Reversing genetically modified T cell suppression in a model of liver metastases

在肝转移模型中逆转转基因 T 细胞抑制

• 批准号: 8300398
• 负责人: STEVEN C KATZ
• 金额: $ 16.76万
• 依托单位: ROGER WILLIAMS HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-12 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300398
• 关键词: Area; Bypass; Carcinoembryonic Antigen; Cause of Death; Cell Therapy; Cell physiology; Cells; Cellular biology; Centers of Research Excellence; Cessation of life; Clinical; Clinical Oncology; Clinical Protocols; Clinical Trials; Colorectal; Colorectal Cancer; Complex; Critiques; Data; Dermatology; Development; Disease; Disseminated Malignant Neoplasm; Effectiveness; Ensure; Environment; Fellowship; Foundations; Funding; Future; Grant; Growth and Development function; Hepatology; Immune; Immune response; Immune system; Immunobiology; Immunologic Receptors; Immunologics; Immunologist; Immunology; Immunology procedure; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Institution; Journals; Laboratories; Liver; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Medical; Medical center; Memorial Sloan-Kettering Cancer Center; Mentors; Metastatic Neoplasm to the Liver; Modeling; Monitor; Mus; Myelogenous; Nature; New York; Operative Surgical Procedures; Paper; Pathway interactions; Patient Care; Patients; Primary Neoplasm; Publications; Publishing; Recruitment Activity; Regulatory T-Lymphocyte; Research; Resources; Series; Site; Suppressor-Effector T-Lymphocytes; Surgical Oncologist; Surgical Oncology; T cell response; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Time; Training; Tumor Antigens; United States; United States National Institutes of Health; Universities; Work; authority; base; cancer research center director; career development; cellular engineering; cytotoxicity; design; experience; host neoplasm interaction; in vivo; insight; knowledge base; medical schools; member; novel; novel therapeutics; programs; receptor; research study; response; success; translational medicine; treatment strategy; tumor

DESCRIPTION (provided by applicant): I am a surgical oncologist dedicated to caring for patients with complex malignancies and to developing novel immunotherapeutic approaches for metastatic liver cancer. Early in my medical training, I developed a passion for immunology and host-tumor interactions. After graduating from the New York University (NYU) School of Medicine with the top academic record in my class, I trained in general surgery at NYU and Bellevue. I spent two years as a research fellow with Dr. Ronald DeMatteo at Memorial Sloan-Kettering (MSK), where I gained valuable experience in immunologic research and published papers on liver immune cells in Hepatology and the Journal of Immunology. During my clinical surgical oncology fellowship at MSK, I studied immune infiltrates in liver metastases, work published in the Annals of Surgical Oncology and featured in Nature Reviews Clinical Oncology. I was recruited to Roger Williams to join a strong immunotherapy program and build a lab focused on investigating how suppressive liver immune cells may contribute to the development and progression of liver metastases. My K08 proposal is a critical step in my career development as the project represents a fusion of my basic liver immunology background with a therapeutic platform, genetically modified or "designer" T cells (dTc), we are presently using in clinical trials at Roger Williams. The associated training plan, as noted below, will provide me with important educational opportunities to facilitate my transition toward independent funding. Environment - The Roger Williams Medical Center (RWMC) is an ideal environment for my academic growth and development. Dr. Richard Junghans, my mentor, is a well established immunologist with a rich experience with immunotherapy trials and dTc. I also work with Dr. Vincent Falanga, the RWMC Chief of Dermatology, as he shares valuable resources obtained through their COBRE grant. As the RWMC is of modest size, my laboratory and career development are top priorities for the institution. I receive a tremendous level of support from th administration and my Division Chief and Cancer Center Director, Dr. N. Joseph Espat. This enables me to have the necessary protected time and maintain a high level of focus on my laboratory work. Development and Training Plan - I have assembled a mentoring team of well respected experts to monitor my progress, support my research, and promote my career development. Each member of the team has successfully competed for NIH funding and offers a particular area of expertise that meshes well with my proposal. Dr. Junghans will be the primary mentor, and his experience with immunotherapy and T cell biology will be invaluable. The three co- mentors will make important contributions as well. Dr. Espat, an authority on liver metastases, will ensure that the work and publications maintain a translational focus. My mentor from MSKCC, Dr. DeMatteo, will provide important insight and critique from the vantage point of an expert in liver immune cell biology. Dr. Alfred Ayala at Brown, with whom I have recently begun to collaborate, is another well respected expert in liver immunobiology. I have also included translational medicine and immunology course-work at Brown to expand my knowledge base in critical areas. Research Plan - Based upon the work I have published to date, I hypothesize that suppressive liver immune cells limit the effectiveness of T cell based therapies for eradicating liver metastases. T regulatory cells (Treg) and myeloid derived suppressor cells (MDSC) are likely contributors to liver tolerance. Our lab has spent over one year optimizing our murine model of CEA+ colorectal liver metastases and the immunologic assays described in the proposal. My first specific aim focuses on elucidating the mechanisms by which Treg and MDSC may limit anti-CEA dTc function in the liver. I have designed the experiments to focus on each component of the model separately, including the Treg or MDSC, dTC, and immune receptor express by dTc. In addition, contact-dependent mechanisms such as the programmed death-1 pathway and secreted factors will be studied. For the second specific aim, specific strategies for blocking the suppressive interactions between Treg or MDSC an dTc will be tested in vivo. We hope some of our immunologic manipulations will be translatable into the clinical arena.

