Multiplexed and dynamically targeted photoimmunotherapy of heterogeneous, chemoresistant micrometastases guided by online in vivo optical imaging of cell-surface biomarkers

由细胞表面生物标志物在线体内光学成像引导的异质性、耐药性微转移的多重动态靶向光免疫疗法

• 批准号: 10358581
• 负责人: Bryan Quilty Spring
• 金额: $ 62.06万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10358581
• 关键词: Acute; Address; Antibodies; Binding; Biological Markers; Biological Models; Calibration; Cancer Patient; Cancer cell line; Carcinomatosis; Cell Death; Cell membrane; Cell surface; Cells; Chemoresistance; Chemosensitization; Clinical; Complement; Complex; Culture Techniques; Deposition; Development; Disease; Disease Resistance; Drug Kinetics; Drug resistance; Epidermal Growth Factor Receptor; Epithelial ovarian cancer; Evolution; Feedback; Fluorescence; Genetically Engineered Mouse; Genotype; Goals; Greater sac of peritoneum; Heterogeneity; Human; Image; Image Enhancement; Imaging technology; Immunocompetent; Immunoconjugates; In Vitro; Informatics; Intestines; Lead; Left; Malignant Neoplasms; Measures; Membrane; Methods; Micrometastasis; Microscope; Microscopic; Modality; Modeling; Molecular Target; Monitor; Mus; Operative Surgical Procedures; Optical Biopsy; Organ; Ovarian; Patients; Pelvic cavity structure; Peritoneal; Pharmaceutical Preparations; Phenotype; Phototoxicity; Polymerase Chain Reaction; Population; Preservation Technique; Proteolysis; Protocols documentation; Receptor Protein-Tyrosine Kinases; Recurrence; Regimen; Residual Cancers; Residual Tumors; Residual state; Resistance; Resolution; Reverse Transcription; Salvage Therapy; Series; Site; Source; Specificity; Testing; Therapeutic Agents; Therapeutic Index; Time; Translating; Tumor Burden; Visualization; Work; Xenograft procedure; antagonist; arm; base; bioimaging; cancer cell; cancer recurrence; cancer stem cell; cancer therapy; chemotherapy; clinical imaging; image guided; image guided therapy; imaging agent; imaging biomarker; imaging modality; imaging platform; improved; in vivo; in vivo Model; in vivo imaging; in vivo optical imaging; microendoscope; microendoscopy; microscopic imaging; miniaturize; minimally invasive; molecular imaging; mortality; mouse model; neoplastic cell; novel; novel strategies; novel therapeutics; optical imaging; overexpression; patient derived xenograft model; personalized cancer therapy; personalized medicine; photoimmunotherapy; receptor; response; standard care; targeted treatment; therapy resistant; three dimensional cell culture; three-dimensional modeling; tomography; treatment optimization; treatment response; tumor; tumor heterogeneity; uptake

