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

描述（由申请人提供）：候选人的目标是成为一个实验室的主要研究者，该实验室配备有进行翻译研究的设备，重点是调节免疫系统以靶向癌症的新方法。由于她已经获得了很大一部分相关培训，以实现这一目标，K 08将允许她完成最后的步伐，实现独立助理教授的地位。具体而言，候选人希望解决高风险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。在HCT后，已经施用了对WT 1特异的CD 8 + T细胞克隆，该CD 8 + T细胞克隆是在白血病干细胞（LSC）中表达水平最高的白血病细胞中过表达的蛋白质，该CD 8 + T细胞克隆产生自HLA匹配的供体，没有显著毒性，并且观察到优先定位于骨髓。然而，由于缺乏长期体内T细胞持久性、对WT 1靶点的低亲合力，抗白血病疗效在一些患者中受到限制，并且可能通过同时靶向其他表位而增强。为了解决这些障碍，该项目在I/II期试验中提出，从匹配的供体中产生EBV或CMV特异性记忆T细胞，并在输注给HCT后的高危AML，CML和MDS患者之前使其表达高亲和力WT 1特异性TCR。候选人将评估转移细胞的安全性、持久性、定位和功能，并将参数与预防CR后HCT患者复发的疗效（临床研究组1）以及转移细胞在可检测疾病患者中的潜在抗白血病活性（临床研究组2）相关联。然后，她建议通过测试白血病供体的非基因修饰的T细胞产物是否可以用于未来的临床试验以评估安全性，来探索用T细胞疗法靶向新发现的LSC和癌症睾丸抗原CCNA 1的可行性。同时，她将筛选CCNA 1特异性高亲和力/亲和力CD 8 + T细胞克隆，并分离其TCR作为“现成”试剂的潜在用途。如果证明单独靶向任一抗原的安全性，则这些试剂可在未来的临床试验中同时使用。候选人将接受最近开发的基于质谱的新方法的高级培训，以同时评估输注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，分子免疫学和基因修饰临床试验的FDA相关监管行为。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，该中心是基础，临床和转化研究的绝佳环境，特别是在HCT领域。候选人将由Phil Greenberg博士指导，他是一位经验丰富且成功的导师，在转化免疫学和免疫治疗领域拥有成熟的职业生涯。拟议的转化研究旨在为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，并指导靶向LSC蛋白的高亲和力T细胞的设计和安全部署。具体目标是：1。在I/II期试验中评估供体来源的C4-CTL在 预防AML/MDS/CML复发高风险缓解患者的复发。2.在I/II期研究中评价供体来源的C4-CTL在MRD或复发性AML/MDS/CML患者中抗白血病活性的安全性、有效性和潜在局限性。3.探索用T细胞疗法靶向CCNA 1作为WT 1的替代靶抗原的潜力。

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.