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

尽管出现了预防感染致癌人类的预防性疫苗 由于人乳头瘤病毒(HPV)，由HPV引起的癌症的发病率仍然很高，在美国和 世界范围内。上皮内HPV癌前体为癌症阻断提供了机会： 它们相对容易获得，临床上也不费力，因此有可能进行窗口式 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， 在测试治疗性HPV疫苗治疗HPV宫颈癌前驱疾病CIN2/3的试验中， 已经显示出部分成功，他们的重点一直是产生HPV特异性免疫反应。 驱动转化的HPV癌基因呈现合理的抗原靶向，但对此知之甚少 组织学退变的机制。我们建议的项目将专注于病变本身。有一个 越来越多的人认识到肠道和其他利基环境中的微生物在癌症中的作用，以及 CIN背景下的生物失调。目前，我们对功能贡献的理解是 肿瘤微生物群对组织的治疗敏感性是不完整的，部分原因是难以 从人体干预试验中获得纵向数据。我们将分析与受试者匹配的， 在治疗前、治疗中和治疗后收集的临床注释标本，来自一项新的 改用局部制剂治疗CIN2/3的介入性临床试验 青蒿琥酯，一种从植物中提取的化合物，用于急性疟疾的一线治疗。 (NCT02354534)临床结果影响很大；组织学回归(HR) 发生在接受治疗的受试者中的19/28(68%)--是预期自发性的两倍多 在相同的时间范围内观察到的回归。我们现在将在这一充满希望的临床数据的基础上 确定ART反应的基于组织的生物标志物，以及治疗耐药性的表型， 旨在开发下一代干预措施来治疗CIN和HPV相关 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资源库，以及一个 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，在与受试者匹配的样本中 应答者与非应答者。所获得的见解将为克服ART治疗的策略提供依据 抵抗。最后，这项工作将开始解决无障碍的巨大临床需求 早期HPV癌的治疗选择，现在要么切除，要么消融，需要 循序渐进地获得医疗保健基础设施。一种廉价的，自我管理的，非手术的 没有冷链要求的治疗将是变革性的。

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.