Biology and Transplantation of the Hematopoietic Stem Cell

描述（由申请人提供）：淋巴-造血系统癌症是发病率和死亡率的主要原因，随着人口年龄的增长，骨髓增生异常综合征和非霍奇金淋巴瘤的发病率不断增加，既往癌症存活的人数也越来越多。同种异体造血干细胞移植（HSCT）可以治愈一部分常规化疗失败或已知失败风险高的患者。然而，这种可能挽救生命的手术在其可获得性方面受到限制，并且其本身与高发病率和死亡率相关，主要来自免疫并发症，包括移植物抗宿主病（GVHD）和缓慢的免疫重建。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）后淋巴造血恢复的目标，在项目1中，我们提出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)优化胸腺祖细胞的体外扩增以加速免疫恢复。为了实现我们设计一种更安全、更有效的过继T细胞疗法来预防和治疗白血病复发的目标，在项目2中，我们提出：1)证明药物调节的表达抗hcd19sfv嵌合抗原受体（CAR）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；2)证明人类T干细胞记忆（Tsm）细胞可以被重编程和基因修饰，以表达CAR，提供自我再生的CAR-Tsm细胞，用于过继性肿瘤免疫治疗，提高生存率；4)鉴定和验证Tsm状态的基本调节因子，以进一步优化基于Tsm的CAR治疗。而且，为了实现我们设计一种安全、更有效的用于复发治疗的适应性NK细胞疗法的目标，在项目3中，我们建议：1)确定适应性NK细胞分化的潜在机制，这些细胞具有有效和长期的抗白血病活性，并在I期试验中诱导其扩增，以消除复发性白血病患者的白血病原细胞；2)利用双特异性杀手接合器（BiKE）抗体优化NK激活和肿瘤靶向，随后在UCBT后复发的CD33+恶性肿瘤患者中进行“首次人体”临床试验。这些策略中的每一种都是高度创新的，具有巨大的希望，可以单独或结合起来克服最重要的障碍-免疫功能低下和复发-以前限制生存的障碍，并继续我们长期以来对实现移植医学中UCB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.