Biology and Transplantation of the Hematopoietic Stem Cell

描述(申请人提供)：淋巴-造血系统癌症是发病率和死亡率的主要原因，随着人口老龄化和更多的人在先前的癌症中存活下来，骨髓增生异常综合征和非霍奇金淋巴瘤的发病率不断上升。异基因造血干细胞移植(HSCT)对一部分常规化疗失败或已知失败风险较高的患者是治愈的。然而，这一潜在的挽救生命的程序在可获得性方面受到限制，本身就与发病率和死亡率的高风险有关，主要是由于免疫并发症，包括移植物抗宿主病(GVHD)和免疫重建缓慢。对于那些在移植治疗的直接风险中幸存下来的人来说，复发仍然是一个障碍。为了促进脐带血(UCBT)后淋巴-造血恢复，在项目1中，我们建议1)确定大剂量UCB CD34细胞对免疫重建速度的影响，2)优化T调节细胞的剂量以预防急性GVHD，3)优化胸腺前体细胞的体外扩增以加速免疫恢复。为了设计一种更安全和更有效的预防和治疗白血病复发的过继T细胞疗法，在项目2中，我们建议：1)证明药物调控的抗hCD19SFv嵌合抗原受体(CAR)表达的T细胞可以根除恶性CD19 B细胞，确定CAR的持久性是否依赖于肿瘤或宿主来源的B细胞抗原信号，并证明药物拮抗剂的输注可以通过阻止二聚体来迅速停止CAR信号；2)证明人类T干细胞可以被重新编程和基因修饰以表达CARS，为过继肿瘤免疫治疗提供自我更新的CAR-TSM细胞，以提高存活率。4)识别和验证TSM状态的基本调节因素，以进一步优化基于TSM的汽车治疗。为了设计一种安全和更有效的针对复发治疗的过继NK细胞疗法，在项目3中，我们建议1)确定具有强大而持久的抗白血病活性的适应性NK细胞分化的潜在机制，并在I期试验中诱导它们的扩张，以消除复发白血病患者的白血病母细胞，以及2)在UCBT后复发的CD33恶性肿瘤患者中使用双特异性杀伤分子(Bike)抗体优化NK激活和肿瘤靶向。这些策略中的每一种都是高度创新的，无论是单独还是联合使用，都有很大的希望克服以前限制生存的最重要的障碍-免疫功能低下和复发-以及继续我们长期持有的实现UCB在移植医学中的全部潜力的兴趣。

DESCRIPTION (provided by applicant): Cancers of the lympho-hematopoietic system are a major cause of morbidity and mortality, with an increasing incidence of myelodysplastic syndrome and non-Hodgkins Lymphoma as the population ages and greater numbers survive prior cancers. Allogeneic hematopoietic stem cell transplant (HSCT) is curative in a proportion of patients who otherwise fail conventional chemotherapy or are known to be high risk of failure. However, this potentially life-saving procedure is restricted in its availability and is itself associated with the high risks of morbidity and mortality, primarily from immunological complications, including graft-versus-host disease (GVHD), and slow immune reconstitution. For those that survive the immediate risks of transplant therapy, relapse is still an obstacle. Toward our goal of facilitating lympho-hematopoietic recovery after umbilical cord blood (UCBT), in Project 1, we propose to 1) determine the impact of large doses of UCB CD34+ cells on the pace of immune reconstitution, 2) optimize dosing T regulatory cells for prevention of acute GVHD, and 3) optimize ex vivo expansion of thymic progenitors for accelerating immune recovery. Toward our goal of engineering a safer and more effective adoptive T cell therapy for leukemia relapse prevention and treatment, in Project 2, we propose to 1) demonstrate that drug regulated anti-hCD19SFv chimeric antigen receptor (CAR) expressing T cells can eradicate malignant CD19+ B cells, determine whether CAR persistence is dependent upon tumor- or host- derived B cell antigenic signals, and demonstrate that infusion of drug antagonists can rapidly halt CAR signaling by precluding dimerization, 2) demonstrate that human T stem-memory (Tsm) cells can be reprogrammed and genetically modified to express CARs providing self-renewable CAR-Tsm cells for adoptive tumor immunotherapy with enhanced survival, and 4) identify and validate essential regulators of the Tsm state to further optimize Tsm-based CAR therapy. And, toward our goal of engineering a safe and more effective adoptive NK cell therapy for relapse treatment, in Project 3 we propose to 1) determine the mechanism underlying the differentiation of adaptive NK cells which have potent and long-lived anti-leukemia activity, and induce their expansion in a phase I trial to eliminate leukemic blasts in patients with relapsed leukemia, and 2) optimize NK activation and tumor-targeting using bispecific killer engager (BiKE) antibodies with a subsequent 'first-in-human' clinical trial in patients with relapsed CD33+ malignancy after UCBT. Each of these strategies is highly innovative with substantial promise individually and in combination for overcoming the most important barriers - immunoincompetence and relapse - previously limiting survival as well as continuing our long-held interest in realizing the full potential of UCB in transplant medicine.