A-007: Immune Modulation of HPV - Associated Neoplasia

描述（由申请人提供）：4,4'-二羟基苯甲酮-2,4-二硝基苯腙（A-007）最初是作为免疫缺陷相关癌症生长的免疫调节剂而开发的。在最近的一项研究中，a -007作为外用凝胶用于治疗与人乳头瘤病毒（HPV）相关的肛门生殖器癌。没有局部或全身性毒性反应，反应率为76%，所有宫颈或阴道肿瘤患者都完全消除了HPV感染，或者病毒类型从高危组减少到低危组。免疫组织化学（IHC）和计算机模型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。后者的改变覆盖了局部肿瘤CIN转化。本研究为评价A-007治疗宫颈上皮内瘤变（CIN）与HPV相关提供了支持。文献表明，高达70%的CIN疾病可自行消失。因此，目前的研究已被设计成随机分配CIN I到安慰剂和a -007。安慰剂组将允许在活组织检查后进行任何免疫刺激和与子宫颈操作相关的局部物理刺激。晚期疾病- CIN II/Ill -只能用A-007治疗；由于没有其他药物可以治疗这个阶段的疾病，手术将是下一个治疗选择。接受安慰剂治疗的CIN患者在一个疗程后，如果疾病仍然存在，可以选择接受A-007。这项II期研究的具体目标是局部治疗250例不同阶段的HPV感染CIN，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，并进行标准的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。

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.