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: 10045939
• 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 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10045939
• 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是必要的， 任何癌症手术的成功。荧光成像由于其灵敏度高、成本低、便携性好， 并且实时能力具有改善手术结果的巨大潜力。我们的实验室开创了 荧光团缀合的肿瘤特异性抗体用于检测和切除胃肠道癌的用途， 原位小鼠模型，具有高度改善的结果。到目前为止，我们使用的荧光团有 在可见光的范围内。近红外（NIR）荧光团具有许多优点， 与可见光范围内的荧光团相比，具有更好的组织穿透深度。此外，我们现在 具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。 本授权申请提出开发使用人源化抗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以标记原发性肿瘤的抗体 及其转移，用于荧光腹腔镜分期、荧光引导手术（FGS）和辅助 在患者源性原位异种移植（PDOX）模型中对胰腺癌和结肠癌进行光免疫治疗。 该基金的具体目标是：1）验证近红外荧光团标记的肿瘤特异性人源化抗CEA 和抗CA 19-9抗体来标记胰腺和胰腺癌的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具有不同性质的抗体的剂量反应，信号持续时间，光漂白，信号- 在人胰腺癌和结肠癌的PDOX模型中的背景比率和光毒性，3）开发 使用人源化抗CEA和抗CA 19-9抗体的术中光免疫疗法（PIT），或 在目的1和2中显示有效的其他抗体，与IRDye 700DX缀合作为辅助治疗， FGS用于PDOX裸小鼠和NSG人源化小鼠模型中的胰腺癌和结直肠癌。 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， 改变外科肿瘤学的范式，大大改善复发性癌症的预后。 资助申请特点： 人源化肿瘤特异性单克隆抗体 超亮组织穿透近红外染料 靶向胰腺癌和结直肠癌的PDOX小鼠模型 荧光引导手术 辅助光免疫疗法