A Phase 1, Open-Label Study to Evaluate the Safety, Tolerability, and Immunogenicity of GTL001 Vaccine Adjuvanted With Imiquimod Cream in HPV 16- and/or HPV 18-Infected Women Aged 25 to 65 Years, With Normal Cytology, ASCUS, or LSIL

开始日期2015-08-01

申办/合作机构

Genticel SA

[+1]

NCT01957878 / Completed临床2期

A Double-blind, Randomised, Placebo-controlled, Phase II Study to Evaluate ProCervix Efficacy to Clear HPV 16 and HPV 18 Infection in Women With Normal Cytology or ASCUS/LSIL

Human Papillomavirus (HPV) 16 and HPV 18 (the two virus genotypes targeted by the ProCervix vaccine) are the most common HPV genotypes associated with at least 70% of squamous cell carcinomas and 82% of adenocarcinomas of the cervix The strategy of therapeutic vaccination with ProCervix is to activate and enhance the patient's cellular immune response to HPV . The therapeutic vaccine will be used for women infected by HPV 16, HPV 18, or both. The vaccine targets these HPV infected women with normal or mild cervical cellular dyskaryosis as detectable infections with oncogenic potential.
This will be a double-blind, randomised, placebo-controlled, parallel group study assessing the efficacy of ProCervix or placebo (concomitantly administered with imiquimod cream).
ProCervix will be delivered with a topical agent, imiquimod, applied to the injection sites as a vaccine adjuvant.
The population proposed for this study represents an otherwise healthy female population who are infected with HPV 16 and/or HPV 18. The safety and tolerability of this therapeutic vaccine has been shown in the ongoing Phase I study, and the proposed population may in theory derive benefit from this vaccine.

开始日期2013-12-01

申办/合作机构

Genticel SA

NL-OMON35990 / CompletedN/A

Tolerance and immunogenicity of ProCervix, a therapeutic vaccine composed of 2 Human Papillomavirus (HPV) antigens vectored in recombinant adenylate cyclases, in HPV 16 and/or HPV 18 infected women with normal cytology - Tolerance and immunogenicity of ProCervix, a HPV-16 /18 therapeutic vaccine

开始日期2012-01-12

申办/合作机构-

100 项与 GTL-001 相关的临床结果

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100 项与 GTL-001 相关的转化医学

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100 项与 GTL-001 相关的专利（医药）

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项与 GTL-001 相关的文献（医药）

2023-06-12·Laboratory animal research

Development of HPV16 mouse and dog models for more accurate prediction of human vaccine efficacy.

Article

作者: Martin, Nicolas ; Bousquet-Melou, Alain ; Misseri, Yolande ; Boullier, Severine ; Pavlovic, Guillaume ; Sorg, Tania ; Iché, Alexandra ; Lindner, Loïc ; Totain, Emmanuelle ; Duthoit, Christine ; Herault, Yann ; Bouillé, Pascale ; Birling, Marie-Christine

BACKGROUNDAnimal models are essential to understand the physiopathology of human diseases but also to evaluate new therapies. However, for several diseases there is no appropriate animal model, which complicates the development of effective therapies. HPV infections, responsible for carcinoma cancers, are among these. So far, the lack of relevant animal models has hampered the development of therapeutic vaccines. In this study, we used a candidate therapeutic vaccine named C216, similar to the ProCervix candidate therapeutic vaccine, to validate new mouse and dog HPV preclinical models. ProCervix has shown promising results with classical subcutaneous murine TC-1 cell tumor isografts but has failed in a phase II study.RESULTSWe first generated E7/HPV16 syngeneic transgenic mice in which the expression of the E7 antigen could be switched on through the use of Cre-lox recombination. Non-integrative LentiFlash^® viral particles were used to locally deliver Cre mRNA, resulting in E7/HPV16 expression and GFP reporter fluorescence. The expression of E7/HPV16 was monitored by in vivo fluorescence using Cellvizio imaging and by local mRNA expression quantification. In the experimental conditions used, we observed no differences in E7 expression between C216 vaccinated and control groups. To mimic the MHC diversity of humans, E7/HPV16 transgenes were locally delivered by injection of lentiviral particles in the muscle of dogs. Vaccination with C216, tested with two different adjuvants, induced a strong immune response in dogs. However, we detected no relationship between the level of cellular response against E7/HPV16 and the elimination of E7-expressing cells, either by fluorescence or by RT-ddPCR analysis.CONCLUSIONSIn this study, we have developed two animal models, with a genetic design that is easily transposable to different antigens, to validate the efficacy of candidate vaccines. Our results indicate that, despite being immunogenic, the C216 candidate vaccine did not induce a sufficiently strong immune response to eliminate infected cells. Our results are in line with the failure of the ProCervix vaccine that was observed at the end of the phase II clinical trial, reinforcing the relevance of appropriate animal models.

