Engineering the Next Generation of T Cells

设计下一代 T 细胞

基本信息

批准号：
10578324
负责人：
CARL H. JUNE
金额：
$ 24.38万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-25 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10578324
关键词：
Adoptive Cell Transfers Adoptive Transfer Autologous B lymphoid malignancy Biocompatible Materials CRISPR/Cas technology Cancer Patient Cell Culture Techniques Cells Cessation of life Childhood Collaborations Communication Computer Models Coupled Cytokine Receptors Data Management Resources Development Directed Molecular Evolution Discipline Effectiveness Engineering Evaluation Evolution Generations Genes Genetic Genetic Engineering Goals Hematologic Neoplasms Hematopoietic Neoplasms Human Immune Immune system Immunologic Memory Immunoprevention Immunotherapy In complete remission Malignant Neoplasms Mediating Modification Multiple Myeloma Mus Nanotechnology Patients Pennsylvania Persons Prior Chemotherapy Protein Engineering Proteins Publishing Refractory Research Activity Research Personnel Research Project Grants Resistance Resource Sharing Safety Solid System Systems Biology T cell therapy T-Lymphocyte Technology Testing Therapeutic Toxic effect United States Universities Vision anti-cancer antitumor effect authority cancer immunotherapy cancer therapy canine model cell killing cellular engineering chimeric antigen receptor chimeric antigen receptor T cells conditioning cost cytokine release syndrome design engineered T cells epigenome editing immunoengineering improved in vivo innovation leukemia/lymphoma mathematical model multidisciplinary neoplastic cell next generation oncolytic vector prevent response structural biology success synthetic biology tumor

项目摘要

OVERALL SUMMARY This U54 “Immuno-engineering to Improve Immunotherapy (i3) Center” was developed in response to RFA-CA-19-013. The purpose of this U54 is to employ immuno-engineering principles to design more durable, accessible, and less toxic immunoprevention and immunotherapy strategies. A national priority set by the Cancer Moonshot initiative is to support studies incorporating next-generation genetic engineering, engineered biomaterials, nanotechnology, computational and mathematical modelling, or systems biology approaches in the design, implementation and evaluation of next generation immunotherapies focused on overcoming immunosuppressive barriers, targeting tumor cells for killing, and generating long-lasting anti-cancer immunological memory. The focus of our U54 entitled “Engineering the next generation of T cells” is on developing next-generation gene-editing or modification of immune cells to improve persistence in vivo, control and manipulate the immune system to reduce oﬀ-target toxicities and enhance anti-tumor eﬀectiveness of adoptive cell therapy. Our central hypothesis is that next generation engineering can improve the safety and efficacy of CAR T cells while decreasing the cost of goods. There are three scientific projects in our U54 Center. The shared goal of these projects is to enable this powerful therapy to reach a broader spectrum of patients with blood cancer and solid cancers. In Project 1, we are using CRISPR/Cas9 to edit the epigenome of T cells and to make cells resistant to cytokine release syndrome (CRS), while employing engineering technologies to automate CAR T cell culture. The goal of Project 2 is to generate universal CAR T cells (UCART) using advanced genetic editing technologies and then to compare UCAR to autologous CAR T in a unique model of canine cancer. In Project 3 we will use advanced protein engineering, cell engineering and oncolytic vectors to test synthetic cytokine and cytokine receptor systems in mouse and human T cells, with the long-term goal of eliminating or reducing the need for lymphodepleting conditioning chemotherapy prior to adoptive cell transfer. Our approach is multidisciplinary and multi- institutional. We have brought together a cadre of exceptional investigators from multiple disciplines who have collaborated and published together for many years. State of the art genetic editing with CRISPR/Cas9 and cell culture technologies at the University of Pennsylvania are synergistically coupled with world-class protein engineering and structural biology at Stanford University. Each project is led by recognized authorities in the field. The Administrative Core for this U54 is designed to manage and coordinate all i3 Center Research Project activities and serve as the liaison between the i3 Center and the IOTN Data Management and Resource-sharing Center (U24) and other Cancer Moonshot consortia, including the Pediatric Immunotherapy Discovery and Development Network (PI-DDN). In addition, the Administrative Core will coordinate collaborative research activities between the i3 Center Research Project PD(s)/PI(s) and IOTN (or other) investigators. The potential for paradigm-shifting impact this U54 is to transform the lessons of first-generation CAR T for leukemia and lymphoma into meaningful efficacy against all malignancies.

总体总结这个U54“免疫工程改善免疫治疗（i3）中心”是为了响应而开发的 RFA-CA-19-013。该U54的目的是利用免疫工程原理来设计更多持久、可及且毒性较小的免疫预防和免疫治疗策略是国家优先事项。癌症登月计划设立的目标是支持纳入下一代遗传基因的研究工程学、工程生物材料、纳米技术、计算和数学建模，或下一代系统生物学方法的设计、实施和评估免疫疗法的重点是克服免疫抑制障碍，靶向杀死肿瘤细胞，并产生持久的抗癌免疫记忆，这是我们U54的重点。 “工程下一代 T 细胞”致力于开发下一代基因编辑或修饰免疫细胞以提高体内持久性、控制和操纵免疫系统减少脱靶毒性并增强过继细胞疗法的抗肿瘤功效。假设下一代工程可以提高 CAR T 细胞的安全性和有效性同时降低商品成本。我们的 U54 中心有三个科学项目。这些项目的目标是使这种强大的疗法能够惠及更广泛的患者在项目 1 中，我们使用 CRISPR/Cas9 来编辑 T 的表观基因组。细胞并使细胞抵抗细胞因子释放综合征（CRS），同时采用工程技术自动化 CAR T 细胞培养技术项目 2 的目标是生成通用 CAR T 细胞。 (UCART) 使用先进的基因编辑技术，然后将 UCAR 与自体 CAR 进行比较在项目 3 中，我们将使用先进的蛋白质工程、细胞。用于测试小鼠合成细胞因子和细胞因子受体系统的工程和溶瘤载体和人类 T 细胞，长期目标是消除或减少淋巴细胞清除的需要我们的方法是多学科和多学科的。我们聚集了一批来自多个学科的杰出审查员。他们与最先进的基因编辑技术合作并共同发表了多年。宾夕法尼亚大学的 CRISPR/Cas9 和细胞培养技术具有协同作用加上斯坦福大学世界一流的蛋白质工程和结构生物学项目。由该领域公认的权威领导。 U54 的管理核心旨在管理和协调所有 i3 中心研究项目活动并充当 i3 中心和 IOTN 数据管理和之间的联络人资源共享中心 (U24) 和其他癌症登月联盟，包括儿科此外，免疫疗法发现和开发网络（PI-DDN）。将协调 i3 中心研究项目 PD/PI 和 IOTN（或其他）研究人员的范式转变影响的潜力是改变整个世界。第一代 CAR T 治疗白血病和淋巴瘤的经验教训转化为对所有疾病的有意义的疗效恶性肿瘤。