Optimization of adoptive immunotherapy with autologous CD20-specific T cells

自体 CD20 特异性 T 细胞过继免疫治疗的优化

• 批准号: 8638901
• 负责人: Brian Till
• 金额: $ 17.17万
• 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: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638901
• 关键词: Ablation; Academic Medical Centers; Address; Adoptive Immunotherapy; Adoptive Transfer; Advisory Committees; Allogenic; American; Antibody Therapy; Antigens; Appointment; Area; Attenuated; Autoimmune Process; Autologous; Autologous Stem Cell Transplantation; Award; B-Cell Lymphomas; B-Lymphocytes; Binding; Biometry; CD28 gene; Cancer Etiology; Cell membrane; Cell physiology; Cell surface; Cells; Cellular biology; Chemicals; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Comprehensive Cancer Center; Development; Development Plans; Diagnosis; Disease; Disease Outcome; Dose; Educational workshop; Equipment; Faculty; Fred Hutchinson Cancer Research Center; Funding; Generations; Goals; Golgi Apparatus; Golgi Targeting; Grant; Housing; Human; Immune response; Immunologic Techniques; Immunologics; Immunotherapeutic agent; Immunotherapy; Institution; Investigational New Drug Application; Laboratories; Lead; Lentivirus Vector; Lymphoma; Lymphopoiesis; MS4A1 gene; Mediating; Medical Research; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Nature; Non-Hodgkin' s Lymphoma; Outcome; Patients; Peer Review; Phase; Physicians; Positioning Attribute; Predisposition; Principal Investigator; Protein Biosynthesis; Publications; Recombinant DNA; Refractory; Refractory Disease; Regulation; Regulatory T-Lymphocyte; Relapse; Research; Research Personnel; Research Project Grants; Resources; Safety; Salvage Therapy; Scientist; Series; Signal Transduction; Stem cell transplant; Surface; T cell therapy; T-Cell Lymphoma; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Training; Translational Research; Transplantation; Tumor Escape; United States; United States National Institutes of Health; Universities; Washington; Work; aggressive therapy; base; career; career development; caspase-9; chemotherapy; chimeric antigen receptor; cytotoxic; design; effective therapy; experience; gene therapy; genetically modified cells; hematopoietic cell transplantation; improved; improved functioning; innovation; medical schools; member; neoplastic cell; novel; novel strategies; outcome forecast; pre-clinical; prevent; professor; research facility; research study; response; safety testing; skills; small hairpin RNA; suicide gene; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): Optimization of adoptive immunotherapy with autologous CD20-specific T cells Non-Hodgkin lymphoma is diagnosed in more than 70,000 Americans each year, and aggressive B-cell lymphomas comprise approximately 35-40% of these cases. Significant proportions of patients relapse or have refractory disease after induction chemotherapy, and the outcomes for these patients are poor. We propose here a novel immunologic therapy for these diseases, using adoptive immunotherapy with genetically modified CD20-specific T cells. CANDIDATE: Dr. Till is an Assistant Member in the Clinical Research Division at the Fred Hutchinson Cancer Research Center (FHCRC) and Assistant Professor in the University of Washington (UW) School of Medicine with 6 years of experience as principal investigator of two phase I adoptive immunotherapy clinical trials using genetically modified T cells. His career goal is to be an independent translational physician-scientist using T cell-based immunotherapeutic to treat lymphoma at a major academic medical center. He gives many indications that he will be successful in his goals, with 6 first-authored peer-reviewed publications, several awards including pilot research grants and career development grants, and a recent appointment to a full faculty position. During the K23 career development period, he intends to address areas of deficiency in laboratory experience, regulatory management, biostatistics, and clinical trial design, using a combination of hands-on experience, formal