Targeted Radiotherapy with 90Y-BC8 Monclonal Antibody, Fludarabine and TBI Follow

描述(由申请人提供)：多发性骨髓瘤(MM)患者的治疗已取得重要进展。自体干细胞移植(ASCT)与传统疗法相比的随机试验显示，存活率显著提高。与旧的诱导方案相比，沙利度胺、来那度胺和硼替佐米联合ASCT的新药物组合进一步提高了无进展生存率。然而，很少有多发性骨髓瘤患者能存活10年以上而没有疾病进展。诸如双ASCT、ASCT后的维持治疗或ASCT后的同种异体移植等策略正在研究中，以此作为改善预后的方法。异基因干细胞移植(Allo SCT)提供了一种无肿瘤的移植物和免疫学的移植物抗骨髓瘤效应。骨髓清除性异基因干细胞移植治疗多发性骨髓瘤有15%-30%的无病生存期超过10年的可能性，这是治愈的最佳证据。然而，清髓性异基因干细胞移植历史上与移植相关死亡率(TRM)高达30-50%有关。低强度的非清髓性异基因干细胞移植已被采用，可将死亡率降低至15-20%，但为了成功，这种方法要求MM患者在接受异基因SCT之前接受细胞减少治疗，通常是ASCT。然而，即使在串联自体同种异体干细胞移植后，复发仍然是治疗失败的主要原因。因此，迫切需要改进的方法来更好地根除骨髓中残留的骨髓瘤细胞。我们已经证明，131I-抗CD45(BC8)抗体对骨髓、脾和白血病部位的辐射至少是任何正常器官的2-3倍。我们进一步证明，在老年髓系恶性肿瘤患者中，大剂量131I-BC8单抗可以安全地与非清髓方案联合使用。虽然CD45在MM患者的肿瘤细胞上没有广泛表达，但CD45在所有其他白细胞上的广泛表达将使我们能够有效地靶向MM的主要疾病部位骨髓。尽管131I在提供靶向放射治疗方面取得了巨大的成功，但由于131I的高伽马发射和相对低的SS能量，对这项技术的安全性和可移植性的担忧已促使策略转向使用90Y-BC8抗体结合物进行多发性骨髓瘤的试验。90Y没有伽马射线发射，SS能量较高，与骨的天然亲和力较高，应该是一种更好的靶向骨髓的同位素。我们将用111In-BC8抗体进行剂量学测试，以确定更多的CD45被靶向骨髓而不是非靶组织，如肝、肺和肾。患者接下来将接受90Y-BC8的消融剂量，随后是一段时间的同位素衰减期，然后接受氟达拉滨90 mg/m2，外部TBI 200Cgy和来自HLA匹配的同胞或非血缘关系供者的异基因SCT。治疗方案将包括在接受异基因SCT的多发性骨髓瘤患者中分两个阶段逐步增加同位素剂量，以确定接受异基因SCT的MM患者在联合氟达拉滨和TBI时90Y抗CD45的最大耐受量。在非清髓性allo-SCT方案中加入骨髓靶向照射应该会增加缓解和改善存活率。

DESCRIPTION (provided by applicant): Important progress has been made in the treatment of patients with multiple myeloma (MM). Randomized trials of autologous stem cell transplant (ASCT) v. conventional therapy alone have demonstrated significant improvements in survival. Novel drug combinations of thalidomide, lenalidomide and bortezomib plus ASCT have further improved progression-free survival compared older induction regimens. Nevertheless few patients with MM survive without disease progression beyond 10 years. Strategies such as double ASCT, maintenance therapy after ASCT or an allogeneic transplant after ASCT are being studied as ways to improve outcomes. Allogeneic stem cell transplant (allo SCT) provides a tumor-free graft and an immunologic, graft-versus- myeloma effect. Myeloablative allo SCT for MM is associated with a 15-30% probability of disease free survival extending beyond 10 years, the best evidence for cure. Myeloablative allo SCT is, however, historically associated with high transplant related mortality (TRM) of 30-50%. Less intensive, nonmyeloablative allo SCT has been adopted which can reduce mortality to 15-20%, but to be successful, this approach requires that patients with MM receive cytoreductive therapy usually with ASCT, prior to the allo SCT. Even after a tandem auto-allo SCT, however, relapses remain the principal cause of treatment failure. Thus, there is a critical need for improved ways to provide better eradication of residual myeloma cells in the bone marrow. We have shown that 131I-anti-CD45 (BC8) Ab can deliver at least 2-3-fold more radiation to marrow, spleen and sites of leukemia than to any normal organ. We have further shown that high-dose 131I-BC8 Ab can be safely combined with a non-myeloablative regimen in older patients with myeloid malignancies. While CD45 is not widely expressed on the tumor cells of patients with MM, the broad expression of CD45 on all other leukocytes will allow effective targeting to marrow, the principal disease site in MM. Although 131I has been highly successful with regard to delivering targeted radiotherapy, concerns about safety and the transportability of this technology due to high gamma emissions of 131I and the relatively low ss energy of 131I have prompted a shift in strategy to the use of a 90Y-BC8 Ab conjugate for trials in multiple myeloma. 90Y with its lack of gamma emissions, higher ss energy and natural affinity for bone, should be a better isotope for targeting marrow. We will perform dosimetry testing with 111In-BC8 Ab, to establish that more CD45 is targeted to marrow than non-target tissues such as liver, lung and kidneys. Patients will next receive an ablative dose of 90Y-BC8, followed by a period for isotope decay, then the administration of fludarabine 90 mg/m2, external TBI 200 cGY and allo SCT from an HLA matched sibling or unrelated donor. The treatment protocol will involve a 2-stage dose escalation of isotope in patients designed to determine the maximum tolerated dose of 90Y anti-CD45, when combined with fludarabine and TBI in patients with MM receiving allo SCT. Adding marrow targeted radiation to a nonmyeloablative allo-SCT regimen should increase remissions and improve survival.