Immunomodulatory effects of topical artesunate on cervical intraepithelial neoplasia 2/3.

局部青蒿琥酯对宫颈上皮内瘤变2/3的免疫调节作用。

• 批准号: 10434298
• 负责人: Cornelia L Trimble
• 金额: $ 22.97万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434298
• 关键词: Acute; Address; Aftercare; Anatomy; Automobile Driving; Biopsy; Cancer Etiology; Cell Death; Cervical; Cervical Intraepithelial Neoplasia; Clinical; Clinical Data; Clinical Trials; Cold Chains; Complement; Data; Disease; Excision; Exploratory/Developmental Grant; Formulation; Funding; Genotype; Goals; Histologic; Human; Human Papilloma Virus Vaccine; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Immune; Immune response; Immunophenotyping; Incidence; Indolent; Infection prevention; Inflammation; Infrastructure; Intercept; Intervention; Intervention Trial; Knowledge; Lesion; Longitudinal Studies; Malaria; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mediating; Microbe; Mucous Membrane; Oncogenic; Outcome; Pap smear; Phenotype; Plants; Predisposition; Preventive vaccine; Resistance; Role; Sampling; Sampling Studies; Scientist; Self Administration; Specimen; Swab; Testing; Therapeutic; Tissues; Treatment Efficacy; Treatment outcome; Tumor-infiltrating immune cells; Vagina; Viral; Virus; Work; artesunate; base; biobank; cervicovaginal; cytokine; dysbiosis; health care availability; human data; human papilloma virus oncogene; immunoregulation; improved; insight; intraepithelial; metabolome; metagenome; microbial; microbiome; microbiome research; microbiota; next generation; novel; novel therapeutics; responders and non-responders; response; response biomarker; standard of care; success; therapeutic evaluation; therapy resistant; treatment response; treatment trial; tumor; tumor microbiome; tumor microenvironment

Despite the advent of prophylactic vaccines to prevent infection with oncogenic human papillomaviruses (HPVs), the incidence of cancers caused by HPV remains high, both in the US and world-wide. Intraepithelial HPV cancer precursors present an opportunity for cancer interception: they are relatively accessible and clinically indolent, making it possible to carry out window-of- opportunity, proof-of-concept treatment trials without compromising standard of care. However, while trials testing therapeutic HPV vaccines to treat CIN2/3, the precursor to HPV cervical cancers, have shown partial success, their focus has been upon generating HPV-specific immune responses. HPV oncogenes driving transformation present rational antigenic targets, yet little is known about mechanisms of histologic regression. The projects we propose will focus on the lesion itself. There is an increasing appreciation of the role of microbes at the gut and other niches in cancer, and evidence of dysbiosis in the context of CIN. Currently, our understanding of the functional contributions of tumor microbiomes to tissue susceptibility to treatment is incomplete, in part owing to difficulty in obtaining longitudinal data from human interventional trials. We will analyze subject-matched, clinically annotated specimens collected before, during, and after treatment, from a novel interventional clinical trial testing treatment of CIN2/3 with a repurposed, topical formulation of artesunate, a plant-derived compound used as part of frontline treatment for acute malaria. (NCT02354534) The clinical outcomes from were highly impactful; histologic regression (HR) occurred in 19/28 (68%) of treated subjects -- more than twice the expected rate of spontaneous regression observed over the same timeframe. We will now build on this promising clinical data to determine tissue-based biomarkers of response to ART, as well as phenotypes of treatment resistance, with the intent of developing next-generation interventions to treat CIN and HPV-related malignancies at other anatomic sites. We will capitalize on a unique extant biorepository, and an outstanding team of expert scientists to study constituents of the tumor microenvironment (TME), including tumor and immune cells, microbes, and metabolites, in subject-matched samples of responders vs non-responders. Insights gained will inform strategies to overcome ART treatment resistance. Finally, this work will begin to address an enormous unmet clinical need for accessible treatment options for incipient HPV cancers, which now are either excisional or ablative, and require sequential access to health care infrastructure. An inexpensive, self-administered, non-surgical treatment without cold chain requirements would be transformative.

尽管预防性疫苗出现以防止感染过性人类 在美国和 全世界。上皮内HPV癌的前体为癌症截断提供了机会： 它们相对易于访问和临床上的懒惰，使得执行 - 机会，概念验证治疗试验而不会损害护理标准。然而， 在试验测试治疗性HPV疫苗以治疗CIN2/3的同时，HPV宫颈癌的前体， 已经表现出部分成功，他们的重点一直放在产生HPV特异性免疫反应上。 HPV癌基因驱动转化目前的抗原靶标，但对 组织学回归的机制。我们提出的项目将重点放在病变本身上。有一个 对微生物在肠道和其他小甲基癌症中的作用的认识增加，并证明 CIN背景下的营养不良。当前，我们对功能贡献的理解 肿瘤微生物组对组织对治疗的敏感性是不完整的，部分原因是 从人类介入试验中获得纵向数据。我们将分析主题匹配， 从新颖的临床注释的标本之前，期间和之后收集的标本 介入性临床试验测试CIN2/3的治疗，并具有重新构图的局部配方 Artesunate，一种植物来源的化合物，用作急性疟疾前线治疗的一部分。 （NCT02354534）来自影响很大的临床结果；组织学回归（HR） 发生在经过治疗的受试者的19/28（68％）中 - 自发性的预期率是两倍以上 回归在同一时间范围内观察到。现在，我们将基于这些有希望的临床数据 确定基于组织的对ART反应的生物标志物，以及治疗耐药性的表型 旨在制定下一代干预措施以治疗CIN和HPV相关 其他解剖部位的恶性肿瘤。我们将利用独特的现存生物座席，一个 杰出的专家科学家团队研究肿瘤微环境（TME）的成分， 包括肿瘤和免疫细胞，微生物和代谢物，在受试者的样本中 响应者与无反应者。获得的见解将为克服艺术治疗的策略提供信息 反抗。最后，这项工作将开始解决巨大的未满足的临床需求 初期HPV癌症的治疗选择，现在是散布或烧蚀的，需要 顺序访问医疗保健基础设施。廉价，自我管理，非手术 没有冷链要求的治疗将是变革的。