A-007: Immune Modulation of HPV - Associated Neoplasia

A-007：HPV 的免疫调节 - 相关肿瘤

• 批准号: 7121580
• 负责人: BINH NGUYEN
• 金额: $ 77.69万
• 依托单位: TIGRIS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-09 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7121580
• 关键词: A-007; Amnesia; Anogenital cancer; Antigen-Presenting Cells; Basement membrane; Biopsy; Cancerous; Cell membrane; Cell surface; Cells; Cervical; Cervical Intraepithelial Neoplasia; Cervix Uteri; Clinical; Computer Simulation; Dendritic Cells; Dendritic cell activation; Dermis; Disease; Epithelial; Epithelium; Gel; Growth; Health Care Costs; Histopathology; Human; Human Papillomavirus; Human papilloma virus infection; Immune; Immunity; Literature; Lymphatic; Measures; Medical; Monitor; Morbidity - disease rate; Neoplasms; Operative Surgical Procedures; PTPRC gene; Patients; Phase II Clinical Trials; Physical Stimulation; Placebos; Population; Protein Tyrosine Phosphatase; Protocols documentation; Qualifying; Quality of life; Randomized; Research Project Grants; Risk; Signal Transduction; Site; Staging; Standards of Weights and Measures; Study models; T memory cell; T-Lymphocyte; Toxic effect; Transcriptional Activation; Up-Regulation; Upper arm; Vagina; Viral; Virus; animal data; cytokine; design; immunoregulation; improved; neoplastic; receptor; response; treatment program

DESCRIPTION (provided by applicant): 4,4'-Dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) was originally developed as an immune modulator of immune deficiency associated cancerous growths. In a recent study, A-007 was administered as a topical gel to treat anogenital cancers associated with the human papillomavirus (HPV). There were no local or systemic toxicities and excellent responses were seen -76% CR. All patients with cervical or vaginal neoplasia either had complete elimination of HPV infections or the viral types reduced from high risk to low risk groups. Immunohistochemical (IHC) and computer modeling studies support animal data and the hypothesis that A-007 interacts with the protein tyrosine phosphatase (PTP) T-cell membrane receptor CD45 up-regulating T-cells and improving local immunity. The latter changes override the local neoplastic CIN transformations. Support is provided in the present application to evaluate A-007 as therapy for cervical intraepithelial neoplasia (CIN) associated with HPV. Literature indicates that up to 70% of the CIN I disease can spontaneously disappear. Thus, the present studies have been designed to randomize CIN I to a placebo vs. A-007. The placebo arm will allow for any immune stimulation that follows biopsies and local physical stimulation associated with manipulations of the cervix. The advanced stages of the disease - CIN II/Ill - will be treated only with A-007; since there are no other medical treatments for this stage of disease and surgery would be the next treatment of choice. The CIN I patients treated with placebos will be given the option to receive A-007 after one course, if disease remains. The specific objectives of this Phase II study will be to topically treat 250 with various stages of CIN infected with HPV and evaluate A-007's ability to reverse CIN changes and eliminate HPV. Local immune modulation will be closely monitored, and standard histopathology and viral assessments will be performed. The study will be performed at three qualified clinical centers.

描述（由申请人提供）： 4,4'-二羟基二苯甲酮-2,4-二硝基苯腙 (A-007) 最初被开发为免疫缺陷相关癌性生长的免疫调节剂。在最近的一项研究中，A-007 作为局部凝胶使用，用于治疗与人乳头瘤病毒 (HPV) 相关的肛门生殖器癌症。 没有局部或全身毒性，并且反应良好，CR 为 -76%。所有患有宫颈或阴道肿瘤的患者要么完全消除了 HPV 感染，要么将病毒类型从高风险人群减少到低风险人群。免疫组织化学 (IHC) 和计算机建模研究支持动物数据和假设，即 A-007 与蛋白酪氨酸磷酸酶 (PTP) T 细胞膜受体 CD45 相互作用，上调 T 细胞并改善局部免疫力。后者的变化覆盖了局部肿瘤性 CIN 转化。本申请提供了评估A-007作为与HPV相关的宫颈上皮内瘤变(CIN)的疗法的支持。文献表明，高达70%的CIN I疾病可以自行消失。因此，本研究旨在将 CIN I 随机分为安慰剂和 A-007。安慰剂臂将允许在活检后进行任何免疫刺激以及与子宫颈操作相关的局部物理刺激。该疾病的晚期阶段 - CIN II/Ill - 将仅使用 A-007 进行治疗；由于此阶段的疾病没有其他治疗方法，手术将是下一个治疗选择。如果疾病仍然存在，接受安慰剂治疗的 CIN I 患者将可以选择在一个疗程后接受 A-007。 这项 II 期研究的具体目标是局部治疗 250 名患有 HPV 感染的不同阶段 CIN 的患者，并评估 A-007 逆转 CIN 变化和消除 HPV 的能力。将密切监测局部免疫调节，并进行标准组织病理学和病毒评估。 该研究将在三个合格的临床中心进行。