PROJECT SUMMARY Despite advances in surgery, chemotherapy and targeted therapies, survival of metastatic epithelial ovarian cancer remains dismal due in part to tumor heterogeneity and residual microscopic disease undetectable by traditional imaging modalities. This malignancy involves peritoneal carcinomatosis at advanced stages; that is, extensive tumor studding of the pelvic cavity and its resident organs. To address these “invisible” tumors, we introduce a series of molecular-targeted and cell-activatable imaging and therapeutic agents integrated with a newly developed miniaturized microscope for multiplexed molecular imaging in vivo—a cellular-resolution hyperspectral fluorescence microendoscope—that uniquely enable visualization of microscopic deposits of tumor cells deep inside the body. The multiplexed biomarker imaging feature is motivated by the critical need to quantitatively monitor cancer cell phenotypes salient to treatment resistance and escape (e.g., cancer stem cells are defined by multiple cell-surface biomarkers). In parallel, we have also developed near-infrared photocytotoxic immunoconjugates (PICs) that target cell membrane molecules overexpressed by cancer cells, including the epidermal growth factor receptor (EGFR), to create a combined photodynamic and receptor antagonist therapeutic agent for tumor-targeted, activatable photoimmunotherapy (taPIT). The photodynamic and fluorescence components become de-quenched (activated) upon cancer cell binding, cellular internalization and lysosomal antibody proteolysis. This strategy overcomes off-target phototoxicity, including bowel phototoxicity, the major clinical obstacle for photoactivated treatments in complex sites such as the pelvic cavity. Here, we build on our prior work that shows the PIC is activated within ovarian micrometastases with 93% sensitivity and 93% specificity in vivo, in a xenograft mouse model using EGFR overexpressing human epithelial ovarian cancer cells, enabling accurate recognition of tumors as small as 30 μm and selective destruction of disseminated peritoneal micrometastases. We propose to further develop this platform to address tumor heterogeneity and chemoresistant phenotypes lurking within residual tumor deposits, which represents a critical niche in cancer therapy. Current clinical imaging technologies cannot resolve microscopic tumor deposits left behind by surgery and chemotherapy, and there are limited treatment options for patients with recurrent, chemoresistant tumors. We anticipate that this new paradigm for microendoscopy-guided taPIT will complement current treatment modalities for patients with advanced-stage disease and those receiving salvage therapies, opening new avenues for personalized medicine. The new capabilities will be applied to guide dynamically targeted taPIT adaptive to phenotype evolution in response to therapy and for monitoring treatment response of microscopic residual disease.

项目摘要 尽管手术，化学疗法和靶向疗法取得了进步，但转移性上皮卵巢的存活 癌症仍然令人沮丧，部分原因是肿瘤异质性和残留微观疾病无法检测到 传统的成像方式。这种恶性肿瘤涉及晚期腹膜癌变；那是， 骨盆腔及其居民器官的广泛肿瘤牙齿。为了解决这些“无形”肿瘤，我们 引入一系列分子靶向和细胞活化成像和与A的治疗剂 新开发的微型显微镜用于体内多路复用分子成像 - 一个细胞分辨率 高光谱荧光显微镜 - 独特的可视化显微镜沉积物的可视化 肿瘤细胞在体内深处。多路复用生物标志物成像功能是由关键需求激励的 定量监测癌细胞表型显着的治疗耐药性和逃脱（例如，癌症茎 细胞由多个细胞表面生物标志物定义）。同时，我们还发展了近红外 光毒性免疫缀合物（PICS）靶向细胞膜分子，由癌细胞过表达， 包括表皮生长因子受体（EGFR），以创建一个组合的光动力和受体 针对肿瘤的拮抗剂治疗剂，可激活的摄影疗法（磁带）。光动力学 在癌细胞结合，细胞结合后，荧光成分被解冻（激活） 内在化和溶酶体抗体蛋白水解。该策略克服了靶向的光毒性，包括 肠光毒性，这是复杂部位中光活化治疗的主要临床障碍 骨盆腔。在这里，我们以先前的工作为基础，该工作显示图片在卵巢微转移中被激活 在体内具有93％的敏感性和93％的特异性，在异种移植小鼠模型中使用EGFR过表达 人类上皮卵巢癌细胞，可以准确识别30μm的肿瘤和选择性 破坏腹膜腹膜微转移酶的破坏。我们建议进一步开发这个平台 解决潜伏在残留肿瘤沉积物中的肿瘤异质性和化学抗性表型，这些表型 代表癌症治疗中的关键利基市场。当前的临床成像技术无法解析微观 手术和化学疗法留下的肿瘤沉积物，患者的治疗选择有限 复发性化学抗性肿瘤。我们预计微观镜检查引导的这种新范式 将对患有晚期疾病的患者和接受的患者完成当前的治疗方式 打捞疗法，为个性化医学开辟了新的途径。新功能将应用于 在响应治疗和监测时，动态靶向磁带对表型演化的自适应 微观残留疾病的治疗反应。