2021-10-01·Advanced Materials1区 · 材料科学

A Novel Immunomodulator Delivery Platform Based on Bacterial Biomimetic Vesicles for Enhanced Antitumor Immunity

1区 · 材料科学

Article

作者: Long, Qiong ; Hua, Liangqun ; Yang, Zhongqian ; Zheng, Peng ; Ye, Chao ; He, Jinrong ; Li, Weiran ; Zheng, Xiao ; Ren, Zhaoling ; Sun, Wenjia ; Li, Duo ; Chen, Yongjun ; Huang, Weiwei ; Ma, Yanbing ; Bai, Hongmei ; Yang, Xu ; Zhang, Qishu

AbstractT cell activation‐induced cell death (AICD) during tumor pathogenesis is a tumor immune escape process dependent on dendritic cells (DCs). Proper immune‐modulatory therapies effectively inhibit tumor‐specific CD8+ T cell exhaustion and enhance antitumor immune responses. Here, high‐pressure homogenization is utilized to drive immunomodulator IL10‐modified bacteria to extrude through the gap and self‐assemble into bacterial biomimetic vesicles exposing IL10 (IL10‐BBVs) on the surface with high efficiency. IL10‐BBVs efficiently target DCs in tumor‐draining lymph nodes and thus increase the interaction between IL10 on BBVs and IL10R on DCs to suppress AICD and mitigate CD8+ T cell exhaustion specific to tumor antigens. Two subcutaneous peripheral injections of IL10‐BBVs 1 week apart in tumor‐bearing mice effectively increase systemic and intratumoral proportions of CD8+ T cells to suppress tumor growth and metastasis. Tumor‐specific antigen E7 is enclosed into the periplasm of IL10‐BBVs (IL10‐E7‐BBVs) to realize concurrent actions of the immunomodulator IL10 and the tumor antigen human papillomavirus (HPV) 16E7 in lymph nodes, further enhancing the antitumor effects mediated by CD8+ T cells. The development of this modified BBV delivery platform will expand the application of bacterial membranes and provide novel immunotherapeutic strategies for tumor treatment.

2018-05-01·Gene3区 · 生物学

Human gene expression microarray analysis of the HPV 6bE7-HaCaT stable cell line

3区 · 生物学

Article

作者: Zhou, Qiang ; Cheng, Hao ; Zhang, Boya ; Sun, Siyuan ; Chen, Xianzhen ; Song, Yinjing

OBJECTIVEHuman papillomavirus (HPV) is the most common sexually transmitted agent in the world. HPV6b is a low-risk type of HPVs that causes benign verrucous hyperplastic lesions of the skin and anal genital mucosa. Previous research has indicated that HPV genotype 6 is sometimes associated with high-grade lesions and anal cancer. The pathogenesis of low-risk HPV infection and its relationship to high-risk HPV is not clear at present. The E7 protein, which is encoded by HPV early -expressing genes, plays an important role in HPV infection. The aim of this study is to investigate the human gene expression signature of the HPV6b E7-transfected HaCaT stable cell line. The identification of differentially expressed genes might provide a more comprehensive understanding of HPV6b infection and will allow us to explore the specific role of E7 protein.METHODSWe established a stable cell line transfected with the HPV6b E7 gene and analyzed the line's genome-wide expression profile by microarray. Quantitative real-time PCR (qRT-PCR) was used to verify the differentially expressed genes. GO enrichment analysis was applied for gene annotation according to functions. KEGG analysis, a system for analyzing gene function and genome information, was used to help us integrate differentially expressed genes into pathways.RESULTSA total of 3519 genes were identified to be significantly differentially expressed between the HPV 6bE7-HaCaT stable cell line and a control cell line, among which 1884 genes were up-regulated and 1635 genes were down-regulated with a fold-change > 2.0 between the two groups. The expression profiles of the top 20 up-regulated and the top 20 down-regulated genes in the HPV 6bE7-HaCaT stable cell line as analyzed by qRT-PCR were consistent with the microarray data. The most significantly enhanced genes HPV 6bE7-HaCaT cells were SIMC1, S100A8 and S100A9, whereas PXDN expression was markedly down-regulated. GO analysis showed that HPV 6bE7 primarily affected biological processes and that the most significant difference was in heart induction (GO:0003129). Many differentially expressed genes were linked to histone H4-K20 demethylation (GO:0035574). KEGG analysis showed that the most significant changes in gene expression were related to primary bile acid biosynthesis, and the most diverse biological processes were related to systemic lupus erythematosus pathogenesis.CONCLUSIONSThe global gene expression profile of the HPV 6bE7-HaCaT stable cell line was analyzed, revealing the genes regulated by E7 protein and providing insight into the pathogenesis of HPV6b infection.

