DEVELOPMENT OF IMMUNOCONJUGATE THERAPY FOR BREAST CANCER

这个项目的目标是开发有效的乳房治疗方法。 生物活性放射免疫结合物联合化疗治疗癌症 其他策略。大约一半的乳腺癌患者死于 尽管检测和标准治疗有所改进，但这种疾病仍然存在。乳腺癌 为固体放射免疫治疗的应用提供了一个极好的模型 肿瘤，因为它对辐射相对敏感，经常发生在 便于通过考试进行准确评估的肤浅位置， 成像和活组织检查。在上一次赠款期间，可测量的肿瘤 在乳腺癌患者中观察到超过50%的反应 用131I-嵌合体L6(ChL6)治疗。尽管这些结果是 晚期乳腺癌患者的I期治疗试验引人注目 使用单一药物治疗癌症，需要进一步加强治疗 用于放射免疫治疗，以获得持久和完全的反应。一个 研究了一些改善治疗指数的策略： 各种放射性核素和抗体，共轭放射化学， 放射和细胞因子以增加对肿瘤的输送， 免疫吸收以减少对n个正常组织、克隆的辐射 降低骨髓毒性和自体外周血细胞毒性的刺激因子 血液干细胞以增加骨髓储备。在下一次拨款期间 我们选择关注两个具有生物活性的嵌合体 抗体，Chl6和H170，因为它们的生物学和免疫学 特征与我们宣布的目标最相关。当 目前131I-ChL6疗法的试验已经完成，未来的治疗试验 与ChL6或H170将结合90Y和新的大环络合物 在项目4中开发，因为这些放射性标记抗体构建 显著提高治疗指数，因为90Y保留在 与肝、骨和其他组织中最低90岁相关的癌组织 正常组织。骨髓自体外周造血干细胞移植 重组和环孢素A抑制免疫原性反应将 用于延长MTD并增加DO的数量 给你的。使用的方法包括1)定量成像 药物动力学和剂量学；2)经典MTD方案设计；3) 体内生物激活的体外血清学和细胞学检测 效应器机构。该项目的优势包括凝聚力 致力于乳腺癌治疗的调查小组和 在放射免疫治疗方面的记录。这个项目受益于 项目4中的研究，其中新的构造和放射化学 生成并来自项目1，允许比较机会 放射化学的变化和增强递送的机制 淋巴瘤与乳腺在生物学和放射生物学上的差异 癌症。

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.