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: 7585358
• 负责人: DAVID G MALONEY
• 金额: $ 22.2万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585358
• 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; Cyclosporins; 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; Malignant Neoplasms; Modeling; Multiple Myeloma; Non-Hodgkin' s Lymphoma; Patients; Peripheral Blood Stem Cell; Philadelphia Chromosome; Progress Reports; Proliferating; Protocols documentation; Public Health; Refractory; Relapse; Risk; Stem cells; Tacrolimus; Toxic effect; Transplantation; Treatment Protocols; Tyrosine Kinase Inhibitor; conditioning; ethnic minority population; flu; fludarabine; high risk; improved; leukemia; mortality; mycophenolate mofetil; response; rituximab; tositumomab; tumor; tumor progression; tumor specificity

PROJECT 4: ALLOGENEIC HCT FORHEMATOLOGIC MALIGNANCIES: PHARMACOLOGIC MANIPULATIONS 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.

项目4：同种异体HCT FROHATOLOGIC恶性肿瘤：药理操纵 低剂量TBI（2 Gy）+/-氟达拉滨（30 mg/m2 x 3）和后移植后的非甲状腺素调节 用环孢星和霉酚酸酯的免疫抑制可提供可靠的植入 来自HLA匹配的相关供体或无关的供体的同种异体G-CSF动员了外周血干细胞。这 产生全面的供体嵌合，并提供免疫学的移植物-VS肿瘤（GVT）效应。确实，这样 平台，几乎所有的抗肿瘤活动都来自GVT免疫反应 条件方案。我们的结果表明，此响应可能会提供长期的抗肿瘤 许多B细胞恶性肿瘤患者的活性在低度患者中注意到 非霍奇金淋巴瘤（NHL），地幔细胞NHLAND慢性淋巴细胞性白血病（CLL）。局限性 进近也很明显，因为可能会出现侵略性，笨重或快速增殖的患者 肿瘤进展前或尽管GVT效应。项目4的重点是增加 通过改善，非乳不公动条件对B细胞恶性肿瘤治疗的抗肿瘤作用 移植前的细胞减少，增强同种异体GVT效应，并将其他药物与 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 通过使用新的捐助者匹配的相关或不相关的捐助者 HLA单倍体移植物。具体目的是使用： 1。使用细胞补充性高剂量疗法和自体造血细胞的串联移植 移植（HCT），然后是非甲状腺素同种异体HCT的。 一个。 HLA与淋巴瘤相关或无关供体的同种异体HCT匹配。 b。 HLA匹配相关或无关供体的同种异体HCT，然后进行维护治疗 与硼替佐米一起用于高风险或复发多发性骨髓瘤（mm）。 ; c。 HLA单倍体同种异体HCT与复发或难治性淋巴瘤相关的供体。 2。在流感/TBI的非甲状腺不全能条件中添加靶向疗法，然后 来自HLA的同种异体HCT匹配相关或无关的供体： 一个。单甲基极抑制素E共轭抗CD30抗体（SGN35）用于复发或难治性HL。 b。费城染色体阳性白血病的酪氨酸激酶抑制剂。 c。 CD20阳性B细胞NHL和Fludarabine难治性CLL的抗CD20抗体利妥昔单抗。 该项目的公共卫生益处是患有各种恶性血液疾病的患者。 否则，由于年龄和合并症而受益于 同种异体HCT。陷入困境，使用HLA-HAPLOIDENTIL捐赠者将将HCT的选择扩展到更大的选择 包括少数民族在内的患者人数。