Adult Leukemia Research Center

项目总结/摘要 整体 该计划项目赠款的总体目标是为患有以下疾病的患者开发更好的治疗方法： 主要关注过继细胞治疗和造血细胞移植的血液恶性肿瘤 （HCT）。由于HCT通常提供最佳的治愈机会，全世界约有70，000名患者接受了HCT治疗。 血液恶性肿瘤的移植手术HCT后的疾病复发是导致肝硬化的主要原因。 治疗失败。通过基因转移工程化以表达合成的T细胞受体（TCR）或嵌合的T细胞 靶向肿瘤相关抗原的抗原受体（CAR）具有作为治疗剂的巨大潜力，但是 关于如何优化有效性、消除毒性以及如何将它们与HCT联合收割机结合，还有很多需要学习。 该计划项目资助的目标是为患有最严重疾病的患者开发有效的T细胞疗法。 同种异体HCT、急性髓性白血病（AML）和自体HCT的常见适应症，多发性 骨髓瘤，并确定移植物抗宿主病（GVHD）预防的类型，最好允许使用 HCT后的过继性T细胞治疗。这些目标将在三个互动项目中实现。 项目1将探索使用高亲和力WT 1特异性TCR的特异性过继免疫疗法的使用 转导的T细胞治疗未能实现初始完全应答的AML患者， 常规化疗。除了确定这种处理的毒性和功效外，本项目 将测试来自TN、TCM或TEBV的细胞是否在其行为上不同，并将解决TCR T细胞的特征 和急性髓细胞白血病，导致治疗的成功或失败。项目2将评估BCMA的安全性和有效性 本发明提供了用于治疗复发性多发性骨髓瘤患者的特异性CAR T细胞。与CAR T的直接比较 将制备含有两种不同共刺激结构域（CD 28与4-1BB）的细胞，以确定它们是否 疗效或毒性不同。进一步的实验将探索增强BCMA CAR T效用的方法。 包括增加靶细胞上BCMA表达或改善CAR T细胞功能的方法 来那度胺的细胞。在项目3中，两种预防GVHD的新方法， 将外周血HCT（TN细胞耗竭和HCT后环磷酰胺）与当前HCT进行比较。 标准护理，以确定哪种方法导致最高的无GVHD百分比，无复发 生存将评价骨髓和外周血淋巴细胞，以确定免疫重建 以及可能最好地支持随后的过继免疫治疗的因素。成功地追求 该计划项目的目标将为治疗AML和多发性骨髓瘤提供强有力的工具， 帮助确定在基因修饰T细胞时代预防GVHD的最佳方法。

Project Summary/Abstract Overall The overall goal of this Program Project Grant is to develop improved curative therapies for patients with hematological malignancies focusing primarily on adoptive cell therapy and hematopoietic cell transplantation (HCT). Because HCT often offers the best chance for cure, approximately 70,000 patients worldwide received transplants for hematological malignancies last year. Disease recurrence post HCT is the leading cause of treatment failure. T cells engineered by gene transfer to express a synthetic T cell receptor (TCR) or chimeric antigen receptor (CAR) targeting a tumor-associated antigen have great potential as therapeutic agents, but there is much to learn about how to optimize effectiveness, eliminate toxicities and combine them with HCT. The objectives of this Program Project Grant are to develop effective T cell therapies for patients with the most common indication for allogeneic HCT, acute myeloid leukemia (AML), and autologous HCT, multiple myeloma, and to define the type of graft-versus-host disease (GVHD) prophylaxis that will best allow the use of adoptive T cell therapy post HCT. These objectives will be pursued in three interactive projects. Project 1 will explore the use of specific adoptive immunotherapy using high affinity WT1-specific TCR transduced T cells to treat patients with AML who have failed to achieve an initial complete response with conventional chemotherapy. In addition to determining the toxicity and efficacy of such treatment, this Project will test if cells derived from TN, TCM, of TEBV differ in their behavior, and will address features of TCR T cells and AML that lead to success or failure of treatment. Project 2 will evaluate the safety and efficacy of BCMA specific CAR T cells for treatment of patients with recurrent multiple myeloma. A direct comparison of CAR T cells containing two different co-stimulatory domains, CD28 versus 4-1BB, will be made to determine if they differ in efficacy or toxicity. Further experiments will explore methods to enhance the utility of BCMA CAR T cells including approaches to increase expression of BCMA on target cells or improve the function of CAR T cells by exposure to lenalidomide. In Project 3, two novel approaches to GVHD prophylaxis following peripheral blood HCT (TN cell depletion and post-HCT cyclophosphamide) will be compared to the current standard of care to determine which approach results in the highest percent of GVHD-free, relapse-free survival. Bone marrow and peripheral blood lymphocytes will be evaluated to determine immune reconstitution as well as factors that may best support subsequent adoptive immunotherapy. Success in the pursuit of the goals of this Program Project will provide powerful tools for treating AML and multiple myeloma, and should help define the best approach to GVHD prevention in the era of gene-modified T cells.