coursework, intensive workshops, and mentored guidance. The proposed research strategy and 4-year career development plan will provide excellent training for Dr. Till and will allow him to b highly competitive to apply for R01 funding during the last 2 years of the K23 award period. ENVIRONMENT: Dr. Till is fortunate to be in an outstanding position for launching a career in academic medicine. His mentor, Dr. Oliver Press, has >25 years' experience as a leader in translational research developing immunologic therapies for lymphoma, abundant grant funding, and a strong track record of mentoring young investigators to independence. The UW is one of the leading academic medical research institutions in the world, consistently in the top 3 recipients of NIH funding. The FHCRC is an NCI-designated comprehensive cancer center with a focus in immunologic research that has produced 3 Nobel laureates among its faculty. The FHCRC houses world-class research facilities that are available for Dr. Till's use, including a GMP Cell Processing Facility in which clinical grade genetically modified autologous T cells are generated and expanded for use in the clinical trial described in Aim 1, as well as extensive shared equipment and resources encompassing all of the needs for Dr. Till's proposed laboratory experiments. Dr. Till has also assembled an extremely strong team of consultants, including Dr. Stanley Riddell, a world leader in adoptive T cell therapy, Drs. Jeffrey and Martha Ledbetter, experts in T cell biology and development of immunologic therapeutics, and Dr. Ted Gooley, an excellent biostatistician. RESEARCH: The research plan designed by Dr. Till and his mentor is well-suited to developing the skills he needs to become an independent investigator. The clinical trial in Aim 1 will provide valuable experience in navigating regulatory issues such as FDA Investigational New Drug application, NIH Recombinant DNA Advisory Committee, etc., as well as managing the many other facets of a gene therapy trial as principal investigator. In this trial, autologous T cells modified with a lentiviral vector encoding a CD20-specific chimeric antigen receptor (CAR) with CD28 and CD137 (4-1BB) costimulatory domains and an inducible caspase 9 safety switch will be expanded and infused into patients with relapsed or refractory aggressive B cell lymphoma following autologous stem cell transplantation. We believe this approach addresses several of the weaknesses identified in our two previous CD20 CAR clinical trials, and will be a highly effective treatment. Ideally, this adoptive T cell therapy approach would be applicable in the non-transplant setting, and given the difficult nature of treating relapsed or refractory aggressive B cell lymphomas, it is likely that further augmentation of CAR T cell function is needed. In Aims 2 and 3 we outline a novel strategy to improve CAR T cell function through CTLA-4 blockade, in a series of experiments that is designed to provide Dr. Till with intensive experience in the laboratory using a wide array of immunological techniques. In these experiments, T cells will be modified to co-express anti-CTLA-4 scFv-Ig as well as a 3rd-generation fully-human anti-CD20 CAR. The anti-CTLA-4 scFv-Ig will be expressed as either 1) a surface-bound or Golgi-targeted molecule that will effectively prevent or reduce CTLA-4 expression; and 2) as a secreted molecule that hypothesize will have an inhibitory effect on regulatory T cells in the tumor microenvironment. Knockdown of CTLA-4 synthesis using shRNA is another potential strategy to improve the function of CAR-expressing effector T cells through checkpoint inhibition. We are confident that this innovative research plan will provide Dr. Till with a strong transition to independence as an investigator. Furthermore, we are optimistic that the resulting work will have widespread applicability in the field of adoptive T cel immunotherapy, and will ultimately lead to a well- tolerated and potentially curative treatment for aggressive B cell lymphomas.

