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 非霍奇金淋巴瘤(NHL)患者会复发，一旦发生，只有少数人可能会复发 用目前的治疗方法治愈了。该项目的主要目标是开发和优化 使用大剂量放射性标记单抗靶向泛造血的创新策略 抗原、CD45联合自体干细胞移植治疗复发性卵巢癌 难治性B细胞或T细胞淋巴瘤。这种方法有几个优点。它绕过了潜在的 利妥昔单抗阻断CD20位点，扩大对微小疾病部位的辐射暴露，并允许 用一种安全的，可出口的， 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 确定在ASCT前可给予的[90]Y-BC8的最大耐受量(MTD)。首先， 将确定BCS的最佳抗体蛋白剂量，以确保大多数患者获得更高的 肿瘤部位的辐射照射高于关键的正常器官(目标1)。第二，直接比较 将获得CD45和CD20抗体靶向肿瘤部位的能力，以证实这一点的好处 B-NHL患者的治疗策略(AIM 2)。第三，关于[111]的能力的临界剂量学问题 预测[90]Y的生物分布将通过[86]Y PET成像(目标3)来解决。在此之后 剂量学研究，所有患者都将接受[90]Y-BC8治疗，以便在此治疗之前估计该治疗的MTD 至ASCT(目标4)。这一全面的发展计划应该能够成功地评估这一点 创新治疗策略，实现进一步建立和壮大的长期目标 大剂量放射免疫联合ASCT治疗复发性非霍奇金淋巴瘤

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.