Radiolabeled Antibody Therapy of B-Cell Lymphoma

尽管新诊断的非霍奇金淋巴瘤(NHL)的联合化学免疫治疗取得了显著进展，但很少有复发的B细胞性NHL患者能用常规治疗治愈。该项目的主要目标是优化针对CD20抗原的大剂量放射性标记单抗与自体干细胞移植(ASCT)联合治疗复发或难治性B细胞淋巴瘤的疗效。在本申请中，我们提出了四种实现这一目标的方法。首先，我们将进行一项疾病特异性的II期试验，将(131)I-抗CD20抗体与依托泊苷(VP16)、环磷酰胺(CY)和ASCT联合使用，以确定该方案对三种最常见的复发性B-NHL组织学亚型(AIM I)的疗效。其次，我们将探索协同化疗药物(氟达拉滨)增强卵巢癌疗效的能力。 (131)ASCT环境中老年患者的I-抗CD20抗体(AIM II)。第三，我们将研究使用预靶向技术(AIM III)提高肿瘤部位辐射剂量传递的特异性的可行性和安全性。最后，我们将对接受(131)I-抗CD20抗体+ASCT治疗的I期和II期试验的患者进行长期随访，以确定长期疗效和延迟毒性(AIM IV)。这一系列研究应该使我们能够实现我们的长期目标，即进一步建立和加强大剂量放射免疫治疗和ASCT在治疗复发NHL中的作用。

Despite dramatic advances in combination chemoimmunotherapy for newly diagnosed patients with non-Hodgkin's lymphomas (NHL), few patients with relapsed B cell NHL can be cured with conventional treatments. The primary objective of this project is to optimize the therapeutic utility of high dose radiolabeled monoclonal antibodies targeting the CD20 antigen in conjunction with autologous stem cell transplant (ASCT) for treating patients with relapsed or refractory B cell lymphomas. In this application, we propose four approaches to achieve this goal. First, we will conduct a disease-specific, phase II trial of (131)I-anti-CD20 antibody with etoposide (VP16), cyclophosphamide (CY) and ASCT to establish the efficacy of this regimen for treating three of the most common histologic subtypes of relapsed B NHL (Aim I). Second, we will explore the ability of a synergistic chemotherapeutic agent (fludarabine) to enhance the efficacy of (131)I-anti-CD20 antibody for older patients in the setting of ASCT (Aim II). Third, we will investigate the feasibility and safety of improving the specificity of radiation dose delivery to tumor sites using pre-targeting technology (Aim III). Finally, we will perform long-term follow-up of patients treated on prior Phase I & II trials with (131)I-anti-CD20 antibodies + ASCT to ascertain long term efficacy and delayed toxicities (Aim IV). This sequence of studies should enable us to achieve our long term objectives of further establishing and augmenting the role of high dose radioimmunotherapy and ASCT in the treatment of relapsed NHL.