Combined modality radioimmunotherapy for nonHodgkins lymphoma

项目1的目标是开发“联合放射免疫治疗”(CMRIT)，作为多模式治疗计划的组成部分，为非霍奇金淋巴瘤(NHL)患者提供治疗意图。LYM-1优先靶向存在于大多数恶性B细胞上的HLA-DRIO表位，提供了一个通过特定靶向NHL的放射性核素来提高治疗指数的绝佳机会。加州大学戴维斯分校开发的3种新药之一：131L-LYM-1、67Cu2LT-BAT-LYM-1和90Y-2IT-BAD-LYM-1治疗72例NHL患者，大多数患者有反应。在对危险因素进行调整的多变量分析中，一个与时间相关的比例风险模型最终表明，对1311-Lym-1治疗的反应与存活率的改善有关。有几名患者在RIT后存活超过5年。CMRIT与先进的放射治疗药物90Y-DOTA-多肽-LYM-1和紫杉醇将作为治疗NHL的策略进行评估。在Raji肿瘤裸鼠模型中，90Y-DOTA-多肽-Lym-1和紫杉醇的CMRIT在临床上可以达到的剂量，当在最佳的时间和顺序给药时，在不增加毒性的情况下提供了治疗协同作用。项目1中为新阶段临床方案设计的其他进展包括：针对患者的剂量，用于减轻骨髓毒性并允许更高剂量90Y的外周血液干细胞支持，一种可生物降解的Unker，用于减少正常器官剂量并提高治疗指数的“DOTA肽”，以及用于防止人类抗鼠抗体产生的低剂量环孢菌素A。临床前研究将检验RIT与促进细胞凋亡和/或抑制DNA修复的药物，特别是抗CD22单抗和核苷类似物的治疗协同作用的可能性。项目1中提出的临床前和L期临床研究将继续过去几年取得的进展。我们跨学科团队的紧密互动将使我们能够成功完成这些计划。为这项建议设计的L阶段试验将为随后在其他机构进行的第11阶段和第111阶段试验提供便利。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，从而最终造福于NHL患者。

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.