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.

项目概要 尽管手术、化疗和靶向治疗取得了进展，但转移性上皮性卵巢的存活率仍然很高。 癌症仍然令人沮丧，部分原因是肿瘤异质性和残留的微观疾病无法检测到 这种恶性肿瘤涉及晚期腹膜癌； 盆腔及其驻留器官的广泛肿瘤分布为了解决这些“看不见的”肿瘤。 推出一系列分子靶向和细胞可激活的成像和治疗剂，与 新开发的微型显微镜，用于体内多重分子成像——细胞分辨率 高光谱荧光显微内窥镜——独特地实现了微观沉积物的可视化 体内深处的肿瘤细胞的多重生物标志物成像功能是出于迫切的需求。 定量监测对治疗抵抗和逃逸显着的癌细胞表型（例如，癌症干 同时，我们还开发了近红外光。 针对癌细胞过度表达的细胞膜分子的光细胞毒性免疫偶联物（PIC）， 包括表皮生长因子受体 (EGFR)，以创建组合的光动力和受体 用于肿瘤靶向、可激活光免疫疗法（taPIT）的拮抗剂治疗剂。 和荧光成分在癌细胞结合后去猝灭（激活），细胞 该策略克服了脱靶光毒性，包括内化和溶酶体抗体蛋白水解。 肠道光毒性，复杂部位（例如肠道）光激活治疗的主要临床障碍 在此，我们以之前的研究为基础，表明 PIC 在卵巢微转移中被激活。 在使用 EGFR 过表达的异种移植小鼠模型中，体内灵敏度为 93%，特异性为 93% 人上皮性卵巢癌细胞，能够准确识别小至30μm的肿瘤，并具有选择性 我们建议进一步开发该平台以破坏播散性腹膜微转移。 解决残留肿瘤沉积物中潜伏的肿瘤异质性和化疗耐药表型， 代表了癌症治疗的一个关键领域，目前的临床成像技术无法解决微观问题。 手术和化疗留下的肿瘤沉积物，患者的治疗选择有限 我们预计这种显微内窥镜引导的 taPIT 的新范例。 将补充目前针对晚期疾病患者和接受治疗的患者的治疗方式 挽救疗法，为个性化医疗开辟新途径。 指导动态靶向 taPIT 适应表型进化，以响应治疗和监测 微观残留病灶的治疗反应。