Development of immunoconjugate therapy for breast and prostate cancer

乳腺癌和前列腺癌免疫偶联疗法的发展

• 批准号: 6254387
• 负责人: CAROL M. RICHMAN
• 金额: $ 18.05万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-15 至 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6254387
• 关键词: athymic mouse; breast neoplasms; clinical research; clinical trial phase I; combination cancer therapy; human subject; human therapy evaluation; immunoconjugates; integrins; neoplasm /cancer blood supply; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy; paclitaxel; prostate neoplasms; radiation dosage; radiopharmacology

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.

项目2的目的是继续转化研究，以开发与乳腺癌和前列腺癌患者结合的放射免疫疗法（CMIIIT）具有治愈性的意图。单药131i-CHL6、90y-DOTA肽-CHL6或90Y21T-BAD-MI70无需外周血干细胞支持晚期乳腺癌或前列腺癌患者的试验提供了治疗反应的证据，但在大多数情况下，尽管如此，尽管大多数情况下，但患者。当通过免疫组织病理学和核成像判断时，M170几乎与几乎所有乳腺和前列腺腺癌的反应。基于过去的工作，提议的乳腺癌和前列腺癌的试验使用：1）90y-Dota肽-M170，因为其治疗指数大约是相应13ii〜标记的抗体的IO倍。 2）高剂量的，具有外周血干细胞支撑的分离RIT，以提供更大和更均匀的肿瘤辐射； 3）紫杉醇（紫杉醇）是一种协同的放射增敏，以克服乳房和前列腺癌常见的p53和BCL2治疗耐药性。患者特异性剂量测定将指导放射性核素给药。在具有与人类乳腺癌的分子畸变相当的裸小鼠异种移植模型中，90y-DOTA肽共轭抗体和紫杉醇的患者可以在临床上获得的剂量，在最佳时间和序列时给予治疗性协同，而无需增加毒性，而无需增加毒性。当在临床前研究中显示出有望在项目3中生成的较新的肽连接的免疫缀合物时，将开发一项方案，以在下一项竞争性提交中进行这些放射性药物的临床试验。同样，将进行整联蛋白结合肽的临床前试验，以发现与已经提出的肽的其他药物协同作用。整联蛋白结合肽会诱导新生血管凋亡，这可能会导致早期血管泄漏，肿瘤摄取增加。后来的血管塌陷可能会增加90-DOTA肽M170的保留率。 因此，肿瘤辐射将增加，并且有可能导致肿瘤血管阻断。该项目的优势包括一个具有凝聚力的团队，在这种类型的翻译调查中具有可靠的记录。项目1、2和核心C和项目3中新型肽化学发展的临床前研究的策略将在CMRIT方面进一步进步。该项目的信息与计划项目的其余部分以及使用CMRIT进行癌症有关。