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: 10578829
• 负责人: Cornelia L Trimble
• 金额: $ 18.76万
• 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/10578829
• 关键词: Acute; Address; Aftercare; Anatomy; Automobile Driving; Biopsy; Cancer Etiology; Cell Death; Cells; Cervical; Cervical Intraepithelial Neoplasia; Clinical; Clinical Data; Clinical Trials; Cold Chains; Complement; Data; Development; Disease; Excision; Exploratory/Developmental Grant; Formulation; Funding; Genotype; Goals; Histologic; Human; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Immune; Immune response; Immunophenotyping; Incidence; Indolent; Infection prevention; Inflammation; Inflammatory Response; Infrastructure; Intervention; Intervention Trial; Knowledge; Lesion; Longitudinal Studies; Malaria; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mediating; Microbe; Mucous Membrane; Oncogenic; Outcome; Pap smear; Phenotype; Phytochemical; Predisposition; Preventive vaccine; Resistance; Role; Sampling; Sampling Studies; Scientist; Self Administration; Specimen; Swab; Testing; Tissues; Treatment Efficacy; Treatment outcome; Vagina; Viral; Virus; Work; artesunate; 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 HPV vaccine; 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.

尽管出现了预防性疫苗来预防人类致癌物的感染 papillomaviruses (HPVs), the incidence of cancers caused by HPV remains high, both in the US and 全世界。上皮内 HPV 癌症前体为癌症拦截提供了机会： 它们相对容易接近并且临床上惰性，使得可以进行窗口- 在不影响护理标准的情况下进行机会、概念验证治疗试验。然而， 同时测试治疗性 HPV 疫苗治疗 CIN2/3（HPV 宫颈癌的前兆）的试验， 已经取得了部分成功，他们的重点是产生 HPV 特异性免疫反应。 驱动转化的 HPV 癌基因呈现出合理的抗原靶标，但人们对此知之甚少 组织学回归的机制。我们提出的项目将重点关注病变本身。有一个 人们越来越认识到微生物在肠道和癌症中其他生态位中的作用，以及证据 CIN 背景下的生态失调。目前，我们对功能贡献的理解 肿瘤微生物组对组织治疗敏感性的研究并不完整，部分原因是难以 从人体干预试验中获取纵向数据。我们将分析主题匹配， 治疗前、治疗期间和治疗后收集的临床注释样本 介入临床试验测试用重新调整用途的局部制剂治疗 CIN2/3 青蒿琥酯，一种植物源性化合物，用作急性疟疾一线治疗的一部分。 (NCT02354534) 临床结果具有高度影响力；组织学回归（HR） 19/28 (68%) 的治疗受试者发生了这种情况——是预期自发发生率的两倍多 在同一时间范围内观察到的回归。我们现在将基于这一有希望的临床数据 确定对 ART 反应的基于组织的生物标志物以及治疗抵抗的表型， 旨在开发下一代干预措施来治疗 CIN 和 HPV 相关的 malignancies at other anatomic sites.我们将利用一个独特的现存生物样本库和一个 杰出的专家科学家团队研究肿瘤微环境（TME）的组成部分， 包括肿瘤和免疫细胞、微生物和代谢物，在受试者匹配的样本中 响应者与非响应者。获得的见解将为克服 ART 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 早期 HPV 癌症的治疗选择，现在要么是切除要么是消融，并且需要 顺序访问医疗保健基础设施。一种廉价的、自我管理的、非手术的 无需冷链要求的治疗将具有变革性。