方案编码 HPV16 和 HPV18 E6/E7 抗原，随后进行剂量递增研究（每质粒 0.3、1 和 3mg 的 EP）。免疫接种耐受性良好，仅报告有轻度注射部位反应，无研究相关严重或 3 级和 4 级不良事件。未观察到剂量限制性毒性，疼痛通过视觉模拟量表评估，平均评分在 10 分钟内从 6.2/10 降至 1.4。与 0.3 和 1mg 队列相比，3mg 队列的平均干扰素-γ酶联免疫斑点幅度最高，表明存在剂量效应趋势。流式细胞术分析显示，所有队列均诱导 HPV 特异性 CD8+T 细胞，这些细胞有效地加载颗粒酶 B 和穿孔素，并表现出完整的细胞溶解功能。这些数据表明，VGX-3100 能够引发针对高危 HPV 血清型抗原的强烈免疫反应，并有助于消除 HPV 感染的细胞和随后的发育不良过程的消退。
