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.

尽管预防性疫苗的出现，以防止感染致癌的人类， 尽管存在乳头瘤病毒（HPV），但在美国和 世界范围内。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，临床上不痛，使得有可能进行开窗手术， 机会，概念验证治疗试验，而不影响护理标准。然而，在这方面， 虽然试验测试治疗性HPV疫苗来治疗CIN 2/3，HPV宫颈癌的前兆， 已经显示出部分成功，他们的重点是产生HPV特异性免疫应答。 驱动转化的HPV癌基因提出了合理的抗原靶点，但对 组织学退化的机制。我们提出的项目将集中在病变本身。有一个 越来越多的人认识到微生物在肠道和其他癌症壁龛中的作用， 在CIN的背景下，目前，我们了解的功能性贡献， 肿瘤微生物组对组织对治疗的敏感性是不完整的，部分原因是难以确定肿瘤微生物组对治疗的敏感性。 从人类干预试验中获得纵向数据。我们会分析匹配的受试者 在治疗前、治疗期间和治疗后收集的临床注释标本，来自一种新的 介入性临床试验，测试用重新设计的局部制剂治疗CIN 2/3， 青蒿琥酯是一种植物衍生化合物，用作急性疟疾一线治疗的一部分。 （NCT 02354534）临床结局具有高度影响力;组织学消退（HR） 19/28例（68%）接受治疗的受试者发生--超过预期自发发生率的两倍 在同一时间段内观察到的回归。我们现在将建立在这些有希望的临床数据， 确定对ART的反应的基于组织的生物标志物，以及治疗抗性的表型， 目的是开发下一代干预措施，以治疗CIN和HPV相关疾病。 其他解剖部位的恶性肿瘤。我们将利用一个独特的现存生物储存库， 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， 应答者vs无应答者。获得的见解将为克服抗逆转录病毒疗法的战略提供信息 阻力最后，这项工作将开始，以解决巨大的未满足的临床需求， 早期HPV癌症的治疗选择，现在是切除或消融， 按顺序获得卫生保健基础设施。一种便宜的，自我管理的，非手术的 没有冷链要求的治疗将是变革性的。