Radioimmunotherapy for Lymphoma

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 患有非霍奇金淋巴瘤（NHL）的患者会复发，一旦发生这种情况， 用目前的治疗方法治愈。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干细胞的创新策略 抗原，CD 45联合自体干细胞移植（ASCT）治疗复发性或 难治性B或T细胞淋巴瘤。这种方法有几个优点。它规避了潜在的 利妥昔单抗阻断CD 20位点，增加了对微小病变部位的辐射暴露， 用一种安全的、可出口的、 治疗性放射性核素，[90]Y。在I期临床试验的背景下提出了四个目的， 确定ASCT前可给予的[90] Y-BC 8的最大耐受剂量（MTD）。一是 将确定BCS的最佳抗体蛋白剂量，以确保大多数患者获得更高的免疫应答。 肿瘤部位的辐射暴露量高于关键正常器官（目标1）。第二，直接比较 将获得CD 45和CD 20抗体靶向肿瘤部位的能力，以证实其益处。 B-NHL患者的治疗策略（目的2）。第三，关于[111]In的能力的关键剂量学问题， 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 剂量测定研究中，所有患者将接受[90] Y-BC 8治疗，以估计该治疗的MTD， ASCT（目标4）。这项全面的发展计划应能成功地评估这一点， 创新的治疗策略，并实现进一步建立和增强 大剂量放射免疫治疗和ASCT在治疗复发性NHL中的作用。

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.