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

基本信息

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
项目类别：
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

项目摘要

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

外科医生准确可视化肿瘤边缘并识别转移的能力是任何癌症操作的成功。荧光成像，由于其高灵敏度，低成本，便携性，实时功能具有改善手术结果的巨大潜力。我们的实验室开创了使用荧光团结合的肿瘤特异性抗体检测和切除GI癌症原位小鼠模型具有高度改善的结果。那远，我们使用的荧光团已经我们处于可见光范围。近红外（NIR）荧光团有许多优势与可见范围内的荧光团相比，具有更好的组织深度。此外，我们现在具有人性化肿瘤特异性抗CEA和抗CA 19-9抗体，可用于将来的临床试验。目前的赠款申请提案，以开发使用人源化抗CEA和抗CA 19-9的潜力 NIR 700至800 nm范围内与适当的荧光团结合的抗体以标记原发性肿瘤及其转移用于荧光腹腔镜分期，荧光引导手术（FGS）和调整患者衍生的原位异种移植（PDOX）模型中胰腺癌和结肠癌的摄影疗法。该赠款的具体目的是：1）验证NIR荧光团标记的肿瘤特异性人性化抗CEA 和抗CA的19-9抗体在胰腺和PDOX小鼠模型中标记原发性肿瘤和转移的抗体结直肠癌，2）比较与人源化抗CEA和抗CA结合的近感染荧光团 19-9具有不同特性的抗体，用于给药响应，信号持续时间，光漂白，信号到信号背景比和光毒性，在人胰腺和结肠癌的PDOX模型中，3）发育使用人源化抗CEA和抗CA 19-9抗体的术中摄影疗法（PIT）或其他证明在目标1和2中有效的抗体，与irdye 700dx共轭作为调整处理 PDOX裸体和NSG人类化的小鼠模型中的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FG的临床试验奠定了基础改变手术肿瘤学的范式，并大大改善顽固癌的结局。授予应用程序功能： 人性化肿瘤特异性单克隆抗体 在感染染料附近非常明亮的组织穿透 针对顽固胰腺癌和结直肠癌的PDOX小鼠模型 荧光引导手术 调整摄影疗法

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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
影响因子：
0
作者：
Hollandsworth, Hannah M;Amirfakhri, Siamak;Bouvet, Michael
通讯作者：
Bouvet, Michael

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

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。