Morrow Matthew P, Kraynyak Kimberly A, Sylvester Albert J, Shen Xuefei, Amante Dinah, Sakata Lindsay, Parker Lamar, Yan Jian, Boyer Jean, Roh Christian, Humeau Laurent, Khan Amir S, Broderick Kate, Marcozzi-Pierce Kathleen, Giffear Mary, Lee Jessica, Trimble Cornelia L, Kim J Joseph, Sardesai Niranjan Y, Weiner David B, Bagarazzi Mark L
Inovio Pharmaceuticals , Plymouth Meeting, Pennsylvania, USA.
Unified Women's Clinical Research , Winston-Salem, North Carolina, USA.
Mol Ther Oncolytics. 2016 Nov 30;3:16025. doi: 10.1038/mto.2016.25. eCollection 2016.
We have previously demonstrated the immunogenicity of VGX-3100, a multicomponent DNA immunotherapy for the treatment of Human Papillomavirus (HPV)16/18-positive CIN2/3 in a phase 1 clinical trial. Here, we report on the ability to boost immune responses with an additional dose of VGX-3100. Patients completing our initial phase 1 trial were offered enrollment into a follow on trial consisting of a single boost dose of VGX-3100. Data show both cellular and humoral immune responses could be augmented above pre-boost levels, including the induction of interferon (IFN)γ production, tumor necrosis factor (TNF)α production, CD8+ T cell activation and the synthesis of lytic proteins. Moreover, observation of antigen-specific regulation of immune-related gene transcripts suggests the induction of a proinflammatory response following the boost. Analysis of T cell receptor (TCR) sequencing suggests the localization of putative HPV-specific T cell clones to the cervical mucosa, which underscores the putative mechanism of action of lesion regression and HPV16/18 elimination noted in our double-blind placebo-controlled phase 2B trial. Taken together, these data indicate that VGX-3100 drives the induction of robust cellular and humoral immune responses that can be augmented by a fourth "booster" dose. These data could be important in the scope of increasing the clinical efficacy rate of VGX-3100.
我们之前在一项1期临床试验中证明了VGX - 3100的免疫原性，VGX - 3100是一种用于治疗人乳头瘤病毒（HPV）16/18阳性的CIN2/3的多组分DNA免疫疗法。在此，我们报告了用额外剂量的VGX - 3100增强免疫反应的能力。完成我们初始1期试验的患者被纳入一项后续试验，该试验包括单次注射VGX - 3100加强剂量。数据显示，细胞免疫和体液免疫反应均能增强至加强前水平以上，包括干扰素（IFN）γ产生、肿瘤坏死因子（TNF）α产生、CD8 + T细胞活化以及裂解蛋白的合成。此外，对免疫相关基因转录本的抗原特异性调控的观察表明，加强注射后会诱导促炎反应。T细胞受体（TCR）测序分析表明，假定的HPV特异性T细胞克隆定位于宫颈黏膜，这强调了我们在双盲安慰剂对照2B期试验中所观察到的病变消退和HPV16/18清除的假定作用机制。综上所述，这些数据表明VGX - 3100能诱导强大的细胞免疫和体液免疫反应，且可通过第四次“加强”剂量增强。这些数据对于提高VGX - 3100的临床有效率可能具有重要意义。
