Development of immunoconjugate therapy for breast and prostate cancer

项目2的目标是继续转化研究，以开发具有乳腺癌和前列腺癌患者治愈意图的联合模式放射免疫治疗（CMIIIT）。在晚期乳腺癌或前列腺癌患者中进行的单药131 I-ChL 6、90 Y-DOTA-肽-ChL 6或90 Y21 T-BAD-mI 70的试验，在没有和有外周血干细胞支持的情况下，为大多数患者的治疗反应提供了证据，尽管是短暂的。当通过免疫组织病理学和核成像判断时，M170与几乎所有的乳腺癌和前列腺癌强烈反应。基于过去的工作，建议在乳腺癌和前列腺癌中进行试验：用途：1）90 Y-DOTA-肽-m170，因为其治疗指数是相应13 II标记抗体的约10倍; 2）高剂量、分级RIT与外周血干细胞支持，以递送更大和更均匀的肿瘤辐射;和3）紫杉醇（Taxol）作为协同放射增敏剂以克服乳腺癌和前列腺癌中常见的p53和BCL 2治疗抗性。患者特异性剂量测定将指导放射性核素给药。在具有与人乳腺癌相当的分子畸变的裸鼠异种移植模型中，当以最佳时间和顺序施用时，在患者中临床上可达到的剂量的90 Y-DOTA-肽缀合的抗体和紫杉醇提供治疗协同作用而不增加毒性。当在项目3中使用肽库生成的较新的肽连接免疫缀合物在临床前研究中显示出前景时，将制定一项方案，以在下一次竞争性提交中开始对这些放射性药物进行临床试验。类似地，将进行整合素结合肽的临床前试验以发现与已经提出的那些协同的另外的药剂。整合素结合肽诱导新生血管凋亡，这可能导致早期血管渗漏和肿瘤摄取增加。后期血管塌陷可能增加90 Y-DOTA-肽-m170的保留。 因此，肿瘤辐射将增加，并且存在肿瘤血管阻断的潜力。该项目的优势包括一支有凝聚力的团队，在此类翻译调查中拥有良好的记录。在项目1、2和核心C中的临床前研究中开发的策略以及项目3中的新型肽化学开发将为CMRIT提供进一步的进展。该项目的信息与该项目的其余部分以及使用CMRIT治疗癌症的其他团体有关。

The goal of Project 2 is to continue translational research to develop combined modality radioimmunotherapy (CMIIIT) with curative intent for patients with breast and prostate cancer. Trials of single agent 131I-ChL6, 90Y- DOTA-peptide-ChL6 or 90Y21T-BAD-mI70 without and with peripheral blood stem cell support in patients with advanced breast or prostate cancer have provided evidence for therapeutic response, albeit brief, in the majority of patients. M170 reacts intensely with almost all breast and prostate adenocarcinomas when judged by immunohistopathology and nuclear imaging. Based on past work, proposed trials in breast and prostate cancer use: 1) 90Y-DOTA-peptide-m170 because its therapeutic index is about IO times that of the corresponding 13II~ labeled antibody; 2) high dose, fractionated RIT with peripheral blood stem cell support to deliver greater and more uniform tumor radiation; and 3) paclitaxel (Taxol) as a synergistic radiosensitizer to overcome p53 and BCL2 therapy resistance common in breast and prostate cancer. Patient-specific dosimetry will direct radionuclide dosing. In a nude mouse xenograft model with molecular aberrations comparable to those of human breast cancer, 90Y-DOTA-peptide conjugated antibody and Taxol, in doses clinically achievable in patients, provided therapeutic synergy without increased toxicity, when administered at the optimal time and sequence. When newer peptide-linked immunoconjugates to be generated in Project 3, using a peptide library, are shown promising in preclinical studies, a protocol will be developed to conduct clinical trials of these radiopharmaceuticals beginning in the next competitive submission. Similarly, preclinical trials of integrin binding peptides will be conducted to find additional agents synergistic with those already proposed. Integrin binding peptides induce neovascular apoptosis that may cause early vascular leak with increased tumor uptake. Later vascular collapse may increase retention of 90Y-DOTA-peptide-m170. Thereby, tumor radiation will be increased and there is potential for tumor vascular blockade. Strengths of this project include a cohesive team with a proven record in translational investigations of this type. Strategies developed in preclinical studies in Projects 1, 2, and Core C and novel peptide chemistry developments in Project 3 will provide further advances in CMRIT. Information from this project is relevant to the remainder of the Program Project and to other groups using CMRIT for cancer.