Development of Near Infrared Fluorescence-Guided Surgical Navigation and Tumor Specific Photoimmunotherapy for Improved Outcomes for GI Cancers

开发近红外荧光引导手术导航和肿瘤特异性光免疫疗法以改善胃肠道癌症的治疗效果

• 批准号: 10515777
• 负责人: Michael Bouvet
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515777
• 关键词: Achievement; Adjuvant; Anti-CEA Antibody; Antibodies; Applications Grants; Cancer Etiology; Cessation of life; Clinical; Clinical Trials; Colon Carcinoma; Colorectal Cancer; Deposition; Detection; Development; Disease; Dose; Dyes; Excision; Exposure to; Fluorescence; Fluorescent Antibody Technique; Future; Gastrointestinal Neoplasms; Goals; Grant; Hematoxylin and Eosin Staining Method; Heterogeneity; Human; Image; Immunohistochemistry; Individual; Label; Laboratories; Light; Liver; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Methods; Monoclonal Antibodies; Mus; Neoplasm Metastasis; Nude Mice; Operative Surgical Procedures; Outcome; Patient-Focused Outcomes; Patients; Penetration; Photobleaching; Photosensitizing Agents; Phototoxicity; Primary Neoplasm; Principal Investigator; Property; Recurrence; Regimen; Research; Research Personnel; Signal Transduction; Specificity; Staging; Stains; Surgeon; Surgical Oncology; Testing; Time; Tissues; Tumor Antigens; Tumor Burden; Tumor stage; Validation; Visualization; Xenograft Model; Xenograft procedure; absorption; antibody conjugate; antibody detection; base; cancer type; clinically translatable; cost; cytotoxic; experimental study; fluorescence imaging; fluorescence-guided surgery; fluorophore; human model; humanized antibody; humanized monoclonal antibodies; humanized mouse; improved; improved outcome; in vivo; irradiation; lead candidate; military veteran; mouse model; near infrared dye; novel; operation; pancreatic cancer model; photoimmunotherapy; phthalocyanine; portability; response; success; surgery outcome; tumor

The ability of the surgeon to accurately visualize tumor margins and identify metastases is necessary for the success of any cancer operation. Fluorescence imaging, because of its high sensitivity, low cost, portability, and real-time capabilities has great potential to improve surgical outcomes. Our laboratories have pioneered the use of fluorophore-conjugated tumor-specific antibodies for detection and resection of GI cancers in orthotopic mouse models with highly improved outcomes. Thus far, the fluorophores that we have utilized have been in the visible range of light. There are numerous advantages to near infrared (NIR) fluorophores which have better tissue depth of penetration compared to fluorophores in the visible range. Furthermore, we now have humanized tumor-specific anti-CEA and anti-CA 19-9 antibodies that can be used for future clinical trials. The present grant application proposes to develop the potential of using humanized anti-CEA and anti-CA 19-9 antibodies conjugated with appropriate fluorophores in the NIR 700 to 800 nm range to label primary tumors and their metastases for fluorescence laparoscopic staging, fluorescence-guided surgery (FGS), and adjuvant photoimmunotherapy of pancreatic and colon cancer in patient-derived orthotopic xenograft (PDOX) models. The specific aims of this grant are: 1) Validation of NIR fluorophore-labeled tumor-specific humanized anti-CEA and anti-CA 19-9 antibodies to label primary tumors and metastases in PDOX mouse models of pancreatic and colorectal cancer, 2) Comparison of near infrared fluorophores conjugated to humanized anti-CEA and anti-CA 19-9 antibodies with different properties for dosing response, signal duration, photobleaching, signal-to- background ratio, and phototoxicity, in PDOX models of human pancreatic and colon cancer, 3) Development of intraoperative photoimmunotherapy (PIT) using the humanized anti-CEA and anti-CA 19-9 antibodies, or other antibodies shown to be effective in Aims 1 and 2, conjugated to IRDye 700DX as adjuvant treatment to FGS for pancreatic and colorectal cancer in PDOX nude and NSG-humanized mouse models. The completion of these aims will set the stage for clinical trials of fluorescent-antibody-based FGS that can change the paradigm of surgical oncology and greatly improve outcomes of recalcitrant cancers. Grant application features:  Humanized tumor specific monoclonal antibodies  Very bright tissue penetration near infrared dyes  PDOX mouse models targeting recalcitrant pancreatic and colorectal cancer  Fluorescence guided surgery  Adjuvant photoimmunotherapy

