Mechanisms regulating chimeric antigen receptor T-cell activity in cancer

项目总结 建议的研究重点是确定嵌合抗原受体(CAR)T细胞的分子调节因子。 细胞具有抗癌活性。汽车疗法因其在治疗中的有效性而引起了极大的热情。 对于B细胞肿瘤，然而，显著的限制仍然阻碍了其更广泛的成功。大约1/2的 非霍奇金淋巴瘤患者无反应，反映细胞毒性失败，许多患者 急性淋巴细胞性白血病患者治疗后因CAR T细胞持久力失败而复发。这个 提出的研究旨在确定CAR T细胞中这些基本T细胞功能是如何调节的。 初步数据表明，死亡受体，即启动细胞凋亡的表面蛋白，在CAR-T中是必不可少的。 细胞毒性。利用来自Penn‘s Car的T细胞和肿瘤样本的分子图谱和基因编辑 在临床试验中，我将确定死亡受体在汽车驱动的细胞毒性和肿瘤逃逸中的机制作用。 持久性是通过免疫记忆的形成来调节的，数据显示CARS激活了细胞 抑制记忆形成的程序。这项提案中概述的研究将利用异种移植小鼠 确定PI3K信号通路的CAR激活如何阻碍白血病形成的人类白血病模型 并损害CAR T细胞的持久性。利用临床试验样本，这项工作将进一步旨在 使用蛋白质组和磷蛋白质组分析确定限制持久性的其他分子途径。 拟议的五年培训计划的目标是发展我的独立研究事业 作为一名专注于细胞免疫疗法的内科科学家。我在内科完成了住院医师培训 医学，我正在接受血液学/肿瘤学奖学金培训的最后一年。我现在正在扩展我的 分子生物学和免疫学方面的科学专长，以及同种异体基因治疗的临床专长 造血细胞移植。我在不久的将来的目标是发展必要的技能来驾驶一辆 独特的科学调查方案。具体地说，我寻求获得基因组编辑方面的专业知识， 通过蛋白质组学和计算生物学的教学和实践训练，以增强我的科学能力 掌握技能并建立独立性。我的长期目标是提高T细胞免疫疗法的疗效和 改善血液病患者的预后。我将由卡尔·琼博士指导，他是一位国际医生 他是细胞免疫治疗领域的领导者，装备精良，能为我提供成功所需的指导。 为了增加我的科学和职业指导的广度和深度，我成立了一个指导委员会 由杰出的科学家组成。宾夕法尼亚大学在细胞免疫治疗领域处于领先地位 科学和临床实践，为我作为细胞治疗研究员的培训提供了理想的环境。 拟议中的研究有可能为汽车生物学提供关键的见解。技术的应用 询问临床试验样本并剖析限制CAR活动的机制的尖端技术 将确定预测成功的功能，并直接为更有效的汽车疗法的设计提供信息。

PROJECT SUMMARY The proposed research focuses on defining the molecular regulators of chimeric antigen receptor (CAR) T- cell activity against cancer. CAR therapy has generated great enthusiasm in light of its efficacy in the treatment of B-cell neoplasms, however significant limitations still prevent its broader success. Approximately ½ of patients with non-Hodgkin lymphoma do not respond, reflecting a failure of cytotoxicity, and many patients with acute lymphoblastic leukemia relapse after treatment due to a failure of CAR T-cell persistence. The studies proposed aim to determine how these essential T-cell functions are regulated in CAR T cells. Preliminary data suggest that death receptors, surface proteins that initiate apoptosis, are essential in CAR T- cell cytotoxicity. Using molecular profiling and gene editing of T-cell and tumor samples from Penn's CAR clinical trials, I will define the mechanistic role of death receptors in CAR-driven cytotoxicity and tumor escape. Persistence is mediated by the formation of immune memory, and data show that CARs activate cellular programs that suppress memory formation. The studies outlined in this proposal will utilize xenograft mouse models of human leukemia to determine how CAR activation of the PI3K signaling pathway impedes formation of memory cells and impairs CAR T-cell persistence. Using clinical trial samples, this work will further aim to identify additional molecular pathways that limit persistence using proteomic and phosphoproteomic analysis. The goal of the proposed five-year training program is the development of my independent research career as a physician-scientist focused on cellular immunotherapies. I completed residency training in Internal Medicine and am in my final year of fellowship training in Hematology/Oncology. I am now expanding my scientific expertise in molecular biology and immunology, as well as clinical expertise in allogeneic hematopoietic cell transplantation. My goal for the near future is to develop the skills necessary to drive a distinctive program of scientific investigation. Specifically, I seek to gain expertise in genome editing, proteomics and computational biology through didactic and practical training in order to augment my scientific skillset and establish independence. My long-term goal is to enhance the efficacy of T-cell immunotherapy and improve outcomes for patients with hematologic cancers. I will be mentored by Dr. Carl June, an international leader in cellular immunotherapy who is well equipped to provide me with the mentorship I need to succeed. To add breadth and depth to my scientific and career guidance, I have assembled a Mentoring Committee composed of exceptional scientists. The University of Pennsylvania had led the field of cellular immunotherapy science and clinical practice, and provides the ideal environment for my training as a cell therapy investigator. The proposed studies have the potential to provide critical insight into CAR biology. The application of cutting-edge techniques to interrogate clinical trial samples and dissect the mechanisms limiting CAR activity will identify features that predict success and directly inform the design of more effective CAR therapies.