DEVELOPMENT OF IMMUNOCONJUGATE THERAPY FOR BREAST CANCER

乳腺癌免疫结合疗法的开发

• 批准号: 6295926
• 负责人: SALLY J DENARDO
• 金额: $ 6.49万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 1999-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6295926
• 关键词: athymic mouse; biological response modifiers; blood transfusion; breast neoplasms; chelating agents; clinical trials; colony stimulating factor; combination cancer therapy; cyclosporines; cytokine; hematopoietic stem cells; human subject; human therapy evaluation; hybrid antibody; immunoconjugates; iodine; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy; pharmacokinetics; radiation therapy dosage; radiopharmacology; radiotracer; yttrium

The goal of this project is to develop effective therapy for breast cancer using biologically active radioimmunoconjugates combined with other strategies. About half of patients with breast cancer die of their disease despite improved detection and standard therapy. Breast cancer provides an excellent model for the use of radioimmunotherapy in solid tumors because it is relatively radiosensitive and often occurs in superficial locations that facilitate accurate evaluation by examination, imaging and biopsy. During the last grant period, measurable tumor responses greater than 50% were observed in breast cancer patients that were treated with 131I-Chimeric L6 (ChL6). Although these results are remarkable for a Phase I therapy trial in patients with advanced breast cancer using a single agent, further therapeutic enhancement is needed for radioimmunotherapy to achieve enduring and complete responses. A number of strategies were examined to improve the therapeutic index: various radionuclides and antibodies, conjugation radiochemistries, radiation and cytokines to increase delivery to the tumor, immunoabsorption to decrease radiation to n normal tissues, colony stimulating factors to decrease marrow toxicity and autologous peripheral blood stem cells to increase marrow reserve. During the next grant period we have chosen to focus on two biologically active chimeric antibodies, Chl6 and H170, because their biologic and immunologic characteristics are most relevant to our stated objectives. When the current trial of 131I ChL6 therapy is completed, future trials of therapy with ChL6 or H170 will incorporate 90Y and novel macrocyclic chelates developed in Project 4 because these radiolabeled antibody constructs dramatically improve the therapeutic index due to retention of 90Y in cancer tissue in association with minimum 90Y in liver, bone and other normal tissues. Autologous peripheral blood stem cells for marrow reconstitution and Cyclosporin A repression of immunogenic response will be used to extend the MTD and increase the number of does that can be given. Methods to be used include 1) quantitative imaging for pharmacokinetics and dosimetry; 2) classic MTD protocol design; and 3) in vitro serologic and cellular assays of in vivo biologic activation of effector mechanisms. Strengths of this project include a cohesive investigative team that has a commitment to breast cancer therapy and a track record in radioimmunotherapy. This project benefits from the studies in Project 4 where new constructs and radiochemistry are generated and from Project 1 which allows opportunities to compare variations of radiochemistry and mechanisms for enhanced delivery as well as differences in the biology and radiobiology of lymphoma and breast cancer.

该项目的目的是为乳房开发有效的疗法 使用生物活性放射免疫共轭物结合的癌症 其他策略。 大约一半的乳腺癌患者死于 尽管检测和标准疗法得到改善，疾病。 乳腺癌 为在固体中使用放射免疫疗法提供了出色的模型 肿瘤是因为它相对放射敏感，并且经常发生 表面促进通过检查促进准确评估的位置， 成像和活检。 在最后一个赠款期间，可测量的肿瘤 在乳腺癌患者中观察到大于50％的反应 用131-Chimeric L6（CHL6）处理。 尽管这些结果是 对于晚期乳房患者的I期治疗试验而引人注目 使用单个药物的癌症，需要进一步的治疗性增强 用于放射免疫疗法以实现持久和完整的反应。 一个 检查了改善治疗指数的策略数量： 各种放射性核素和抗体，偶联放射化学， 辐射和细胞因子增加向肿瘤的递送， 免疫吸收以降低对N正常组织的辐射，菌落 刺激因素降低骨髓毒性和自体周围 血干细胞增加骨髓储备。 在下一个赠款期间 我们选择专注于两个生物活性嵌合 抗体CHL6和H170，因为它们的生物学和免疫学 特征与我们既定的目标最相关。 什么时候 当前的131i CHL6治疗试验已完成，未来的治疗试验 使用CHL6或H170将结合90年和新型的大环螯合物 在项目4中开发，因为这些放射标记的抗体构建体 由于保留90年的保留，大大改善了治疗指数 癌症组织与肝，骨和其他中至少90岁相关 正常组织。 自体外周血干细胞骨髓 重构和环孢菌素对免疫反应的抑制作用将 用于扩展MTD并增加可以是 给出。 要使用的方法包括1）定量成像 药代动力学和剂量法； 2）经典MTD协议设计； 3） 体内体内生物学生物学激活的体外血清学和细胞测定 效应器机制。 该项目的优势包括一个凝聚力 对乳腺癌疗法有承诺的调查团队 放射免疫疗法的记录。 该项目受益于 在项目4中的研究，新的结构和放射化学是 生成和从项目1产生的，该项目允许机会比较 放射化学和机制的变化也可以增强交付 作为淋巴瘤和乳房生物学和放射生物学的差异 癌症。