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

外科医生准确显示肿瘤边缘和识别转移的能力对于 任何癌症手术的成功。荧光成像，由于其高灵敏度，低成本，便携， 而实时能力在改善手术结果方面具有巨大的潜力。我们的实验室已经开创了 荧光素标记的肿瘤特异性抗体在胃癌诊断和切除中的应用 结果显著改善的原位小鼠模型。到目前为止，我们使用的荧光团已经 一直在可见光的范围内。近红外(NIR)荧光团有许多优点， 在可见光范围内，与荧光团相比，具有更好的组织渗透深度。此外，我们现在 拥有人源化的肿瘤特异性抗CEA和抗CA19-9抗体，可用于未来的临床试验。 目前的赠款申请建议开发人源化抗CEA和抗CA19-9的潜力 在近红外700-800 nm范围内与适当的荧光团结合的抗体标记原发肿瘤 以及用于荧光腹腔镜分期、荧光引导手术(FGS)和辅助治疗的转移 患者来源的原位异种移植(PDOX)模型中胰腺和结肠癌的光免疫治疗。 这项资助的具体目的是：1)验证近红外荧光团标记的肿瘤特异性人源化抗CEA 和抗CA19-9抗体标记PDOX小鼠胰腺癌模型中的原发肿瘤和转移瘤 结直肠癌，2)人源化抗CEA和抗CA标记近红外荧光团的比较 19-9抗体具有不同的特性，用于给药反应、信号持续时间、光漂白、信号到信号 人胰腺癌和结肠癌PDOX模型的背景比和光毒性，3)发展 术中使用人源化抗CEA和抗CA19-9抗体的光免疫治疗(PIT)，或 其他抗体在AIMS 1和AIMS 2中被证明有效，与IRDye 700DX结合作为辅助治疗 FGS对PDOX裸鼠和NSG人源化小鼠胰腺癌和结直肠癌的治疗作用。 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FGS可以 改变外科肿瘤学的范式，极大地改善顽固性癌症的预后。 授予应用程序功能： 人源化肿瘤特异性单抗 超亮近红外组织穿透性染料 以难治性胰腺癌和结直肠癌为靶点的-PDOX小鼠模型 荧光引导手术 佐剂光免疫疗法

项目成果

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

• DOI: 10.18632/oncotarget.26484
• 发表时间: 2018-12-18
• 期刊: Oncotarget
• 作者: Lwin, Thinzar M;Miyake, Kentaro;Bouvet, Michael
• 通讯作者: Bouvet, Michael

Advantages of patient-derived orthotopic mouse models and genetic reporters for developing fluorescence-guided surgery.

• DOI: 10.1002/jso.25150
• 发表时间: 2018-08
• 期刊: Journal of surgical oncology
• 影响因子: 2.5
• 作者: Lwin TM;Hoffman RM;Bouvet M
• 通讯作者: Bouvet M

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

• DOI: 10.18632/oncotarget.27446
• 发表时间: 2020-01-28
• 期刊: Oncotarget
• 作者: Hollandsworth, Hannah M;Amirfakhri, Siamak;Bouvet, Michael
• 通讯作者: Bouvet, Michael

A review of tumor-specific fluorescence-guided surgery for colorectal cancer.

结直肠癌肿瘤特异性荧光引导手术的综述。

• DOI: 10.1016/j.suronc.2020.11.018
• 发表时间: 2021-03
• 期刊: Surgical oncology
• 作者: Hollandsworth HM;Turner MA;Hoffman RM;Bouvet M
• 通讯作者: Bouvet M

Fluorescent Anti-CEA Nanobody for Rapid Tumor-Targeting and Imaging in Mouse Models of Pancreatic Cancer.

• DOI: 10.3390/biom12050711
• 发表时间: 2022-05-16
• 期刊: BIOMOLECULES
• 影响因子: 5.5
• 作者: Lwin, Thinzar M.;Turner, Michael A.;Nishino, Hiroto;Amirfakhri, Siamak;Hernot, Sophie;Hoffman, Robert M.;Bouvet, Michael
• 通讯作者: Bouvet, Michael