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.

使用非肌纤维造血细胞移植（HCT），使用非甲状腺素的调节，具有200 CGY全身照射+/-氟达拉滨与麦康苯甲酸盐的莫夫替尔和环孢菌素结合使用后的免疫抑制，可通过HLA相同的SIBlige graft液和多样性的HLA植物症患者进行了可靠的植入术。这将同种疗法（Graft-Vs-tumor [GVT]效应和骨髓功能的替代）的好处扩展到老年患者或患有医疗状况的患者，这些患者排除了常规的高剂量调节，所有患者均具有较低的非雷神死亡率（NRM）。这种方法将抗肿瘤活性的负担从细胞毒性剂转移到GVT和GRAFT-VS-HOST免疫反应。这些反应需要时间来发展，并且在生长缓慢或通过先前治疗减轻其负担的疾病患者中更成功。我们已经使用了高剂量自体HCT的抗肿瘤效应来减轻疾病负担，并为GVT效应带来消除残留疾病的时间。这种两步方法可以为非霍奇金淋巴瘤（NHL）和骨髓瘤（MM）的老年患者提供治疗疗法。我们在AIM 1中的假设是，串联自动/Allo移植将允许同种异体HCT获得更好的肿瘤控制，而NRM比常规同种异体进行了，并且可以扩展到老年患者。对于MM患者，我们假设结果将优于串联自体移植。我们在54例患者中的初步经验，中位年龄为54岁，已显示出79％的生存期，中位随访18个月，构成了全国试验的基础。自体移植时 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染色体阳性急性淋巴细胞性白血病（STI-571）。这些方法将进一步推进对B细胞恶性肿瘤患者的潜在治愈性同种异体GVT治疗的使用。