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: 6254386
• 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: 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/6254386
• 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的目的是开发“联合模态免疫疗法”（CMRIT），作为多模式治疗计划的组成部分，对非霍奇金淋巴瘤（NHL）患者的治疗意图。 LYM-1优先靶向大多数恶性B细胞中存在的HLA-DRIO表位，这为增强治疗指数提供了非凡的机会，可以通过将放射性核素靶向NHL来增强治疗指数。在加州大学戴维斯（UC Davis）开发的3种新药物之一的72例NHL患者中，大多数人在131L-LYM-1、67CU-2LT-BAT-LYM-1和90Y-2IT-BAD-LYM-1患者中做出了回应。时间依赖的比例危害模型最终表明，在针对风险因素调整的多元分析中，对1311-LYM-1治疗的反应与提高的生存率有关。在RIT后5年以上，有几名患者还活着。带有晚期放射性毛骨管的CMRIT 90y-DOTA肽-1和紫杉醇将被评估为NHL的治疗策略。在拉吉（Raji）肿瘤的裸小鼠模型中，具有90y-DOTA肽-1和紫杉醇的CMRIT，在人类临床上可实现的剂量，在最佳时间和序列施用时，可以在人类临床上达到的剂量，而无需增加毒性。针对项目1的新阶段临床方案而设计的其他进展是：患者特异性剂量，外周血干细胞支持以改善骨髓毒性，并允许更高剂量的90y，一种可生物降解的Unker，“ Dota-Peptide”，“ DOTA肽”，以减少正常的器官剂量并增加治疗型指数，并增加人类倾向的人类倾斜的倾向，以防止人类的倾斜倾斜。临床前研究将检查RIT的治疗性协同作用和促进凋亡和/或抑制DNA修复的药物的潜力，具体是抗CD22单克隆抗体和核苷类似物。项目1中提出的临床前和L期临床研究将继续在过去几年中取得的进展。我们跨学科小组的凝聚力互动将允许成功完成这些计划。为该建议设计的相位L CMRIT试验将促进其他机构的随后的11和111阶段试验。临床前研究中制定的新策略将继续允许从实验室转换为诊所的新进展，以获得NHL患者的最终好处。