描述（由申请人提供）：用自体 CD20 特异性 T 细胞优化过继性免疫疗法每年有超过 70,000 名美国人被诊断出非霍奇金淋巴瘤，其中侵袭性 B 细胞淋巴瘤约占这些病例的 35-40%。很大一部分患者在诱导化疗后复发或出现难治性疾病，并且这些患者的预后很差。我们在这里提出了一种针对这些疾病的新型免疫疗法，即使用转基因 CD20 特异性 T 细胞的过继免疫疗法。候选人：Till 博士是 Fred Hutchinson 癌症研究中心 (FHCRC) 临床研究部的助理成员，也是华盛顿大学 (UW) 医学院的助理教授，拥有 6 年担任使用转基因 T 细胞的 I 期过继免疫治疗临床试验首席研究员的经验。他的职业目标是成为一名使用 T 的独立转化医师科学家 在一家大型学术医疗中心使用基于细胞的免疫疗法来治疗淋巴瘤。他多次表示自己将成功实现自己的目标，发表了 6 篇第一作者的同行评审出版物，获得了多项奖项，包括试点研究资助和职业发展资助，并且最近被任命为正式教职。在K23职业发展期间，他打算结合实践经验、正式课程、强化研讨会和导师指导来解决实验室经验、监管管理、生物统计学和临床​​试验设计方面的不足领域。拟议的研究策略和4年职业发展计划将为Till博士提供出色的培训，并使他在K23奖励期的最后2年申请R01资助时具有高度竞争力。环境：蒂尔博士很幸运能够在学术医学领域开启职业生涯。他的导师 Oliver Press 博士作为淋巴瘤免疫疗法转化研究领域的领导者拥有超过 25 年的经验、丰富的资助资金以及指导年轻研究人员独立的良好记录。华盛顿大学是世界领先的学术医学研究机构之一，一直位居美国国立卫生研究院 (NIH) 资助的前三名。 FHCRC 是 NCI 指定的综合性癌症中心，专注于免疫学研究，其教员中培养了 3 名诺贝尔奖获得者。 FHCRC 拥有可供 Till 博士使用的世界一流的研究设施，包括 GMP 细胞处理设施，用于生成和扩增临床级转基因自体 T 细胞，用于目标 1 中描述的临床试验，以及广泛的共享设备和资源，涵盖 Till 博士提议的实验室实验的所有需求。 Till 博士还组建了一支极其强大的顾问团队，其中包括过继性 T 细胞疗法的世界领先者 Stanley Riddell 博士、 Jeffrey 和 Martha Ledbetter 是 T 细胞生物学和免疫疗法开发方面的专家，Ted Gooley 博士是一位出色的生物统计学家。研究：蒂尔博士和他的导师设计的研究计划非常适合培养他成为独立研究者所需的技能。 Aim 1 的临床试验将为解决监管问题（如 FDA 新药研究申请、NIH 重组 DNA 咨询委员会等）以及作为首席研究员管理基因治疗试验的许多其他方面提供宝贵的经验。在这项试验中，用慢病毒载体修饰的自体 T 细胞将被扩增，并在自体干细胞移植后输注到复发或难治性侵袭性 B 细胞淋巴瘤患者中，该慢病毒载体编码具有 CD28 和 CD137 (4-1BB) 共刺激结构域的 CD20 特异性嵌合抗原受体 (CAR) 和诱导型 caspase 9 安全开关。我们相信这种方法解决了我们之前两项 CD20 CAR 临床试验中发现的几个弱点，并且将是一种非常有效的治疗方法。理想情况下，这种过继性 T 细胞治疗方法将适用于非移植环境，并且考虑到治疗复发性或难治性侵袭性 B 细胞淋巴瘤的困难性，有可能进一步增强 需要了解 CAR T 细胞功能。在目标 2 和 3 中，我们概述了一种通过 CTLA-4 阻断来改善 CAR T 细胞功能的新策略，通过一系列实验，旨在为 Till 博士提供使用各种免疫学技术的实验室丰富经验。在这些实验中，T细胞将被修饰以共表达抗CTLA-4 scFv-Ig以及第三代全人抗CD20 CAR。抗 CTLA-4 scFv-Ig 将表达为： 1) 表面结合或高尔基体靶向分子，可有效预防或减少 CTLA-4 表达； 2) 作为一种分泌分子，假设会对肿瘤微环境中的调节性 T 细胞产生抑制作用。使用 shRNA 敲低 CTLA-4 合成是通过检查点抑制改善表达 CAR 的效应 T 细胞功能的另一种潜在策略。我们相信，这一创新研究计划将为蒂尔博士提供一个强有力的过渡，以成为一名独立的研究者。此外，我们乐观地认为，由此产生的工作将在过继性 T 细胞免疫治疗领域具有广泛的适用性，并最终为 T 细胞免疫疗法带来良好的耐受性和潜在的治愈性治疗。 侵袭性 B 细胞淋巴瘤。