RADIOIMMUNOTHERAPY: CLINICAL STUDIES

放射免疫治疗：临床研究

基本信息

批准号：
7303271
负责人：
JEFFREY Y WONG
金额：
$ 23.05万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7303271
关键词：
90Y Animals Antibodies Antibody Formation Antigen Targeting Area Binding Biodistribution Cancer Patient Capecitabine/Oxaliplatin Carboplatin Carboplatin/Paclitaxel Cell surface Chemotherapy-Oncologic Procedure Clinical Clinical Research Clinical Trials Colorectal Cancer Combined Modality Therapy Data Development Disease Distant Distant Metastasis Dose Drug Kinetics ERBB2 gene Evaluation Excision External Beam Radiation Therapy Extrahepatic Floxuridine Fluorouracil Grant Hematopoietic Hepatic Hepatotoxicity Human Image Infusion procedures Institution Knowledge Label Lesion Metastatic Neoplasm to the Breast Methods Newly Diagnosed Non-Small-Cell Lung Carcinoma Numbers Organ Outcome Paclitaxel/Trastuzumab Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phase I/II Trial Phase II Clinical Trials Population Principal Investigator Property Protein Overexpression Publishing Radiation Radiation enhancer Radiation therapy Radio Radioactive Iodine Radioimmunoconjugate Radioimmunotherapy Radiolabeled Rate Recurrence Refractory Disease Regional Chemotherapy Resectable Residual state Resolution Risk Roche brand of trastuzumab Serological Site Solid Neoplasm Stable Disease Standards of Weights and Measures System Therapeutic Therapy Evaluation Toxic effect Trastuzumab Treatment Protocols Tumor Antibodies Unresectable antiangiogenesis therapy bevacizumab chemotherapy chimeric antibody cytotoxic dehalogenation design dosimetry gemcitabine immunogenic immunogenicity improved malignant breast neoplasm metastatic colorectal next generation outcome forecast partial response pilot trial prognostic radiation effect radiotracer response success tumor uptake

项目摘要

Project 1 Project Leader: Wong, Jeffrey Principal Investigator: RaubltSChek, Andrew DESCRIPTION: Clinical trials with ^Y-chimeric T84.66 anti-CEA demonstrate the feasibility and promise of combining radioimmunotherapy (RIT) with radiation-enhancing chemotherapy. Results indicate that clinically meaningful outcomes are achievable, with the greatest promise expected when RIT is integrated into other established therapies in the setting of small volume and subclinical disease. Results also show that the primary limitation of 90Y-cT84.66 is its immunogenicity, which limits the number of therapy cycles. Further refinements in the antibody and in how RIT is combined with other established therapies are therefore needed. To more effectively integrate RIT into established chemotherapy and radiotherapy regimens, the next generation of Phase I and II trials in Aim will focus on the most promising areas and evaluate strategies which: a) reduce the immunogenicity of the antibody, by utilizing a less immunogenic humanized version of T84.66; b) integrate RIT into established, active chemotherapy and radiation/chemotherapy regimens and therefore optimize the clinical impact of the additional pr^artial Hdro\os¿es> fo\f mrardi\ia^tiro\n t/o\ +tui m\rro\rr\r aQc/h*hieiav\a/abHleI^ wlAiti+hH **Y^V-_T8~Q4^.6R6R;¿aonrtdH c/N) \ttreoaott nr*or\n-fc*lhne¿*mrYo\f\-re&frao/c^t+ortri'vw, somaolll v%o/rltuli mimea disease, where the tumor uptake of radiolabeled antibody is expected to be the highest and the clinical impact the greatest. Clinical trials will evaluate 1) RIT as an additional component of front-line multi-agent chemotherapy in colorectal cancer patients with newly diagnosed metastatic disease; 2) RIT as an added component to hepatic arterial chemotherapy in colorectal cancer patients after disease resection who are at high risk of subclinical, occult regional and distant metastases; and 3) RIT as an additional therapy integrated into an established radiation and chemotherapy regimen for CEA+ locally advanced, surgically un-resectable non-small cell lung cancer, who are at high risk of local and distant recurrence despite conventional therapies. These trials will also provide the unique opportunity to evaluate the effects of the anti-angiogenesis antibody, bevacizumab, on 90Y-T84.66 tumor uptake, to assess tumor targeting and pharmacokinetics of iriln-bevacizumab and to ultimately assess its potential as a candidate antibody for RIT. Trials in Aim 2 will evaluate RIT directed against HER2 in breast cancer. At this institution, trastuzumab, radiolabeled with 111ln, has demonstrated tumor targeting and organ dosimetry comparable to cT84.66, justifying its evaluation in a phase I therapy trial labeled with 90Y. This will be followed by a phase I trial which integrates Y-trastuzumab RIT into an established chemotherapy regimen in patients with metastatic breast cancer. Trastuzumab has properties that make it attractive for RIT due to its anti-tumor effects, radiation/chemotherapy enhancing effects, and minimal immunogenicity.

