Adult Leukemia Research Center

项目摘要/摘要 总括 该计划项目赠款的总体目标是为患有癌症的患者开发改进的治疗方法。 血液系统恶性肿瘤主要集中在过继细胞治疗和造血细胞移植 (Hct)。由于HCT通常提供了最好的治愈机会，全球约有7万名患者接受了 去年接受了血液系统恶性肿瘤的移植手术。血细胞移植后疾病复发是导致 治疗失败。通过基因转移来表达合成T细胞受体(TCR)或嵌合体的T细胞 针对肿瘤相关抗原的抗原受体(CAR)具有巨大的治疗潜力，但 关于如何优化有效性、消除毒性并将其与HCT相结合，还有很多需要学习的地方。 该计划项目赠款的目标是为大多数患者开发有效的T细胞疗法 异基因HCT、急性髓系白血病(AML)和自体HCT的常见适应症，多 骨髓瘤，并确定移植物抗宿主病(GVHD)预防的类型将最好地允许使用 HCT后采用T细胞治疗。这些目标将通过三个互动项目来实现。 项目1将探索使用高亲和力WT1特异性TCR进行特定过继免疫治疗 转导T细胞治疗初治完全应答失败的AML患者 常规化疗。除了确定这种治疗的毒性和有效性外，该项目 将测试来自TEBV TN、Tcm、Tcm的细胞是否有不同的行为，并将解决TCR T细胞的特征 和急性髓系白血病，决定治疗的成败。项目2将评估BCMA的安全性和有效性 特异性CAR T细胞治疗复发性多发性骨髓瘤T型轿车的直接比较 含有两个不同共刺激结构域的细胞，CD28和4-1BB，将被用来确定它们是否 在效力或毒性上不同。进一步的实验将探索提高BCMA Car T实用性的方法 包括增加靶细胞上BCMA表达或改善CAR T功能的细胞 细胞暴露于来那度胺。在项目3中，以下是预防GVHD的两种新方法 将外周血红细胞压积(TN细胞耗尽和红细胞压积后环磷酰胺)与目前的 护理标准，以确定哪种方法可获得最高百分比的无GVHD、无复发GVHD 生死存亡。将评估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后续过继免疫治疗的因素。追求成功的目标 该计划项目的目标将为治疗AML和多发性骨髓瘤提供强大的工具，并应 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.