RADIOIMMUNOTHERAPY: CLINICAL STUDIES

放射免疫治疗：临床研究

• 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
• 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

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-Chimeric T84.66抗CEA的临床试验证明了合并的可行性和希望 带辐射增强化疗的放射免疫疗法（RIT）。结果表明临床上有意义 结果是可以实现的，当将RIT融入其他已建立时，预期的是最大的希望 小体积和亚临床疾病的疗法。结果还表明， 90Y-CT84.66是其免疫原性，它限制了治疗周期的数量。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结合使用。更有效地整合 将其纳入既定的化学疗法和放疗方案，这是AIM的下一代I和II期试验 将重点关注最有希望的领域，并评估策略：a）降低的免疫原性 抗体，使用T84.66的免疫原性人性化版本； b）将RIT整合到已建立的活跃 化学疗法和放射/化学疗法方案，因此优化了其他 pr^artial hdro \ os> fo \ f mrardi \ ia^tiro \ n t/o \ + +tui m \ rro \ rro \ rr \ rr \ r aqc/h*hieiav \ a/abhlei^wlaiti^wlaiti +hh ** nr*或\ n-fc*lhne¿ 疾病，预计放射性标记抗体的肿瘤摄取最高，临床影响是 最伟大。临床试验将评估1）RIT作为前线多试剂化学疗法的附加组成部分 结直肠癌患者有新诊断的转移性疾病； 2）RIT作为肝的附加组件 疾病切除后结直肠癌患者的动脉化疗，患有亚临床，高风险 神秘的区域和遥远转移； 3）将RIT作为一种额外的疗法集成到已建立的辐射中 和CEA+局部先进的，外科手术不可切除的非小细胞肺癌的化学疗法，谁 处于局部和遥远的重复目的地常规疗法的高风险。这些试验还将提供 评估抗血管生成抗体贝伐单抗对90y-T84.66肿瘤的影响的独特机会 摄取，评估iriln-Bevacizumab的肿瘤靶向和药代动力学，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HER2乳腺癌的RIT。在这个 用111LN标记的放射性标记的曲妥珠单抗具有肿瘤靶向和器官剂量测定法 与CT84.66相当，证明其在标记为90年的I期治疗试验中的评估是合理的。接下来是 第一阶段试验将Y-贸易珠单抗RIT整合到已建立的化学疗法方案中 转移性乳腺癌。曲妥珠单抗具有抗肿瘤作用，使其对RIT具有吸引力， 辐射/化学疗法增强作用和最小的免疫原性。