DEVELOPMENT OF IMMUNOCONJUGATE THERAPY FOR BREAST CANCER

该项目的目标是开发有效的治疗乳腺癌的方法。 使用生物活性放射性免疫缀合物与 其他战略。 大约一半的乳腺癌患者死于 尽管有改进的检测和标准治疗， 乳腺癌 提供了在固体中使用放射免疫疗法的极好模型， 肿瘤，因为它是相对放射敏感，往往发生在 便于通过检查进行准确评估的浅表位置， 成像和活检。 在上一次资助期间，可测量的肿瘤 在乳腺癌患者中观察到大于50%的反应， 用131 I-嵌合L 6（ChL 6）处理。 虽然这些结果 针对晚期乳腺癌患者的I期治疗试验引人注目 使用单一药物治疗癌症，需要进一步的治疗增强 用于放射免疫治疗以实现持久和完全的反应。 一 研究了多种策略以提高治疗指数： 各种放射性核素和抗体，结合放射化学， 放射和细胞因子以增加对肿瘤的递送， 免疫吸收以减少对正常组织、集落 减少骨髓毒性和自体外周血刺激因子 造血干细胞，以增加骨髓储备。 在下一次赠款期间 在此期间，我们选择关注两种生物活性嵌合体， Chl 6和H170抗体，因为它们的生物学和免疫学特性， 这些特征与我们的既定目标最为相关。 当 目前的131 I ChL 6治疗试验已经完成，未来的治疗试验 与ChL 6或H170结合将引入90 Y和新的大环螯合物 因为这些放射性标记的抗体构建体 由于90 Y在体内的滞留， 肝脏、骨骼和其他组织中与最低90 Y相关的癌组织 正常组织 自体外周血造血干细胞 免疫原性应答的重建和环孢菌素A抑制将 可用于延长MTD并增加可以 给出 使用的方法包括1）定量成像， 药代动力学和剂量测定; 2）经典MTD方案设计;以及3） 体内生物激活的体外血清学和细胞测定 效应器机制 该项目的优势包括具有凝聚力 一个致力于乳腺癌治疗的调查小组， 放射免疫治疗的记录 该项目得益于 项目4中的新结构和放射化学研究 从项目1生成，允许比较机会 放射化学的变化以及增强递送的机制 淋巴瘤和乳腺癌在生物学和放射生物学上的差异 癌

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.