Radioimmunotherapy for Lymphoma

淋巴瘤的放射免疫治疗

• 批准号: 8916572
• 负责人: Ajay Gopal
• 金额: $ 26.96万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916572
• 关键词: 90Y; Address; Adopted; American; Antibodies; Antigen Targeting; Autologous Stem Cell Transplantation; B-Cell Lymphomas; B-Lymphocytes; Biodistribution; Bone Marrow; CD45 Antigens; Clinical Data; Clinical Trials Design; Data; Development Plans; Disease; Disease remission; Disease-Free Survival; Dose; Dose-Limiting; Drug Kinetics; Evaluation; Exposure to; Hematopoietic; Human; Indium-111; Intravenous; Ionizing radiation; Isotopes; Kidney; Label; Liver; Lung; Lymphoma; MS4A1 gene; Maximum Tolerated Dose; Minority; Modality; Monoclonal Antibodies; Newly Diagnosed; Non-Hodgkin' s Lymphoma; Organ; PTPRC gene; Patients; Phase I Clinical Trials; Positron-Emission Tomography; Prior Therapy; Proteins; Protocols documentation; Radiation; Radiation therapy; Radioimmunoconjugate; Radioimmunotherapy; Radioisotopes; Radiolabeled; Radionuclide Imaging; Refractory; Regimen; Relapse; Research; Residual Neoplasm; Role; Safety; Site; Spleen; T-Cell Lymphoma; Testing; Therapeutic; Toxic effect; Translating; Transplantation; Whole-Body Irradiation; Work; base; chemoradiation; chemotherapy; comparative; conditioning; dosimetry; expectation; improved; innovation; leukemia/lymphoma; lymph nodes; novel; phase I trial; pre-clinical; radiation absorbed dose; radiotracer; response; rituximab; success; tositumomab; tumor

Despite impressive advances in combination chemoimmunotherapy, the majority of newly diagnosed patients with non-Hodgkin lymphomas (NHL) will relapse, and once this occurs only a minority can be cured with current treatments. The primary objective of this project is to develop and optimize an innovative strategy using high-dose radiolabeled monoclonal antibodies targeting the pan-hematopoietic antigen, CD45 in conjunction with autologous stem cell transplantation (ASCT) for patients with relapsed or refractory B or T-cell lymphomas. This approach possesses several advantages. It circumvents potential blocking of CD20 sites by rituximab, amplifies radiation exposure to sites of minimal disease, and allows treatment of CD20-negative lymphomas as well as CD20-expressing lymphomas with a safe, exportable, therapeutic radionuclide, [90]Y. Four Aims are proposed within the context of a phase I clinical trial designed to identify the maximally tolerated dose (MTD) of [90]Y-BC8 that can be delivered prior to ASCT. First, the optimal antibody protein dose of BCS will be determined to assure that a majority of patients achieve higher radiation exposures in tumor sites than in critical normal organs (Aim 1). Second, direct comparisons of the ability of CD45 and CD20 antibodies to target tumor sites will be obtained to confirm the benefit of this strategy in patients with B-NHL (Aim 2). Third, the critical dosimetry question regarding the ability of [111]In to predict [90]Y biodistribution will be addressed by means of [86]Y PET imaging (Aim 3). Following these dosimetry studies, all patients will be treated with [90]Y-BC8 in order to estimate the MTD of this therapy prior to ASCT (Aim 4). This comprehensive development plan should enable the successful evaluation of this innovative therapeutic strategy and achieve the long-term objectives of further establishing and augmenting the role of high dose radioimmunotherapy and ASCT in the treatment of relapsed NHL.

尽管联合化学免疫疗法取得了令人印象深刻的进展，但大多数新诊断的患者 非霍奇金淋巴瘤（NHL）患者会复发，一旦发生这种情况，只有少数人可以接受治疗。 通过目前的治疗已治愈。该项目的主要目标是开发和优化 使用高剂量放射性标记单克隆抗体靶向泛造血系统的创新策略 抗原、CD45 联合自体干细胞移植（ASCT）治疗复发或 难治性 B 或 T 细胞淋巴瘤。这种方法有几个优点。它规避了潜力 利妥昔单抗阻断 CD20 位点，放大对最小疾病部位的辐射暴露，并允许 使用安全、可出口、 治疗性放射性核素，[90]Y。在设计的 I 期临床试验的背景下提出了四个目标 以确定在 ASCT 之前可以输送的 [90]Y-BC8 的最大耐受剂量 (MTD)。首先， 将确定 BCS 的最佳抗体蛋白剂量，以确保大多数患者达到更高的剂量 肿瘤部位的辐射暴露量高于重要的正常器官（目标 1）。二、直接比较 将获得 CD45 和 CD20 抗体靶向肿瘤部位的能力，以证实这一点的益处 B-NHL 患者的治疗策略（目标 2）。第三，关于 [111]In 能力的关键剂量测定问题 预测 [90]Y 生物分布将通过 [86]Y PET 成像来解决（目标 3）。遵循这些 剂量测定研究，所有患者都将接受 [90]Y-BC8 治疗，以便事先估计该疗法的 MTD ASCT（目标 4）。这一全面的发展计划应该能够成功评估这一项目 创新治疗策略并实现进一步建立和增强的长期目标 高剂量放射免疫疗法和 ASCT 在治疗复发性 NHL 中的作用。