NOVEL RADIOIMMUNOTHERAPY FOR LYMPHOMA

淋巴瘤的新型放射免疫疗法

• 批准号: 6164170
• 负责人: JAMES E BUTRYNSKI
• 金额: $ 13.37万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-18 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6164170
• 关键词: CD antigens; Macaca nemestrina; NOD mouse; SCID mouse; antibody; athymic mouse; beta lactamase; cephalosporins; clinical research; clinical trials; human subject; human therapy evaluation; immunoconjugates; iodine; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy; neoplasm /cancer relapse /recurrence; nonHodgkin's lymphoma; radionuclides

The candidate's immediate goal is to acquire critical scientific and clinical training to enable him to pursue independent investigation with a long-term goal of developing innovative therapies for non-Hodgkin's lymphoma (NHL). Incidence of NHL is increasing and improvements in therapy are needed. Radiolabeled antibody therapy has proven effective in treating NHL, but is limited by delivery of radiation to normal tissues due to circulating non-tumor bound radiolabeled antibody. The proposed program will integrate two complimentary approaches 1. preclinical development of a novel radioimmunotherapeutic approach and 2. clinical evaluation of radiolabeled antibody therapy. In preclinical studies, we hypothesize that rapidly removing circulating non-tumor bound radioisotope will decrease radiation delivered to normal tissues and improve relative radiation delivery to tumor. Specifically, our strategy involves exogenous administration of an enzyme, beta-lactamase, in order to cleave a circulating cephalosporin-based radioimmunoconjugate (RIC), resulting in rapid cleavage and removal of radioisotope from the body by the kidney. We further hypothesize the effectiveness of this approach will depend on stable intracellular retention of radioisotope in tumor and on more rapid tumor targeting. Biodistribution studies in murine and nonhuman primate models will b e performed with cleavable RICs that are internalized and retained by the tumor cell to ascertain if our approach will result in improvement in the delivery of radiation to tumor compared to normal tissues. In clinical studies, the candidate will assess the risk of secondary malignancies associated with myeloablative Iodine-131 anti-CD20 antibody and autologous stem cell transplant in patients with lymphoma previously treated and in ongoing trials. Furthermore, a proposed dose escalation trial in later years of this grant is anticipated with the optimized cleavable RICs developed in the preclinical proposal. In addition to these preclinical and clinical investigations, a rigorous didactic and mentoring program in clinical trial design will provide the candidate the foundation to implement and supervise clinical trials of novel therapies for NHL.

候选人的近期目标是获得关键的科学和临床培训，使他能够进行独立研究，长期目标是开发非霍奇金淋巴瘤 (NHL) 的创新疗法。 NHL 的发病率正在增加，需要改进治疗方法。 放射性标记抗体疗法已被证明可有效治疗 NHL，但由于循环中的非肿瘤结合放射性标记抗体，放射线输送到正常组织受到限制。 拟议的计划将整合两种互补的方法：1.新型放射免疫治疗方法的临床前开发和2.放射性标记抗体疗法的临床评估。 在临床前研究中，我们假设快速去除循环的非肿瘤结合放射性同位素将减少传递到正常组织的辐射并改善传递到肿瘤的相对辐射。 具体来说，我们的策略涉及外源性施用酶、β-内酰胺酶，以裂解循环的基于头孢菌素的放射免疫缀合物（RIC），从而导致肾脏快速裂解并从体内清除放射性同位素。 我们进一步假设这种方法的有效性将取决于肿瘤中放射性同位素在细胞内的稳定保留以及更快速的肿瘤靶向。 小鼠和非人灵长类动物模型中的生物分布研究将使用可裂解的 RIC 进行，这些 RIC 被肿瘤细胞内化并保留，以确定与正常组织相比，我们的方法是否会改善肿瘤的辐射传递。 在临床研究中，候选人将评估先前接受治疗和正在进行的试验的淋巴瘤患者与清髓性 Iodine-131 抗 CD20 抗体和自体干细胞移植相关的继发性恶性肿瘤的风险。 此外，预计在本次拨款的后期，将利用临床前提案中开发的优化可裂解 RIC 进行剂量递增试验。 除了这些临床前和临床研究之外，临床试验设计中严格的教学和指导计划将为候选人提供实施和监督 NHL 新疗法临床试验的基础。