Combined modality radioimmunotherapy for nonHodgkins lymphoma

非霍奇金淋巴瘤的联合放射免疫治疗

• 批准号: 6347311
• 负责人: ROBERT T O'DONNELL
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2001-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6347311
• 关键词: CD22 molecule; athymic mouse; chelating agents; clinical research; clinical trial phase I; combination cancer therapy; cyclosporines; human subject; human therapy evaluation; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy; nonHodgkin's lymphoma; nucleoside analog; paclitaxel; radiation dosage; radiopharmacology; yttrium

The goal of Project 1 is to develop "combined modality radioimmunotherapy" (CMRIT) as an integral part of a multimodality treatment plan, with curative intent for patients with non-Hodgkin's lymphoma (NHL). Lym-1 preferentially targets an HLA-DRIO epitope present on most malignant B-cells, providing a remarkable opportunity to enhance the therapeutic index by specifically targeting a radionuclide to NHL. The majority of 72 NHL patients treated with one of 3 new drugs developed at UC Davis: 131l-Lym-1, 67Cu-2lT-BAT-Lym-1, and 90Y- 2IT-BAD-Lym-1, responded. A time dependent proportional hazards model conclusively showed that response to 1311-Lym-1 therapy was associated with improved survival in a multivariate analysis that adjusted for risk factors. Several patients are alive more than 5 years after RIT. CMRIT with the advanced radiopharamceuticals 90Y-DOTA-peptide- Lym-1 and Taxol will be evaluated as a therapeutic strategy for NHL. In a Raji-tumored nude mouse model, CMRIT with 90Y-DOTA-peptide-Lym-1 and Taxol, in doses clinically achievable in humans, provided therapeutic synergy without increased toxicity, when administered at the optimal time and sequence. Other advances designed for the new Phase clinical protocols in Project 1 are: patient-specific dosing, peripheral blood stem cell support to ameliorate myelotoxicity and allow higher doses of 90Y, a biodegradable Unker, "DOTA-peptide" to decrease normal organ doses and increase the therapeutic index, and low doses of Cyclosporin A to prevent development of human anti-mouse antibody. Preclinical studies will examine the potential for therapeutic synergy of RIT and agents that promote apoptosis and/or inhibit DNA repair, specifically, anti-CD22 monoclonal antibodies and nucleoside analogues. Preclinical and Phase l clinical studies proposed in Project 1 will continue the progress achieved over the past several years. Cohesive interaction of our interdisciplinary group will allow successful completion of these plans. The Phase l CMRIT trials designed for this Proposal will facilitate subsequent Phase 11 and 111 trials at other institutions. New strategies developed in preclinical studies will continue to allow translation of novel advances from the laboratory to the clinic, for the ultimate benefits of patients with NHL.

项目1的目标是开发“联合模式放射免疫治疗”（CMRIT）作为多模式治疗计划的一个组成部分，用于非霍奇金淋巴瘤（NHL）患者的治疗目的。Lym-1优先靶向存在于大多数恶性B细胞上的HLA-DRI 0表位，提供了通过特异性靶向NHL的放射性核素来增强治疗指数的显著机会。72名NHL患者中的大多数接受了加州大学戴维斯分校开发的3种新药之一的治疗：131 l-Lym-1，67 Cu-21 T-BAT-Lym-1和90 Y-2 IT-BAD-Lym-1，有反应。时间依赖性比例风险模型最终显示，在调整风险因素的多变量分析中，对1311-Lym-1治疗的反应与生存率改善相关。一些患者在RIT后存活超过5年。CMRIT与先进的放射性药物90 Y-DOTA-肽- Lym-1和紫杉醇将作为NHL的治疗策略进行评估。在Raji肿瘤裸鼠模型中，CMRIT与90 Y-DOTA-peptide-Lym-1和Taxol，以临床上可在人体中达到的剂量，在最佳时间和顺序给药时，提供了治疗协同作用而不增加毒性。为项目1中的新阶段临床方案设计的其他进展是：患者特异性给药，外周血干细胞支持以改善骨髓毒性并允许更高剂量的90 Y，可生物降解的Unker，“DOTA-肽”以减少正常器官剂量并增加治疗指数，以及低剂量的环孢菌素A以防止人抗小鼠抗体的产生。临床前研究将检查RIT与促进细胞凋亡和/或抑制DNA修复的药物（特别是抗CD 22单克隆抗体和核苷类似物）的治疗协同作用潜力。项目1中提出的临床前和I期临床研究将延续过去几年取得的进展。我们跨学科小组的凝聚力互动将使这些计划的成功完成。为本提案设计的I期CMRIT试验将促进其他机构的后续11期和111期试验。在临床前研究中开发的新策略将继续允许将新的进展从实验室转化为临床，以使NHL患者最终受益。