Allogeneic HCT for Hematologic Malignancies: Pharmacologic Manipulations

同种异体 HCT 治疗血液系统恶性肿瘤：药理学操作

• 批准号: 8240006
• 负责人: DAVID G MALONEY
• 金额: $ 18.48万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-08 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240006
• 关键词: Acute Lymphocytic Leukemia; Age; Allogenic; Allografting; Antibodies; Autologous; B lymphoid malignancy; B-Cell NonHodgkins Lymphoma; Blast Phase; Bortezomib; CSF3 gene; Calcineurin inhibitor; Canis familiaris; Cell Transplantation; Cells; Chimerism; Chronic Lymphocytic Leukemia; Chronic Myeloid Leukemia; Comorbidity; Cyclosporine; Development; Disease; Dose; Engraftment; Graft vs Tumor Effect; Grant; Health Benefit; Hematologic Neoplasms; Hematological Disease; Hematopoietic; Hodgkin Disease; Immune response; Immunologics; Immunosuppression; Lymphoma; MS4A1 gene; Maintenance Therapy; Malignant - descriptor; Modeling; Multiple Myeloma; Non-Hodgkin' s Lymphoma; Patients; Peripheral Blood Stem Cell; Philadelphia Chromosome; Progress Reports; Proliferating; Protocols documentation; Public Health; Refractory; Regimen; Relapse; Stem cells; TNFRSF8 gene; Tacrolimus; Toxic effect; Transplantation; Tyrosine Kinase Inhibitor; conditioning; ethnic minority population; flu; fludarabine; high risk; improved; leukemia; mortality; mycophenolate mofetil; response; rituximab; tositumomab; tumor; tumor progression; tumor specificity

Nonmyeloablative conditioning with low dose TBI (2 Gy) +/- fludarabine (30 mg/m2 x 3) and post grafting immunosuppression with cyclosporine and mycophenolate mofetil provides reliable engraftment for allogeneic G-CSF mobilized peripheral blood stem cells from HLA matched related or unrelated donors. This results in full donor chimerism and provides immunologic graft-vs-tumor (GVT) effects. Indeed, with this platform, nearly all of the anti-tumor activity comes from GVT immune responses with little contribution from the conditioning regimen. Our results demonstratethat this response may provide long term anti-tumor activity in many patients with B cell malignancies with outstanding activity noted in patients with low-grade non-Hodgkin Lymphoma (NHL), mantle cell NHLand chronic lymphocytic leukemia (CLL). Limitations of this approach were also evident as patients with aggressive, bulky or rapidly proliferating disease may develop tumor progression before the development of, or despite GVT effects. The focus of Project 4 is to augment the anti-tumor effect of nonmyeloablative conditioning for the treatment of B cell malignancies by improving pre-transplant cytoreduction, augmenting allogeneic GVT effects and incorporating additional agents with anti tumor activity, and limited toxicity. Lastly, we plan to expand this approach to patients without HLA matched related or unrelated donors by using a newprotocol that allows successful engraftment of related HLA haploidentical grafts. The Specific Aims are to use: 1. Tandem transplants using cytoreductive high-dose therapy and autologous hematopoietic cell transplantation (HCT) followed by nonmyeloablative allogeneic HCT from : a. HLA matched allogeneic HCT from related or unrelated donors for lymphoma. b. HLA matched allogeneic HCT from related or unrelated donors followed by maintenance therapy with bortezomib for high risk or relapsed Multiple Myeloma (MM). ; c. HLA haploidentical allogeneic HCTfrom related donors for relapsed or refractory lymphoma. 2. Addition of targeted therapies to nonmyeloablative conditioning with Flu/TBI followed by allogeneic HCT from HLA matched related or unrelated donors: a. Monomethyl Aurostatin E conjugated anti-CD30 antibody (SGN35) for relapsed or refractory HL. b. Tyrosine kinase inhibitors for Philadelphia chromosome positive leukemia. c. Anti-CD20 antibody Rituximab for CD20 positive B cell NHL and fludarabine refractory CLL. The public health benefits of this Project are that patients with various malignant blood disorders who . otherwise would have been excluded because of age and comorbidities have benefited from treatment by allogeneic HCT. Inaddition, the use of HLA-haploidentical donors will extend the option of HCT to a greater number of patients, including ethnic minorities.

使用低剂量 TBI (2 Gy) +/- 氟达拉滨 (30 mg/m2 x 3) 和移植后进行非清髓性调理 使用环孢菌素和吗替麦考酚酯进行免疫抑制可提供可靠的植入 同种异体 G-CSF 动员来自 HLA 匹配的相关或无关供体的外周血干细胞。这 导致完全供体嵌合并提供免疫移植物抗肿瘤（GVT）效应。确实，有了这个 平台上，几乎所有的抗肿瘤活性都来自 GVT 免疫反应，而来自 GVT 的贡献很少 调理方案。我们的结果表明这种反应可以提供长期的抗肿瘤作用 在许多患有 B 细胞恶性肿瘤的患者中具有显着的活性，并且在低级别 B 细胞恶性肿瘤患者中注意到显着的活性 非霍奇金淋巴瘤 (NHL)、套细胞非霍奇金淋巴瘤和慢性淋巴细胞白血病 (CLL)。这样做的局限性 方法也很明显，因为患有侵袭性、体积大或快速增殖性疾病的患者可能会发展 在 GVT 效应出现之前或尽管如此，肿瘤仍进展。项目4的重点是增强 非清髓性调理治疗 B 细胞恶性肿瘤的抗肿瘤作用 移植前细胞减灭术，增强同种异体 GVT 效应并结合其他药物 抗肿瘤活性和有限的毒性。最后，我们计划将这种方法扩展到没有 HLA 的患者 通过使用新的协议来匹配相关或不相关的捐赠者，该协议允许相关的成功植入 HLA半相合移植物。具体目标是使用： 1. 大剂量细胞减灭术和自体造血细胞串联移植 移植 (HCT)，然后进行非清髓性同种异体 HCT，来自： 一个。 HLA 与来自相关或无关淋巴瘤捐献者的同种异体 HCT 相匹配。 b. HLA 匹配的来自相关或无关供体的同种异体 HCT，随后进行维持治疗 与硼替佐米一起治疗高风险或复发性多发性骨髓瘤 (MM)。 ; c.来自相关供体的 HLA 单倍体同种异体 HCT，用于治疗复发或难治性淋巴瘤。 2. 在 Flu/TBI 的非清髓性调理基础上添加靶向治疗，然后 来自 HLA 匹配的相关或无关供体的同种异体 HCT： 一个。单甲基 Aurostatin E 偶联抗 CD30 抗体 (SGN35) 用于治疗复发或难治性 HL。 b.用于费城染色体阳性白血病的酪氨酸激酶抑制剂。 c.抗 CD20 抗体利妥昔单抗用于治疗 CD20 阳性 B 细胞 NHL 和氟达拉滨难治性 CLL。 该项目的公共健康益处是患有各种恶性血液疾病的患者。 否则会因年龄和合并症而被排除在外 同种异体 HCT。此外，HLA半相合供体的使用将HCT的选择范围扩大到更多 患者数量，包括少数民族。