Targeting Leukemia with Memory CD8+ T cells Transduced to Express High-Affinity W

应聘者描述(由申请人提供)：应聘者的目标是成为实验室的首席研究员，该实验室配备有执行翻译研究的能力，重点是研究调节免疫系统以针对癌症的新方法。由于她已获得大部分相关培训以实现这一目标，K08将使她在获得独立助理教授身份之前完成最后的步伐。具体地说，候选人渴望解决高危白血病患者异基因造血细胞移植(HCT)后的复发问题，因为这仍然是治疗失败和死亡的重要原因。针对WT1的CD8+T细胞克隆是一种在白血病细胞中过度表达的蛋白质，在白血病干细胞(LSC)中的表达水平最高，来自HLA相合的捐赠者产生的CD8+T细胞克隆在HCT后给予没有明显毒性，并观察到优先定位于骨髓。然而，在一些患者中，由于缺乏体内长期的T细胞持久性，对WT1靶点的亲和力低，抗白血病效果有限，并且可能通过同时靶向额外的表位而得到增强。为了解决这些障碍，该项目建议在I/II期试验中，从匹配的捐赠者中产生EBV或CMV特异性的记忆T细胞，并将它们转导为表达高亲和力的WT1特异性TCR，然后在HCT后高危AML、CML和MDS患者中输注。候选人将评估移植细胞的安全性、持久性、局部性和功能，并将参数与处于CR(临床研究臂1)的HCT后患者预防复发的有效性以及转移细胞在可检测到的疾病患者中的潜在抗白血病活性(临床研究臂2)相关联。然后，她建议通过测试是否可以产生来自白血病捐赠者的非基因修饰的T细胞产品，以探索以新发现的LSC和癌症睾丸抗原CCNA1为靶点的T细胞疗法的可行性，以用于未来的临床试验，以评估安全性。同时，她将筛选CCNA1特异性的高亲和力/亲和力CD8+T细胞克隆，并分离它们的TCR，以用于潜在的现成试剂。如果单独针对任何一种抗原的安全性得到证明，这些试剂可以在未来的临床试验中同时使用。应聘者将接受最近开发的基于质谱学的新方法的高级培训，以同时评估输注的T细胞的多个参数，以及基于流式细胞术的方法、生物统计学、分子免疫学和FDA相关的基因修饰临床试验的监管行为。研究和培训活动将主要在弗雷德·哈钦森癌症研究中心进行，这是一个非常适合基础、临床和翻译研究的环境，特别是在HCT领域。候选人将由菲尔·格林伯格博士指导，他是一位经验丰富、成功的导师，在翻译免疫学和免疫疗法领域拥有成熟的职业生涯。拟议的翻译研究旨在为AML、MDS和CML患者开发有效、无毒的治疗方法，确定成功根除白血病的免疫学参数，并指导针对LSC蛋白的高亲和力T细胞的设计和安全部署。具体目的是：1.在I/II期临床试验中评价供体来源的C4-CTL的安全性和潜在疗效 预防AML/MDS/CML复发高危缓解患者的复发。2.在I/II期中评估Don R来源的C4-CTL在MRD或复发AML/MDS/CML患者中的安全性、有效性和抗白血病活性的潜在局限性。3.探索T细胞治疗靶向CCNA1作为WT1的替代靶抗原的可能性。

DESCRIPTION (provided by applicant): The candidate's objective is to become the principal investigator of a laboratory equipped to perform translational studies focusing on novel ways to modulate the immune system to target cancer. As she has obtained a large part of the relevant training to achieve this goal, the K08 would allow her to complete the final strides before achieving independent Assistant Professor status. Specifically, the candidate aspires to address relapse after allogeneic hematopoietic cell transplantation (HCT) in patients with high-risk leukemias as this remains a significant cause of treatment failure and death. CD8+ T-cell clones specific for WT1, a protein that is over-expressed in leukemic cells with the highest levels expressed in leukemic stem cells (LSC), generated from HLA-matched donors have been administered after HCT without significant toxicity and observed to preferentially localize to the marrow. However, anti-leukemic efficacy was limited in some patients by the lack of long-term in vivo T-cell persistence, low avidity for the WT1 target, and may have been enhanced by simultaneously targeting additional epitopes. To address these obstacles, this project proposes in a Phase I/II trial, to generate EBV- or CMV-specific memory T cells from matched donors and transduce them to express a high affinity WT1-specific TCR before infusion in patients with high-risk AML, CML and MDS post-HCT. The candidate will assess the safety, persistence, localization and function of the transferred cells and correlate the parameters with the efficacy o preventing relapse in post-HCT patients who are in CR (Clinical Study Arm 1), and the potential antileukemic activity of transferred cells in patients with detectable disease (Clinical Study Arm 2). She then proposes to explore the feasibility of targeting the newly identified LSC and cancer testis antigen CCNA1 with T cell therapy by testing if non-gene modified T-cell products from leukemic donors can be generated for use in future clinical trials to assess safety. In parallel, she will screen for CCNA1-specific high-avidity/affinity CD8+ T cell clones, and isolate their TCR for potential use as 'off the shelf' reagents. If safety of targeting either antigen alone is demonstrated, these reagents could be used concurrently in future clinical trials. The candidate will receive advanced training in recently developed novel mass spectrometry- based methods to assess multiple parameters simultaneously on infused T-cells in addition to flow cytometry- based methods, biostatistics, molecular immunology, and FDA related regulatory conduct of gene-modified clinical trials. The research and training activities will be primarily conducted at the Fred Hutchinson Cancer Research Center, which is a superb environment for basic, clinical and translational research, particularly in the field of HCT. The candidate will be mentored by Dr Phil Greenberg, an experienced and successful mentor who has an established career in the field of translational immunology and immunotherapy. The proposed translational studies are aimed at developing potent, non-toxic treatments for patients with AML, MDS and CML, determining immunologic parameters for successful leukemia eradication, and guiding the design and safe deployment of high-affinity T cells targeting LSC proteins. The Specific Aims are: 1. Evaluate in a phase I/II trial the safety and potential efficacy of donor-derived C4-CTL in preventing relapse in remission patients at high risk of AML/MDS/CML recurrence. 2. Evaluate in a Phase I/II the safety, efficacy and potential limitations to the anti-leukemic activity of donr- derived C4-CTL in patients with MRD or recurrent AML/MDS/CML. 3. Explore the potential for targeting CCNA1 with T cell therapy as an alternate target antigen to WT1.