Mixed Chimerism in the Treatment of B-Cell Malignancies

混合嵌合现象在 B 细胞恶性肿瘤治疗中的应用

• 批准号: 7173857
• 负责人: DAVID G MALONEY
• 金额: $ 10.25万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7173857
• 关键词: Hodgkin' s disease; artificial immunosuppression; clinical trial phase I; clinical trial phase II; clinical trial phase III; combination cancer therapy; dexamethasone; hematopoietic tissue transplantation; human subject; human therapy evaluation; melphalan; monoclonal antibody; multiple myeloma; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; nonHodgkin' s lymphoma; patient oriented research; thalidomide; tissue mosaicism; transplantation immunology

AIIogeneic hematopoietic cell transplantation (HCT) using non-myeloablative conditioning with 200 cGy total body irradiation +/- fludarabine combined with postgrafting immunosuppression by mycophenolate mofetil and cyclosporine allows reliable engraftment of HLA identical sibling grafts in patients with a variety of hematologic malignancies. This extends the benefits of allografting (graft-vs-tumor [GVT] effects and replacement of marrow function) to older patients or those with medical conditions that preclude conventional high-dose conditioning, all with a lower non-relapse mortality (NRM). This approach shifts the burden of anti-tumor activity from the cytotoxic agents to the GVT and graft-vs-host immune responses. These responses take time to develop, and are more successful in patients with diseases that are either slow growing or whose burden has been reduced by prior therapy. We have used the anti-tumor effects of preceding high dose autologous HCT to reduce disease burden and allow time for GVT effects to eliminate residual disease. This two-step approach may provide curative therapy to elderly patients with non-Hodgkin lymphoma (NHL) and myeloma (MM). Our hypothesis in Aim 1 is that tandem auto/allo transplants will allow allogeneic HCT to achieve better tumor control and lower NRM than conventional allografting, and this may be extended to older patients. For MM patients, we hypothesize that results will be superior to tandem autologous transplants. Our preliminary experience with 54 MM patients, median age of 54 years, has shown 79% survival with a median follow-up of 18 months and forms the basis for a national trial. When autografts are not possible for MM patients, we will evaluate the addition of intermediate dose melphalan to the allogeneic HCT protocol in Aim 2. Aim 3 will explore the inclusion of newer agents with greater tumor specificity combined with non-myeloablative HCT for control of disease in patients with NHL (radiolabeled anti-CD20 antibody), Hodgkin's Disease (chimeric anti-CD30 antibody) and Philadelphia chromosome positive acute lymphocytic leukemia (STI-571). These approaches will further advance the use of potentially curative allogeneic GVT therapy to patients with B cell malignancies.

使用 200 cGy 全身照射 +/- 氟达拉滨的非清髓性调理，结合吗替麦考酚酯和环孢素的移植后免疫抑制，进行异基因造血细胞移植 (HCT)，可以在患有各种血液恶性肿瘤的患者中可靠地植入 HLA 相同的同级移植物。这将同种异体移植的益处（移植物抗肿瘤 [GVT] 效应和骨髓功能替代）扩展到老年患者或患有无法进行传统高剂量调理的医疗状况的患者，并且所有患者的非复发死亡率 (NRM) 均较低。这种方法将抗肿瘤活性的负担从细胞毒性药物转移到 GVT 和移植物抗宿主免疫反应。这些反应需要时间才能形成，并且对于患有缓慢生长的疾病或通过先前的治疗减轻了负担的患者来说更为成功。我们利用先前高剂量自体 HCT 的抗肿瘤作用来减轻疾病负担，并为 GVT 作用留出时间来消除残留疾病。这种两步法可以为患有非霍奇金淋巴瘤（NHL）和骨髓瘤（MM）的老年患者提供治愈性治疗。我们在目标 1 中的假设是，串联自体/同种异体移植将使同种异体 HCT 比传统同种异体移植实现更好的肿瘤控制和更低的 NRM，并且这可能会扩展到老年患者。对于多发性骨髓瘤患者，我们假设结果将优于串联自体移植。我们对 54 名中位年龄为 54 岁的多发性骨髓瘤患者的初步经验显示，中位随访时间为 18 个月，存活率为 79%，这为全国试验奠定了基础。当自体移植物 对于多发性骨髓瘤患者来说这是不可能的，我们将评估在目标 2 中的同种异体 HCT 方案中添加中等剂量马法兰。目标 3 将探索将具有更高肿瘤特异性的新型药物与非清髓性 HCT 相结合，以控制 NHL（放射性标记抗 CD20 抗体）、霍奇金病（嵌合抗 CD30 抗体）和费城患者的疾病 染色体阳性急性淋巴细胞白血病（STI-571）。这些方法将进一步推动 B 细胞恶性肿瘤患者使用具有潜在疗效的同种异体 GVT 疗法。