描述（由申请人提供）：我是一名外科肿瘤学家，致力于照顾患有复杂恶性肿瘤的患者，并开发用于转移性肝癌的新型免疫治疗方法。在医学培训的早期，我对免疫学和宿主肿瘤互动产生了热情。从纽约大学（NYU）医学院毕业，并在班上获得了最高学术记录后，我在纽约大学和贝尔维尤接受了一般手术培训。我在纪念斯隆 - 凯特林（MSK）的罗纳德·德马特奥（Ronald Dematteo）博士工作了两年，在那里我获得了免疫学研究的宝贵经验，并发表了有关肝病学和免疫学杂志的肝脏免疫细胞的论文。在MSK的临床手术肿瘤学研究金期间，我研究了肝转移的免疫浸润，在手术肿瘤学史上发表的作品，并在《自然评论》临床肿瘤学中发表。我被招募到罗杰·威廉姆斯（Roger Williams）加入了一项强大的免疫疗法计划，并建立了一个专注于研究抑制性肝免疫细胞如何有助于肝转移的发展和发展的实验室。我的K08提案是我职业发展的关键一步，因为该项目代表了我的基本肝脏免疫学背景与治疗平台，转基因或“设计师” T细胞（DTC）的融合，我们目前在Roger Williams的临床试验中使用。如下所述，相关的培训计划将为我提供重要的教育机会，以促进我向独立资助的过渡。 环境 - 罗杰·威廉姆斯医疗中心（RWMC）是我学术成长和发展的理想环境。我的导师Richard Junghans博士是一位知名的免疫学家，拥有免疫疗法试验和DTC的丰富经验。我还与RWMC皮肤病学负责人Vincent Falanga博士合作，因为他分享了通过其鞋底赠款获得的宝贵资源。由于RWMC规模适中，我的实验室和职业发展是该机构的首要任务。我得到了TH政府的大力支持，我的部门负责人兼癌症中心主任N. Joseph Espat博士。这使我能够拥有必要的保护时间，并保持对我的实验室工作的高度关注。 发展和培训计划 - 我组建了一个由良好尊敬的专家组成的指导团队，以监控我的进步，支持我的研究并促进我的职业发展。该团队的每个成员都成功地争夺了NIH资金，并提供了一个特定的专业领域，与我的建议息息相关。 Junghans博士将是主要导师，他在免疫疗法和T细胞生物学方面的经验将是无价的。这三位合作社也将做出重要的贡献。 ESPAT博士是肝转移的权威，将确保工作和出版物保持转化的重点。我来自MSKCC的导师Dematteo博士将从肝脏免疫细胞生物学专家的有利位置提供重要的见解和批评。布朗（Brown）的阿尔弗雷德·阿亚拉（Alfred Ayala）博士是我最近开始合作的布朗（Brown），是肝脏免疫生物学方面的另一位备受推崇的专家。我还包括在布朗的转化医学和免疫学课程工作，以扩大我在关键领域的知识基础。 研究计划 - 根据我迄今为止发表的工作，我假设抑制性肝免疫细胞限制了基于T细胞的疗法消除肝转移的有效性。 T调节细胞（TREG）和髓样衍生的抑制细胞（MDSC）可能是肝耐受的原因。我们的实验室花费了一年多的时间来优化我们的CEA+结直肠肝转移的鼠模型以及提案中描述的免疫学分析。我的第一个特定目的是阐明Treg和MDSC可能限制肝脏中抗CEA DTC功能的机制。我已经设计了实验，以分别关注模型的每个组件，包括DTC的Treg或MDSC，DTC和免疫受体表达。此外，将研究接触依赖性的机制，例如编程的死亡-1途径和分泌因素。对于第二个特定目的，阻止的具体策略 Treg或MDSC和DTC之间的抑制作用将在体内进行测试。我们希望我们的某些免疫操作能够翻译成临床领域。