Development of immunoconjugate therapy for breast and prostate cancer

项目2的目标是继续进行转化性研究，以开发具有治疗意图的乳腺癌和前列腺癌患者的联合放射免疫疗法(CMIIIT)。单剂131I-ChL6、90Y-DOTA-多肽-ChL6或90Y21T-BAD-MI70在没有和有外周血干细胞支持的晚期乳腺癌或前列腺癌患者中的试验已经为大多数患者的治疗反应提供了证据，尽管时间很短。根据免疫组织病理学和核成像判断，M170对几乎所有的乳腺癌和前列腺癌都有强烈的反应。根据过去的工作，拟议的乳腺癌和前列腺癌试验使用：1)90Y-DOTA-多肽-m170，因为其治疗指数约为相应的13II~标记抗体的IO倍；2)高剂量，分次RIT和外周血干细胞支持，以提供更大和更均匀的肿瘤辐射；以及3)紫杉醇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BCL2耐药。患者特定的剂量测定将指导放射性核素的剂量。在分子畸变率与人类乳腺癌相似的裸鼠异种移植模型中，90Y-DOTA-肽结合抗体和紫杉醇在患者临床上可获得的剂量，当在最佳时间和顺序给药时，在不增加毒性的情况下提供治疗协同作用。当项目3中使用多肽库产生的较新的多肽连接免疫结合物在临床前研究中显示出前景时，将开发一种方案，从下一次竞争性提交开始对这些放射性药物进行临床试验。同样，将进行整合素结合肽的临床前试验，以寻找与已提出的药物具有协同作用的其他药物。整合素结合肽诱导新生血管凋亡，这可能导致肿瘤摄取增加而导致早期血管渗漏。以后的血管塌陷可能会增加90Y-DOTA-多肽-m170的保留率。因此，肿瘤的辐射将会增加，并有可能发生肿瘤血管阻塞。这个项目的优势包括一个有凝聚力的团队，在这类翻译调查中有公认的记录。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中的新肽化学开发将为CMRIT提供进一步的进展。来自该项目的信息与该计划项目的其余部分以及使用CMRIT治疗癌症的其他组相关。

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.