项与 GTL-001 相关的新闻（医药）

2023-04-05

·CPHI制药在线

疫苗 | 治疗性人乳头瘤病毒（HPV）疫苗研究进展

关注并星标CPHI制药在线目前，预防性人乳头瘤病毒(HPV)疫苗研发技术日趋成熟（相关阅读：《预防性人乳头瘤病毒（HPV）疫苗研究应用现状》），随着疫苗覆盖率的提高， HPV 相关疾病的发病率也逐步减少。不过，晚期和复发的宫颈癌患者预后仍然较差，死亡率较高，开发HPV的治疗性疫苗并用来治疗HPV 感染导致的宫颈上皮内损害以及宫颈癌成为当前研究的热点。治疗性疫苗不同于预防性疫苗，其旨在诱导细胞介导的免疫反应，而不是产生中和抗体。HPV治疗性疫苗是一类打破慢性感染者体内免疫耐受，重建或增强免疫应答从而治疗 HPV 感染，阻断由 HPV引起的癌前病变和促进病变组织消退的新型疫苗。一般来说，治疗性疫苗以多种形式包含E6、E7抗原，并将这些抗原传递给局部抗原递呈细胞（APCs），进一步通过MHCⅠ类和MHCⅡ类分子刺激抗原表达，从而产生CD8+细胞毒性T细胞（CTL）或CD4+辅助T细胞（Th）反应。E6、E7抗原在被APCs 的MHCⅠ类分子识别之前，先在 APCs被蛋白酶加工、消化成更小的肽段。重要的是，并不是所有的这些肽段都能成功加载到 MHC分子进而被特异性的T 细胞识别。只有一些含有特定抗原表位的肽段能高亲和力地结合到MHC分子，并与能引起免疫反应的特异性T 细胞的受体（TCR）发生相互反应。目前，大多数治疗性HPV疫苗致力于诱导E7抗原的免疫反应，因为在临床前模型中，E7抗原免疫反应性比E6抗原更好。治疗性HPV疫苗研究现状在HPV慢性感染导致宫颈上皮内损害以及癌变的过程中，通常存在致癌蛋白E6、E7的持续表达。所以目前存在多种针对靶抗原E6、E7的治疗性疫苗，其疫苗类型包括活载体疫苗、蛋白或多肽疫苗以、核酸疫苗以及细胞疫苗等，且不少疫苗的研发工作已进入临床前模型和临床试验阶段。 1、活载体细菌减毒疫苗活载体疫苗分为细菌或病毒载体疫苗。这些载体在机体内复制，促进了抗原的传播。活载体疫苗有很高的免疫原性，可以产生强烈的细胞和体液免疫反应。他们还可以将E6、E7抗原递呈给抗原递呈细胞（APCs），促进主要组织相容性复合体(MHC)Ⅰ和Ⅱ类分子识别抗原。但是，活载体疫苗有潜在的安全风险，尤其是在免疫力低下的人群中。此外，重复接种相同的活载体疫苗后，产生的免疫反应疗效是有限的。细菌载体主要包括单核细胞增多性李斯特菌( Listeria monocytogenes，Lm) 、乳杆菌属和沙门菌等。李斯特菌是一类革兰阳性胞内病原体，可诱发固有免疫和获得性免疫，对病毒和寄生虫的感染起到保护机体的作用，作为载体在免疫治疗中具有以下优势：其一可感染巨噬细胞而不被其捕获，具有在 MHC I 和 MHC II 途径中递送抗原的能力，其二通过分泌李斯特菌溶血素( listeriolysin，LLO) 来逃脱吞噬体的吞噬作用。Lm 是一类应用广泛和具有代表性的载体，目前基于Lm 的疫苗已经在大量的临床试验中开展，ADXSⅡ-001 是一种基于HPV16 E7抗原的灭活减毒李斯特菌载体疫苗，可用于治疗HPV相关的口咽癌、宫颈癌和高级别宫颈上皮内瘤变患者。干酪乳酸杆菌( Lactobacillus casei，L. casei) 是另一种常见的细菌载体，在疫苗制备过程中，编码 HPV-E7 的基因被转导至L.casei 表达 E7 蛋白，可被黏膜中APCs识别并递呈给CTLS而诱发细胞免疫。病毒载体主要包括腺病毒、腺相关病毒、α病毒、慢病毒和牛痘病毒等，通过基因工程方法担载编码HPV E6 /E7 的基因序列而发挥递送靶抗原的作用。TG4001 是一种基于重组修饰牛痘病毒( modified vaccinia virus Ankara，MVA) 为载体的疫苗，在一项临床试验中被用于治疗 HPV-16相关性 CIN2/3的患者。