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: 8509478
• 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/8509478
• 关键词: Ablation; Academic Medical Centers; Address; Adoptive Immunotherapy; Adoptive Transfer; Advisory Committees; Allogenic; American; Antibody Therapy; Antigen Receptors; 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-Cell Receptor; 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; 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）：自体CD20特异性T细胞过继免疫治疗的优化每年有超过70，000名美国人被诊断为非霍奇金淋巴瘤，其中侵袭性B细胞淋巴瘤约占35 - 40%。诱导化疗后，相当比例的患者复发或患有难治性疾病，这些患者的结局很差。我们在这里提出了一种新的免疫治疗这些疾病，采用过继免疫治疗与遗传修饰的CD20特异性T细胞。候选人：Till博士是Fred哈钦森癌症研究中心（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年使用转基因T细胞进行的两项I期过继免疫治疗临床试验的主要研究者经验。他的职业目标是成为一名独立的翻译医生-科学家，使用T 在一个主要的学术医疗中心，以细胞为基础的免疫疗法治疗淋巴瘤。他给出了许多迹象表明，他将成功地在他的目标，与6个第一作者同行评审的出版物，几个奖项，包括试点研究补助金和职业发展补助金，以及最近任命为一个完整的教师职位。在K23职业发展期间，他打算解决实验室经验，监管管理，生物统计学和临床试验设计方面的不足，结合实践经验，正式课程，密集研讨会和指导指导。拟议的研究战略和4年职业发展计划将为Till博士提供良好的培训，并使他能够在K23奖期的最后2年内以B的竞争力申请R01资助。环境：蒂尔博士很幸运，能够在学术医学领域开展职业生涯。他的导师奥利弗出版社，有超过25年的经验，在转化研究开发淋巴瘤免疫疗法的领导者，丰富的赠款资金，并指导年轻的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是NIH资助的前三名。FHCRC是一个NCI指定的综合性癌症中心，专注于免疫学研究，其教师中有3位诺贝尔奖获得者。FHCRC拥有世界一流的研究设施，可供Till博士使用，包括GMP细胞处理设施，其中临床级遗传修饰的自体T细胞被生成和扩增，用于Aim 1中描述的临床试验，以及广泛的共享设备和资源，包括Till博士提出的实验室实验的所有需求。Till博士还组建了一个非常强大的顾问团队，包括过继性T细胞疗法的世界领导者Stanley里德尔博士，T细胞生物学和免疫疗法开发专家Jeffrey和Martha Ledbetter博士，以及优秀的生物统计学家Ted Gooley博士。研究：Till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中的临床试验将为FDA研究性新药申请、NIH重组DNA咨询委员会等监管问题提供宝贵的经验，以及作为首席研究员管理基因治疗试验的许多其他方面。在本试验中，将扩增用慢病毒载体修饰的自体T细胞，并将其输注到自体干细胞移植后复发性或难治性侵袭性B细胞淋巴瘤患者体内，所述慢病毒载体编码具有CD28和CD137（4 - 1BB）共刺激结构域和诱导型半胱天冬酶9安全开关的CD20特异性嵌合抗原受体（CAR）。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，并将成为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，很可能需要进一步加强 CAR T细胞的功能。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，在一系列实验中，这些实验旨在为Till博士提供使用广泛的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）将有效阻止或减少CTLA-4表达的表面结合或Golgi靶向分子;和2）假设将对肿瘤微环境中的调节性T细胞具有抑制作用的分泌分子。使用shRNA敲低CTLA-4合成是通过检查点抑制改善CAR表达效应T细胞功能的另一种潜在策略。我们相信，这一创新的研究计划将为蒂尔博士提供一个强大的过渡到独立的研究者。此外，我们乐观地认为，所产生的工作将在过继性T细胞免疫疗法领域具有广泛的适用性，并最终导致耐受性良好且具有潜在治愈性的治疗。 侵袭性B细胞淋巴瘤