RADIOIMMUNOTHERAPY AND MICROHETEROGENEITY

放射免疫治疗和微观异质性

• 批准号: 6563803
• 负责人: SYDNEY WELT
• 金额: $ 29.18万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-28 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563803
• 关键词: SCID mouse; antitumor antibody; clinical research; clinical trial phase I; colorectal neoplasms; combination cancer therapy; genetically modified animals; human subject; human therapy evaluation; iodine; neoplasm /cancer radioimmunotherapy; neoplasm /cancer surgery; radiation therapy dosage; radionuclides; yttrium

The treatment of advanced colon cancer with available modalities has been consistently unsuccessfully, partially due to the lack of reagents with sufficient anti-tumor activity to impact on survival. Recently, antibody based therapies have shown significant anti-tumor effects in solid-tumor patients either as single agents or in combination with chemotherapy. Three humanized antibodies (huA33, huF19, huS193) reactive with colon cancer cells have been identified as promising tumor targeting agents and the feasibility of patient re-treatment has been demonstrated. This proposal addresses the limitation of single antibodies as immuno or radiotherapeutic agents in the treatment of cancer. Due to heterogeneous antigen expression, micro-distribution, leading to under-treated tumor regions and ultimately to resistance to treatment. The theme of this proposal is that combinations of antibodies and small-molecular -weight constructs may improve uniformity of antibody binding and therapeutic efficacy; and therapeutic isotopes with the proper energy and emission path length for each antibody/construct will increase the radiolysis of tumor cells. The aims are to analyze, by quantitative radiosimetry, resected tissues from patients treated with combinations of radiolabeled antibodies/constructs; and to determine toxicity and efficacy of antibody combinations in phase I and II studies. Each of the two components of colon cancer, carcinoma cells and the supporting stromal cells, can now be effectively targeted with these antibodies. A truly uniform radiation field may be achieved in tumors with combinations of antibodies/constructs combinations to tumors, pharmacokinetics, radio- isotope selection, dosimetry modeling, and definition of toxicity profiles in phase I studies will identify the optimal reagent combination for immuno- and radio-immunotherapy of colorectal cancer.

现有的治疗方式对晚期结肠癌的治疗一直不成功，部分原因是缺乏具有足够抗肿瘤活性的试剂来影响生存。近年来，基于抗体的治疗方法在实体瘤患者中显示出显著的抗肿瘤作用，无论是单独使用还是与化疗联合使用。三种与结肠癌细胞反应的人源抗体（hu33, huF19, huS193）已被确定为有前景的肿瘤靶向药物，并已证明患者再治疗的可行性。这一建议解决了单一抗体作为免疫或放射治疗药物在癌症治疗中的局限性。由于抗原的异质表达、微分布，导致肿瘤区域治疗不足，最终产生耐药。这一建议的主题是，抗体和小分子量结构的组合可以改善抗体结合的均匀性和治疗效果；而每个抗体/构建体具有适当能量和发射路径长度的治疗同位素将增加肿瘤细胞的放射溶解。目的是通过定量放射学来分析接受放射标记抗体/构建物联合治疗的患者的切除组织；并在I期和II期研究中确定抗体组合的毒性和有效性。结肠癌的两种组成部分，癌细胞和支持性基质细胞，现在都可以被这些抗体有效地靶向。在I期研究中，抗体/构建物联合肿瘤、药代动力学、放射性同位素选择、剂量学建模和毒性谱定义将确定结肠直肠癌免疫和放射免疫治疗的最佳试剂组合，从而在肿瘤中实现真正均匀的辐射场。