RNA 复制子疫苗的制备是利用 RNA α 病毒作为载体，该类病毒包括辛德毕斯病毒(Sindbis virus，SIN)、委内瑞拉猪脑炎病毒( Venezuelan equine encephalitis virus，VEE) 和塞姆利基森林病毒( Semliki forest virus，SFV)。RNA 复制子能够自我复制，从而诱发抗原的持续表达和增加免疫原性。 2、蛋白或多肽疫苗多肽和蛋白质疫苗中的多肽和蛋白质组分是从HPV 抗原分离出来的，经由树突状细胞（DCs）处理后，被递呈给 MHCⅠ或Ⅱ类分子，能有效刺激CD8+或CD4+T细胞的免疫应答。多肽和蛋白质疫苗安全稳定，易于生产，显示了巨大的应用前景。蛋白疫苗免疫原性较弱，主要通过 MHC II 路径递呈抗原诱发抗体产生，而不是产生 CTL 的免疫应答。近几年来开展的研究主要关注TA-CIN、GTL001( ProCervix) 和 TVGV-1 等蛋白疫苗。TACIN 是一种 HPV-16-E6 /E7 /L2 融合蛋白疫苗，通过联合使用佐剂( GPI-0100) 和顺铂，在 HPV-16 E6 /E7阳性的小鼠模型中诱导了治疗性免疫应答。GTL001 是一种将重组 HPV-16/18-E7 蛋白融合至无催化活性的百日咳博德杆菌CyaA中的治疗性疫苗。一项 I期试验结果表明，在具有正常细胞学形态的 HPV-16/18 感染的女性患者中，间隔6周皮内注射一次 600μg GTL001，并在注射部位联合局部使用咪喹莫特软膏，经过两次治疗能有效清除 HPV-16 /18。TVGV-1 是一种基于HPV-16 E7 抗原的融合蛋白，在临床前试验中联合佐剂( GPI-0100 和 CpG 寡聚核苷酸) 诱导了强烈的抗原特异性 T 细胞免疫应答。多肽疫苗免疫原性弱，常需借助一些免疫佐剂或脂质体来增强其治疗效能。多肽类疫苗呈MHC特异性，在治疗之前需确定患者抗原的特定表位。肽类疫苗种类繁多，其核心是使用HPV-16 E6和/或E7的多肽作为抗原，代表性的疫苗主要包括 PepCan、HPV16-SLP、GL-0810、PDS0101 和 DPX-E7 等。PepCan 包含四种合成性多肽，并添加了白色念珠菌提取物作为佐剂，可通过皮内注射进行接种。HPV16-SLP 是一种合成的长肽链疫苗，研究认为，在 HPV-16 E6 /E7 阳性的 CC 患者中，使用卡铂-紫杉醇化疗以后再进行该疫苗接种可促进疫苗诱导的 T 细胞反应。GL-0810 是一种 HPV-16 特异性多肽疫苗，制备过程中添加了粒-巨噬细胞集落刺激因子和Montanide 佐剂，用于皮下接种治疗头颈部复发/转移性鳞状细胞癌。PDS0101是基于 HPV-16 E6 /E7 多肽开发，其在高危型 HPV 感染和CIN 1女性患者中的治疗安全性和耐受性正在评估中( NCT02065973，I 期)。此外，DPX-E7 也正应用于HPV-16 E7和 HLA-A*02 阳性的口咽癌、CC 和肛门癌( NCT02865135，Ib /II期) 患者的临床试验中。 3、核酸疫苗核酸疫苗包括DNA 和RNA 疫苗，可以多次接种。DNA 疫苗的优点是安全、稳定及易批量生产，比RNA 疫苗在细胞内的抗原表达持续时间更长，常用于肌肉注射。其缺点主要是在肌注过程中，容易被心肌细胞摄取，阻断了诱导持续的免疫原性。此外，递送的DNA体内转染效率有限，故免疫原性较弱。随着基因工程技术的发展，可以在载体抗原序列上加上辅助因子促进序列的有效表达。趋化性抗原DNA疫苗是一种新型DNA肿瘤疫苗。将HPV16E7基因与趋化因子SLC和IgG的Fc片段融合表达，SLC可吸引DC，T、B 淋巴细胞，并且 DC 细胞通过 Fc 受体可高效捕获融合抗原，促进抗原提呈作用。