A comprehensive platform for low-cost screening and image-guided photodynamic therapy (PDT) of pre-malignant and malignant oral lesions in low resource settings

受到印度口腔癌症严峻形势的鼓舞，以及我们在UH2/UH3项目上的成功 癌症前期和早期的诊疗机制--一种新的“屏、影、治”一体化 在目前的应用中提出了光学系统(SITOS)，它结合了美国3个站点在 与2个印度临床团队合作。所有网站都是前两届NCI大奖的参赛者 UH2/UH3项目侧重于检测或治疗。治疗继续采用光动力疗法。 (PDT)，一种基于光化学的FDA批准的模式，而检测是基于荧光和白色 光成像与基于云的深度学习AI相结合的图像分类方法。西托斯夫妇 启用图像引导的PDT，同时局部应用双重性质的荧光团/光敏剂前体 到口腔，更适合LMICs，与以前的局部药物相比，旨在实现更好的肿瘤渗透性 送货，也得到了发展。这些目标将通过三个具体目标来实现。AIM 1建立在以前版本的基础上 分别用于口腔内成像和口腔内成像的低成本设备的成功开发和临床验证 PDT生产了一种新的、手持、低成本、易用的SITOS。集成平台使用户能够使用 用于初始成像的相同硬件，以及用于图像引导的PDT和在线监测的单个热敏分子 在治疗期间。是一种符合人体工程学的口腔内光传递PDT，并在光学上进行了初步验证 体模和体外三维肿瘤模型。Aim 2A为局部光敏化创造了条件 PHOTONAMIC GMBH提供的粘附性ALA贴片在体外猪粘膜模型中的应用。基于来自2A的数据， 目的2B在小鼠异种移植模型中建立最佳的PDT参数。目标2C验证了其中最好的 致癌物诱导的仓鼠颊囊模型的参数重述了从致癌前到致癌前的转变 恶性到恶性的病变。目的3应用SITOS来识别和治疗高危口腔潜在恶性 使用来自临床前研究的广泛指导，对口腔病变(OPML)和早期口腔癌进行研究。筛选 病人将在印度由临床团队领导的营地和偏远村庄进行，就像在UH的努力中一样。病人 经组织学证实的HGD/OPML(并符合其他纳入标准)将符合条件。病人将会是 使用ALA局部贴片治疗(在一小群人确定安全和最佳接触时间后，基于 目标2)。最后，利用光传递和同步成像对高危OPML和早期癌症患者的PDT 将使用新的口腔内探头进行指导。 影响和相关性：该研究首次提供了一种全面的低成本方法，使 不仅检测口腔癌前病变/恶性病变，而且也是一种有效的、受监测的LMIC治疗方法 设置。SITOS平台是移动的、手持的，适合于护理点应用。它汇聚了 协作者(科学家、口腔癌外科医生、肿瘤学家和产业界)帮助FDA清除ALA 帕奇和西托斯。能力建设：一种新的临床模式和人工智能/工程发展的平台。

Motivated by the bleak situation of oral cancer in India and encouraged by our successes in the UH2/UH3 mechanism for diagnosing and treating pre- and early cancers, a new integrated “Screen, Image and Treat Optical System” (SITOS) is proposed in the current application which combines the expertise of 3 US sites in collaboration with 2 clinical Indian teams. All sites were participants in the previous NCI awards as 2 individual UH2/UH3 projects focused on either detection or therapy. The treatment continues to be photodynamic therapy (PDT), a photochemistry-based, FDA approved modality while the detection is based on fluorescence and white light imaging combined with a cloud-based deep-learning AI approach for image classification. The SITOS enables image guided PDT, while a topical application of the dual property flourophore/photosensitizer precursor to the oral cavity, more suitable for LMICs and designed to achieve better tumor penetration than previous topical deliveries, is also developed. The goals will be accomplished in 3 Specific Aims. Aim 1 builds on previous successful development and clinical validation of separate low-cost devices for intraoral imaging, and intraoral PDT to produce a new, handheld, low-cost, easy-to-use, SITOS. The integrated platform enables the use of the same hardware for initial imaging, and a single thernostic molecule for image-guided PDT and online monitoring during therapy. Incorporated is an ergonomic intraoral light delivery for PDT and preliminarily validated in optical phantoms and in vitro 3D tumor models. Aim 2A establishes conditions for topical photosensitization using an adhesive ALA patch provided by Photonamic GmbH in ex vivo porcine mucosa model. Based on data from 2A, Aim 2B establishes optimal PDT parameters in a murine xenograft model. Aim 2C validates the best of these parameters in a carcinogen-induced hamster cheek pouch model which recapitulates transition from pre- malignant to malignant lesions. Aim 3 applies SITOS to identify and treat high-risk oral potentially malignant lesions (OPML), and early-stage oral cancer using broad guidance from the preclinical studies. Screening of patients will take place at camps and remote villages led by the clinical teams in India as in the UH effort. Patients with histologically confirmed HGD/OPML (and meeting other inclusion criteria) will be eligible. Patients will be treated using the ALA topical patch, (after a small cohort establishes safety and optimal contact time, based on Aim 2). Finally, PDT of high-risk OPML and early cancer in patients using light delivery and simultaneous image guidance with the new intraoral probe will be performed. Impact and relevance: The study provides, for the first time, a comprehensive low-cost approach that enables not only detection of pre-malignant/malignant oral lesions, but also an effective, monitored therapy in LMIC settings. The SITOS platform is mobile, handheld and appropriate for point of care applications. It brings together collaborators (scientists, oral cancer surgeons, oncologists and industry) to help with FDA clearance of ALA patch and SITOS. Capacity building: a new clinical modality and a platform for AI/engineering development.