Allogeneic HCT for Hematologic Malignancies: Pharmacologic Manipulations

非清髓性预适应应用小剂量TBI(2Gy2)/-氟达拉滨(30 mg/m2×3)和移植后 环孢素和霉酚酸酯联合免疫抑制提供了可靠的植入 同种异体粒细胞集落刺激因子动员的外周血干细胞来自于人类白细胞抗原相合的亲缘或非亲缘供者。这 导致完全供者嵌合，并提供免疫移植物抗肿瘤(GVT)效应。事实上，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，几乎没有贡献 调理养生法。我们的结果表明，这种反应可能提供长期的抗肿瘤作用。 许多B细胞恶性肿瘤患者的活性，其中低级别B细胞恶性肿瘤患者的活性显著 非霍奇金淋巴瘤(NHL)、套细胞淋巴瘤和慢性淋巴细胞白血病(CLL)。这方面的局限性 方法也很明显，因为患有侵袭性、块状或快速增殖性疾病的患者可能会发展成 在GVT发生之前或在GVT影响下肿瘤进展。项目4的重点是增强 改良非清髓性预适应治疗B细胞恶性肿瘤的抗肿瘤作用 移植前细胞减少，增强同种异体GVT效应，并加入额外的药物 具有抗肿瘤活性，毒性有限。最后，我们计划将这种方法推广到没有人类白细胞抗原的患者 匹配亲属或非亲属捐赠者，使用新的协议，允许成功植入相关的 人类白细胞抗原半相合移植物。具体目标是使用： 1.大剂量细胞还原疗法与自体造血细胞串联移植 移植(HCT)后进行非清髓性同种异体HCT： A.人类白细胞抗原与淋巴瘤相关或无关捐献者的同种异体血细胞移植相匹配。 B.有血缘关系或无血缘关系的捐献者的同种异体血细胞集落匹配，然后进行维持治疗 波特佐米用于高危或复发性多发性骨髓瘤(MM)。； 用于复发或难治性淋巴瘤的亲属供者的半相合同种异体血细胞移植。 2.在使用Flu/TBI的非清髓性条件反射基础上增加靶向治疗 血缘或非血缘关系相匹配的供者的同种异体血细胞移植： A.单甲基Aurostatin E偶联抗CD30抗体(SGN35)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。 抗CD20抗体利妥昔单抗治疗CD20阳性B细胞NHL和氟达拉滨难治性CLL。 该项目对公众健康的好处是，患有各种恶性血液疾病的患者。 否则就会因为年龄和合并症而被排除在外 异基因血细胞移植。此外，人类白细胞抗原半相合捐献者的使用将使血细胞移植的选择范围扩大到更大 患者数量，包括少数族裔。

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.