Resistance To Targeted Immunotherapies:CART19 as a Paradigm

对靶向免疫疗法的耐药性：以 CART19 为范例

基本信息

批准号：
9386483
负责人：
Marco Ruella
金额：
$ 17.41万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-02 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9386483
关键词：
Address Antigens Award B lymphoid malignancy B-Cell Acute Lymphoblastic Leukemia B-Cell Leukemia B-Lymphocytes Bioinformatics Blast Cell Blood CD19 gene CD22 gene CRISPR library Cancer Biology Candidate Disease Gene Cells Clinical Sciences Clinical Trials Clonality Combination Drug Therapy Critical Pathways Data Development Engraftment Exposure to Family Funding Future Genes Genetic Engineering Gills Goals Hematologic Neoplasms Human IL3RA gene Immune Immune system Immunology Immunotherapeutic agent Immunotherapy In Vitro Investigation Knock-out Knowledge Lead Leukemia Acute Lymphoblastic Chemotherapy Leukemic Cell Malignant Neoplasms Maps Mentors Minor Mission Modality Modeling Molecular Biology Myelogenous Outcome Pathogenesis Pathway interactions Patients Pennsylvania Prevention Public Health Refractory Relapse Research Research Activity Resistance Role Scientist Side Solid Stem cells T cell therapy T-Lymphocyte Technical Expertise Techniques Testing Toxic effect Training Training and Education Translational Research Treatment Failure Tumor Escape Universities Xenograft Model academic standard base cancer cell cancer immunotherapy cancer therapy career chimeric antigen receptor curative treatments design experience functional genomics high throughput screening immunoregulation improved in vivo in vivo Model innovation insight leukemia leukemia/lymphoma member mouse model next generation sequencing novel novel strategies pre-clinical prevent progenitor receptor relapse patients resistance mechanism response synaptogenesis translational medicine treatment strategy tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Chimeric-antigen receptor (CAR) T cells have opened a new era for targeted immunotherapy of cancer. The applicant's mentor, Dr. Carl June, is recognized as a world leader in the field of genetically-engineered T cell therapy for hematologic malignancy. Although anti-CD19 CAR T cells (CART19) generate unprecedented responses in patients with B-cell leukemia and lymphoma, relapse represents the major cause of treatment failure. The long term goal of this proposal is to develop an independent research career focused on improving targeted immunotherapy by studying and neutralizing tumor evasion mechanisms. The unifying objective of this application is to design novel strategies for the treatment and prevention of tumor immunoescape based on the mechanisms leading to relapse, using CART19 as a model. The central hypothesis is that multiple mechanisms can lead to escape from immune attack; therefore, combined approaches targeting the problem from multiple sides will prevent escape. The rationale for this research is that identification of key tumor escape mechanisms would allow us to develop specific remedies for these. The central hypothesis of this proposal will be tested by pursuing two specific aims: 1) to characterize the pathogenesis of leukemia relapses occurring after CD19-targeted immunotherapies by studying minor CD19-negative resistant clones present before CART19 treatment and by identifying key resistance pathways in CD19-positive relapses using functional genomics; 2) To design dual-specific chimeric antigen receptor T cells that will prevent tumor escape. This research will be significant because it will contribute depth (of understanding the mechanisms of relapse) and breadth (of novel potentially curative therapy) to the immunotherapeutic arsenal against cancer. Ultimately, such knowledge has the potential to vertically advance the field of CAR-redirected T cell immunotherapy as well as other targeted immunotherapies. This is project is innovative because it combines high throughput screening techniques together with in vitro and in vivo functional studies to study the possible mechanisms of resistance after immunotherapy and therefore to generate novel treatments. The proposed research activities are crucial to the development of the applicant as an independently-funded scientist with a focus on cellular immunotherapy. Dr. Ruella will receive further training in molecular biology, translational medicine, and immunology from his mentors and training in next-generation sequencing, cancer biology and bioinformatics from experienced collaborators at the University of Pennsylvania. Therefore at the conclusion of the training period, the applicant will have acquired a unique set of intellectual and technical skills that will allow him to attack the problem of resistance to targeted immunotherapies from several angles at once. In addition, this award will support a unique training experience in translational research and will establish an academic pathway for the discovery and development of new CAR T cell approaches.

项目概要/摘要嵌合抗原受体（CAR）T细胞开启了癌症靶向免疫治疗的新时代。这申请人的导师Carl June博士被公认为基因工程T细胞领域的世界领先者血液系统恶性肿瘤的治疗。尽管抗CD19 CAR T细胞（CART19）产生了前所未有的 B 细胞白血病和淋巴瘤患者的反应，复发是治疗的主要原因失败。该提案的长期目标是发展独立的研究生涯，专注于提高通过研究和中和肿瘤逃避机制来进行靶向免疫治疗。统一目标该应用旨在设计治疗和预防基于肿瘤免疫逃逸的新策略使用 CART19 作为模型研究导致复发的机制。中心假设是多重机制可以导致逃避免疫攻击；因此，针对该问题的综合方法从多个侧面将阻止逃跑。这项研究的基本原理是识别关键的肿瘤逃逸机制将使我们能够针对这些问题制定具体补救措施。该提案的中心假设将通过追求两个具体目标进行测试：1）描述白血病复发发生的发病机制在 CD19 靶向免疫疗法之后，通过研究之前存在的微小 CD19 阴性抗性克隆 CART19 治疗并通过使用功能性方法确定 CD19 阳性复发的关键耐药途径基因组学； 2）设计双特异性嵌合抗原受体T细胞，防止肿瘤逃逸。这研究将具有重要意义，因为它将有助于加深（了解复发机制）和抗癌免疫疗法的广度（新型潜在治愈疗法）。最终，这些知识有可能垂直推进 CAR 重定向 T 细胞免疫治疗领域以及其他靶向免疫疗法。该项目具有创新性，因为它结合了高吞吐量筛选技术与体外和体内功能研究相结合，研究可能的机制免疫治疗后产生耐药性，从而产生新的治疗方法。拟议的研究活动对于申请人作为一名专注于细胞的独立资助科学家的发展至关重要免疫疗法。 Ruella 博士将接受分子生物学、转化医学和导师的免疫学知识以及下一代测序、癌症生物学和生物信息学方面的培训来自宾夕法尼亚大学经验丰富的合作者。因此在培训结束时在此期间，申请人将获得一套独特的智力和技术技能，使他能够同时从多个角度解决靶向免疫疗法的耐药性问题。此外，这该奖项将支持转化研究方面的独特培训经验，并将建立一个学术机构发现和开发新 CAR T 细胞方法的途径。