项目 1 项目负责人：Wong, Jeffrey 首席研究员：RaubltSCHek, Andrew 描述： ^Y-嵌合 T84.66 抗 CEA 的临床试验证明了联合治疗的可行性和前景放射免疫疗法（RIT）与放射增强化疗的结果表明具有临床意义。当 RIT 集成到其他已建立的项目中时，结果是可以实现的，并且有望带来最大的希望结果还表明，在小体积和亚临床疾病的情况下进行治疗的主要局限性。 90Y-cT84.66的免疫原性限制了抗体的进一步改进。因此，需要如何将 RIT 与其他已建立的疗法相结合，以便更有效地整合。 RIT 纳入既定的化疗和放疗方案，Aim 的下一代 I 期和 II 期试验将重点关注最有前途的领域并评估以下策略：a）降低免疫原性抗体，通过利用免疫原性较低的 T84.66 人源化版本 b) 将 RIT 整合到已建立的活性中；化疗和放疗/化疗方案，从而优化额外的临床影响专业 Hdro\os¿ es> fo\f mrardi\ia^tiro\n t/o\ +tui m\rro\rr\r aQc/h*hieiav\a/abHleI^ wlAiti+hH **Y^V-_T8~Q4^.6R6R; ¿ aonrtdH c/N) \ttreoaott nr*or\n-fc*lhne¿ *mrYo\f\-re&frao/c^t+ortri'vw, somaolll v%o/rltuli mimea 疾病，其中肿瘤对放射性标记抗体的摄取预计最高，并且临床影响临床试验将评估 1) RIT 作为一线多药化疗的附加组成部分。新诊断患有转移性疾病的结直肠癌患者；2) RIT 作为肝脏的附加成分；疾病切除后处于亚临床、隐匿性区域和远处转移；3) RIT 作为已建立的放射治疗的补充疗法 CEA+ 局部晚期、手术不可切除的非小细胞肺癌的化疗方案尽管采用常规疗法，这些试验也将提供局部和远处复发的高风险。评估抗血管生成抗体贝伐珠单抗对 90Y-T84.66 肿瘤效果的独特机会摄取，评估 iriln-bevacizumab 的肿瘤靶向性和药代动力学，并最终评估其潜力作为 RIT 的候选抗体，Aim 2 中的试验将评估针对乳腺癌中的 HER2 的 RIT。机构用 111ln 放射性标记的曲妥珠单抗已证明肿瘤靶向和器官剂量测定与 cT84.66 相当，证明其在标有 90Y 的 I 期治疗试验中的评估是合理的。 I 期试验将 Y-曲妥珠单抗 RIT 整合到已确定的化疗方案中，用于治疗患有以下疾病的患者曲妥珠单抗具有抗肿瘤作用，使其对 RIT 具有吸引力，放射/化疗增强效果，且免疫原性最小。