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

使用转染表达高亲和力 W 的记忆 CD8 T 细胞靶向白血病

• 批准号: 8574854
• 负责人: Aude Chapuis
• 金额: $ 17.14万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8574854
• 关键词: Acute Myelocytic Leukemia; Address; Adoptive Transfer; Affinity; Allogenic; Antigen Targeting; Antigens; Avidity; Basic Science; Biometry; Birth; Bone Marrow; CD34 gene; CD8B1 gene; Cause of Death; Cell Line; Cells; Cessation of life; Chronic Myeloid Leukemia; Clinical; Clinical Research; Clinical Trials; Cytomegalovirus; Cytotoxic T-Lymphocytes; Development; Disease; Disease remission; Donor Lymphocyte Infusion; Dose; Dysmyelopoietic Syndromes; Environment; Epitopes; Fetal Development; Flow Cytometry; Fred Hutchinson Cancer Research Center; Future; Gene-Modified; Goals; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human Herpesvirus 4; Immune system; Immunologics; Immunology; Immunosuppression; Immunotherapy; Infusion procedures; Kidney; Laboratories; Lentivirus Vector; Leukemic Cell; Leukocytes; Maintenance; Malignant Neoplasms; Marrow; Mass Spectrum Analysis; Mediating; Memory; Mentors; Mesoderm Cell; Methods; Molecular Immunology; Morbidity - disease rate; Nephroblastoma; Normal Cell; Organ; Outcome; Patients; Phase; Phase I/II Trial; Phenotype; Pleura; Principal Investigator; Proteins; Reagent; Recurrence; Recurrent disease; Relapse; Research; Research Activity; Risk; Safety; Schedule; Solid Neoplasm; Stem cells; T cell therapy; T memory cell; T-Lymphocyte; T-cell acute lymphocytic leukemia 1 protein; Testing; Testis; Toxic effect; Training; Training Activity; Translational Research; Treatment Failure; Tumor Antigens; Variant; Virus; Withdrawal; arm; base; cancer testis antigen; career; cellular transduction; chemotherapy; cyclin A1; design; experience; fighting; graft vs host disease; hematopoietic cell transplantation; high risk; in vivo; leukemia; leukemic stem cell; malignant phenotype; mortality; novel; pericardial sac; podocyte; prevent; professor; protein expression; public health relevance; receptor; response; screening; tool; transgene expression; translational study

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.

描述（由申请人提供）：候选人的目标是成为一个实验室的首席研究员，该实验室具备开展转化研究的能力，重点关注调节免疫系统以靶向癌症的新方法。由于她已经获得了实现这一目标的大部分相关培训，K08将让她完成获得独立助理教授身份之前的最后一步。具体来说，该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一个重要原因。 WT1 特异的 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) 中表达水平最高，由 HLA 匹配的供体产生，在 HCT 后施用，没有明显毒性，并观察到优先定位于骨髓。然而，由于体内 T 细胞缺乏长期持久性、对 WT1 靶标的亲和力较低，抗白血病功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来增强。为了解决这些障碍，该项目建议在 I/II 期试验中，从匹配的供体中产生 EBV 或 CMV 特异性记忆 T 细胞，并在输注给高危患者之前转导它们表达高亲和力 WT1 特异性 TCR HCT 后的 AML、CML 和 MDS。候选人将评估转移细胞的安全性、持久性、定位和功能，并将这些参数与预防 HCT 后 CR 患者复发的功效（临床研究组 1）以及转移细胞的潜在抗白血病活性相关联。患有可检测疾病的患者（临床研究第 2 组）。然后，她提议通过测试是否可以生成来自白血病供体的非基因修饰 T 细胞产品用于未来的临床试验以评估安全性，探索用 T 细胞疗法靶向新发现的 LSC 和癌症睾丸抗原 CCNA1 的可行性。与此同时，她将筛选 CCNA1 特异性高亲和力/亲和力 CD8+ T 细胞克隆，并分离其 TCR，以用作“现成”试剂。如果证明单独针对任一抗原的安全性，这些试剂可以在未来的临床试验中同时使用。除了基于流式细胞术的方法、生物统计学、分子免疫学和 FDA 相关基因修饰临床试验的监管行为之外，候选人还将接受最近开发的基于质谱的新型方法的高级培训，以同时评估输注 T 细胞的多个参数。研究和培训活动将主要在 Fred Hutchinson 癌症研究中心进行，该中心为基础、临床和转化研究（尤其是 HCT 领域）提供了绝佳的环境。候选人将受到 Phil Greenberg 博士的指导，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。具体目标是： 1. 在 I/II 期试验中评估供体来源的 C4-CTL 的安全性和潜在功效 预防 AML/MDS/CML 复发高风险的缓解患者复发。 2. 在 I/II 期中评估供体来源的 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 T 细胞疗法靶向 CCNA1 作为 WT1 替代靶抗原的潜力。