该DNA疫苗能通过CD4+和CD8+T细胞依赖途径诱发强烈的抗肿瘤免疫反应。另一种pNGVL4a-CRT/E7 疫苗由编码HPV16 E7与钙网蛋白Calreticulin(CRT)序列的 pNGVL4a 表达载体构成。CRT 是热休克蛋白家族成员之一。该疫苗可用于治疗高级别宫颈上皮内瘤变，32例HPV16阳性的CIN2/3患者参加的初步研究显示该疫苗具有可行性、安全性、良好的耐受性和潜在的临床价值。此外，在 HPV16 和 HPV18 阳性 CIN2/3 期患者中开展的随机双盲Ⅱb临床试验显示，编码HPV16和HPV18 E6和E7基因片段的DNA疫苗VGX-3100是第一个对HPV16 和HPV18 阳性CIN 2/3 期患者有效的治疗性疫苗，可用于CIN2/3患者的非手术治疗。与DNA 疫苗相比，RNA 疫苗不会被整合到宿主的染色组中，亦不会诱导细胞转化，但是其不够稳定。目前，尚未有开展RNA 疫苗治疗HPV 相关性疾病的临床试验相关报道。 4、细胞疫苗基于HPV16/18 E7抗原的树突状细胞疫苗的安全性和免疫原性在Ⅰ期临床试验得到证实，已进入Ⅱ期临床试验阶段。有学者给予10例IB或ⅡA的宫颈癌患者重组的HPV16/18 E7抗原冲击致敏的自体DC，免疫后发现在受试者体内均产生了 E7 的特异性CD4+T 细胞反应并产生了抗体反应。此外，过继细胞免疫治疗技术也不断发展，研究结果显示，9例转移性宫颈癌患者注入肿瘤浸润性T淋巴细胞后，有2例患者病变完全消退。用疫苗进行免疫治疗是一种很有前景的癌症治疗方法，在宫颈病变及宫颈癌患者中，治疗性疫苗的使用与癌变前损害的转归以及临床预后密切相关。与传统治疗相比，治疗性疫苗有巨大优势和可行性，具有良好的发展前景。HPV治疗性疫苗研究进展相对缓慢，还处于动物实验或临床试验研究阶段。治疗性疫苗的机制比较复杂，例如肿瘤患者往往免疫功能低下，疫苗可能难于有效激活免疫系统，另外疫苗的安全性，肿瘤细胞和受 HPV感染细胞的免疫逃逸也是必须考虑的问题。参考资料 [1]封婕,高玲娟,许豪勤,吴玉璘,林宁,闫林萍,钟天鹰.HPV治疗性多肽疫苗的研究进展[J].中国计划生育学杂志,2018,26(01):63-69. [2]曾明,邓列华.HPV感染治疗性疫苗新进展[J].皮肤科学通报,2020,37(04):369-374+4. [3]赵爽, 赵方辉. HPV治疗性疫苗研究进展[J]. 中华预防医学杂志, 2018, 52(5):5. 作者简介：小米虫，药品质量研究工作者，长期致力于药品质量研究及药品分析方法验证工作，现就职于国内某大型药物研发公司，从事药品检验分析及分析方法验证。智药研习社近期课程报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

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适应症	最高研发状态	国家/地区	公司	日期
生殖器感染	临床3期	法国	Genticel SA	2013-12-01
生殖器感染	临床2期	比利时	Genticel SA	2013-12-01
生殖器感染	临床2期	荷兰	Genticel SA	2013-12-01
HPV16感染	临床2期	比利时	Genticel SA	2013-12-01
HPV16感染	临床2期	德国	Genticel SA	2013-12-01
HPV16感染	临床2期	芬兰	Genticel SA	2013-12-01
HPV16感染	临床2期	英国	Genticel SA	2013-12-01
HPV16感染	临床2期	西班牙	Genticel SA	2013-12-01
HPV16感染	临床2期	荷兰	Genticel SA	2013-12-01
HPV16感染	药物发现	法国	Genticel SA	2013-12-01