外科医生准确地观察肿瘤边缘和识别转移的能力对于进行手术是必要的。 任何癌症手术的成功，因为其高灵敏度、低成本、便携性， 我们的实验室在改善手术效果方面具有巨大的潜力。 使用荧光团偶联的肿瘤特异性抗体检测和切除胃肠道癌症 迄今为止，我们使用的荧光团具有显着改善的结果。 近红外 (NIR) 荧光团在可见光范围内具有许多优点。 与可见光范围内的荧光团相比，具有更好的组织穿透深度。 拥有人源化肿瘤特异性抗CEA和抗CA 19-9抗体，可用于未来的临床试验。 目前的拨款申请建议开发使用人源化抗 CEA 和抗 CA 19-9 的潜力 与 NIR 700 至 800 nm 范围内的适当荧光团缀合的抗体，用于标记原发性肿瘤 及其转移进行荧光腹腔镜分期、荧光引导手术 (FGS) 和辅助治疗 在患者来源的原位异种移植（PDOX）模型中对胰腺癌和结肠癌进行光免疫疗法。 该资助的具体目的是： 1) 近红外荧光团标记的肿瘤特异性人源化抗 CEA 的验证 和抗 CA 19-9 抗体，用于标记胰腺和胰腺癌 PDOX 小鼠模型中的原发性肿瘤和转移瘤 结直肠癌，2) 与人源化抗 CEA 和抗 CA 缀合的近红外荧光团的比较 19-9 抗体具有不同的给药响应、信号持续时间、光漂白、信号转-特性 人类胰腺癌和结肠癌 PDOX 模型中的背景比和光毒性，3) 开发 使用人源化抗 CEA 和抗 CA 19-9 抗体进行术中光免疫治疗 (PIT)，或 其他被证明对目标 1 和 2 有效的抗体，与 IRDye 700DX 缀合作为辅助治疗 PDOX 裸鼠和 NSG 人源化小鼠模型中胰腺癌和结直肠癌的 FGS。 这些目标的完成将为基于荧光抗体的 FGS 的临床试验奠定基础，该试验可以 改变肿瘤外科的范式并大大改善顽固性癌症的治疗结果。 补助金申请特点：  人源化肿瘤特异性单克隆抗体  近红外染料的组织穿透力非常明亮  针对难治性胰腺癌和结直肠癌的 PDOX 小鼠模型 荧光引导手术  辅助光免疫治疗

项目成果

A Novel Color-Coded Liver Metastasis Mouse Model to Distinguish Tumor and Adjacent Liver Segment.

一种新型颜色编码肝转移小鼠模型，用于区分肿瘤和邻近肝段。

• DOI: 10.1016/j.jss.2021.02.022
• 发表时间: 2021-04-10
• 期刊: The Journal of surgical research
• 作者: H. Nishino;Hannah M. Holl;sworth;sworth;Siamak Amirfakhri;Y. Tashiro;Jun Yamamoto;Michael A. Turner;Thinzar M. Lwin;B. Singer;R. Hoffman;M. Bouvet
• 通讯作者: M. Bouvet

Fluorescence-guided Surgery with Splenic Preservation Prevents Tumor Recurrence in an Orthotopic Nude-mouse Model of Human Pancreatic Cancer.

保留脾脏的荧光引导手术可防止人胰腺癌原位裸鼠模型中的肿瘤复发。

• DOI: 10.21873/anticanres.12270
• 发表时间: 2018-02-01
• 期刊: Anticancer research
• 影响因子: 2
• 作者: H. Hwang;C. Kang;Sung Hwan Lee;T. Murakami;Tasuku Kiyuna;S. H. Kim;R. Hoffman;M. Bouvet
• 通讯作者: M. Bouvet

Fluorescent humanized anti-CEA antibody specifically labels metastatic pancreatic cancer in a patient-derived orthotopic xenograft (PDOX) mouse model.

荧光人源化抗 CEA 抗体特异性标记患者来源的原位异种移植 (PDOX) 小鼠模型中的转移性胰腺癌。

• 发表时间: 2018-12-18
• 作者: Lwin, Thinzar M;Miyake, Kentaro;Murakami, Takashi;DeLong, Jonathan C;Amirfakhri, Siamak;Filemoni, Filemoni;Yoon, Sang Nam;Yazaki, Paul J;Shivley, John E;Datnow, Brian;Clary, Bryan M;Hoffman, Robert M;Bouvet, Michael
• 通讯作者: Bouvet, Michael

ASO Author Reflections: Fluorescent Anti-CEA IR800 for Tumor Labeling.

ASO 作者感言：用于肿瘤标记的荧光抗 CEA IR800。

• 发表时间: 2018
• 影响因子: 3.7
• 作者: Lwin, Thinzar M;Bouvet, Michael
• 通讯作者: Bouvet, Michael

Anti-carcinoembryonic antigen-related cell adhesion molecule antibody for fluorescence visualization of primary colon cancer and metastases in patient-derived orthotopic xenograft mouse models.

抗癌胚抗原相关细胞粘附分子抗体，用于患者来源的原位异种移植小鼠模型中原发性结肠癌和转移瘤的荧光可视化。

• 发表时间: 2020-01-28
• 作者: Hollandsworth, Hannah M;Amirfakhri, Siamak;Filemoni, Filemoni;Schmitt, Verena;Wennemuth, Gunther;Schmidt, Alexej;Hoffman, Robert M;Singer, Bernhard B;Bouvet, Michael
• 通讯作者: Bouvet, Michael