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: 6989535
• 负责人: DAVID G MALONEY
• 金额: $ 9.67万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989535
• 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.

异基因造血细胞移植（HCT）采用200 cGy全身照射+/-氟达拉滨的非清髓预处理，联合移植后用吗替麦考酚酯和环孢素进行免疫抑制，可使多种恶性血液病患者的HLA相合同胞移植物可靠植入。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接受常规高剂量预处理的疾病的患者，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剂转移到GVT和移植物抗宿主免疫应答。这些反应需要时间来发展，并且在患有缓慢生长或其负担已通过先前治疗减轻的疾病的患者中更成功。我们已经使用了先前高剂量自体HCT的抗肿瘤作用来减少疾病负担，并为GVT作用消除残留疾病留出时间。这种两步法可能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/异体移植将允许同种异体HCT实现比传统同种异体移植更好的肿瘤控制和更低的NRM，并且这可以扩展到老年患者。对于MM患者，我们假设结果将上级连续自体移植。我们对54例MM患者（中位年龄为54岁）的初步经验显示，中位随访时间为18个月，生存率为79%，这为国家试验奠定了基础。当自体移植物 对于MM患者不可能，我们将在目的2中评估在同种异体HCT方案中添加中等剂量美法仑。目的3将探索纳入具有更高肿瘤特异性的新型药物联合非清髓性HCT，用于控制NHL（放射性标记抗CD 20抗体）、霍奇金病（嵌合抗CD 30抗体）和费城染色体阳性急性淋巴细胞白血病（STI-571）患者的疾病。这些方法将进一步推进对患有B细胞恶性肿瘤的患者的潜在治愈性同种异体GVT疗法的使用。