Augmenting Chimeric Antibody Receptor Directed T cell Therapy for Cancer

增强嵌合抗体受体定向 T 细胞治疗癌症

基本信息

批准号：
8225814
负责人：
Edmund K. Moon
金额：
$ 17.38万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-07 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8225814
关键词：
Adoptive Transfer Adverse effects Advisory Committees Antibodies Antigen Receptors Antigen Targeting Antigens Asbestos Award Binding Biology Biopsy CD3 Antigens Cancer Center Cell physiology Cells Cellular biology Chest Clinical Combined Modality Therapy Communicable Diseases Critical Care Cyclic AMP-Dependent Protein Kinases Cytoplasmic Tail Development Dominant-Negative Mutation Dose Electroporation Engineering Environment Experimental Designs Exposure to Fc Receptor Fellowship Generations Goals Grant Hematopoietic Human Human Engineering Hypersensitivity IL8 gene IL8RA gene Immune Immunity Immunocompetent Immunodeficient Mouse Immunoglobulin Variable Region Immunosuppression Immunosuppressive Agents Immunotherapy Incidence Individual Knowledge Laboratories Lead Lentivirus Vector Life Lung Lymphocyte Malignant - descriptor Malignant Neoplasms Malignant Pleural Mesothelioma Malignant neoplasm of ovary Malignant neoplasm of pancreas Manuscripts Mediator of activation protein Medicine Mentors Mesothelioma Messenger RNA Modeling Monocyte Chemoattractant Protein-1 Mus Normal tissue morphology PTPN6 gene Pathway interactions Patients Pennsylvania Peripheral Persons Phase I Clinical Trials Physicians Pleural Postdoctoral Fellow Preparation Protein Tyrosine Phosphatase Receptor Activation Regimen Research Research Personnel Resistance Safety Scientist Signal Transduction Signaling Molecule Supervision T cell therapy T-Cell Activation T-Cell Receptor T-Lymphocyte Techniques Therapeutic Thoracic Oncology Time Training Training Programs Translational Research Tumor Antigens Tumor-Infiltrating Lymphocytes Universities Work Writing base career chemokine chemokine receptor chimeric antibody extracellular improved inhibitor/antagonist insight lectures mesothelin mouse model neoplastic cell oncology outcome forecast pre-clinical programs receptor receptor expression resilience response skills symposium trafficking treatment strategy tumor tumor immunology

项目摘要

DESCRIPTION (provided by applicant): This project describes a 5 year training program for a career as a Physician-Scientist with the long term goal of establishing a research program within the field of thoracic and pleural oncology. The applicant has finished a fellowship in Pulmonary, Allergy, and Critical Care Medicine at the University of Pennsylvania. He is currently conducting research in adoptive T cell immunotherapy for malignant pleural mesothelioma (MPM), a deadly asbestos-related pleural malignancy for which treatment options remain limited. The research focus of this proposal is to enhance the anti-tumor effect of chimeric antibody receptor (CAR)-based T cell immunotherapy. The central hypothesis of the proposal is that CAR T cell therapy for MPM can be significantly enhanced by improving T cell trafficking, inhibiting tumor microenvironment immunosuppression, and making T cells more resilient to tumor induced functional inhibition. In Specific Aim 1, CAR T cells will be genetically modified to express chemokine receptors appropriate for the chemokines secreted by MPM tumor in attempt to augment T cell trafficking to tumor. In Specific Aim 2, T cell signaling molecules/domains known to inhibit T cell activation will be genetically inactivated in order to increase T cell resilience to tumor-induced inactivation. In Specific Aim 3, using two complementary mouse models of CAR T cell immunotherapy, established inhibitory mediators secreted into the tumor microenvironment that allow evasion of immunity will be inhibited in attempts to augment T cell anti-tumor efficacy. The training component of this proposal includes formal coursework, participation in a rich environment of post-doctoral lectures and seminars in thoracic/pleural oncology, acquisition of advanced laboratory techniques, and individual mentoring. This project will take place under the supervision of Dr. Steven Albelda who is the Director of Lung Research and the Thoracic Oncology Laboratory at the University of Pennsylvania; and Dr. Carl June who is the Director of Translational Research at the Abramson Cancer Center at Penn. Dr. Albelda and Dr. June have mentored over 100 trainees. In addition, an advisory committee of distinguished scientists will provide experimental assistance, intellectual guidance, and career advice throughout the duration of this award.

描述（由申请人提供）：该项目描述了一项为期5年的培训计划，该计划是一名医师科学家的职业，其长期目标是在胸腔和胸膜肿瘤学领域建立研究计划。申请人已在宾夕法尼亚大学完成了肺部，过敏和重症监护医学的研究金。他目前正在进行有关恶性胸膜间皮瘤（MPM）的收养T细胞免疫疗法研究，这是一种致命的石棉相关胸膜恶性肿瘤，治疗方案仍然有限。该提案的研究重点是增强基于嵌合抗体受体（CAR）的T细胞免疫疗法的抗肿瘤作用。该提案的中心假设是，通过改善T细胞运输，抑制肿瘤微环境免疫抑制，可以显着增强MPM的CAR T细胞治疗，并使T细胞对肿瘤诱导的功能抑制更具弹性。在特定的目标1中，将对CAR T细胞进行遗传修饰，以表达适用于MPM肿瘤分泌的趋化因子的趋化因子受体，以增强T细胞运输到肿瘤。在特定的目标2中，将在遗传上灭活已知的T细胞信号分子/结构域，以增加T细胞对肿瘤诱导的失活的弹性。在特定的目标3中，使用两个互补的CAR T细胞免疫疗法的小鼠模型，建立的抑制性介质分泌到肿瘤微环境中，允许逃避免疫力的抑制作用将被抑制，以增强T细胞抗肿瘤功效。该提案的培训部分包括正式课程，参与胸腔/胸膜肿瘤学的丰富的博士后讲座环境以及研讨会，高级实验室技术的获取以及个人指导。该项目将在宾夕法尼亚大学肺部研究和胸腔肿瘤实验室主任史蒂文·阿尔贝尔达（Steven Albelda）博士的指导下进行；卡尔·六月（Carl June）博士是宾夕法尼亚州艾布拉姆森癌症中心转化研究主任。 Albelda博士和June博士指导了100多名学员。此外，杰出科学家的咨询委员会将在本奖项的整个期间提供实验帮助，智力指导和职业建议。