Engineering the Next Generation of T Cells

设计下一代 T 细胞

• 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
• 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

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.

总体汇总 这个U54 "免疫工程，以改善免疫治疗（i3）中心"是为了响应 RFA-CA-19 - 013。这个U54的目的是利用免疫工程原理来设计更多的 持久的、可获得的和毒性较小的免疫预防和免疫治疗策略。作为国家的优先 癌症登月计划的目的是支持将下一代基因 工程，工程生物材料，纳米技术，计算和数学建模，或 系统生物学方法在设计、实施和评价下一代 免疫疗法集中于克服免疫抑制屏障，靶向杀死肿瘤细胞， 并产生持久的抗癌免疫记忆。我们的U54的焦点， “工程化下一代T细胞”旨在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 以降低过继细胞治疗的靶向毒性并增强抗肿瘤效率。我们的中央 假设下一代工程可以提高CAR T细胞的安全性和功效 同时降低商品成本。我们的U54中心有三个科学项目。共享 这些项目的目标是使这种强大的治疗能够达到更广泛的患者， 血癌和实体癌。在项目1中，我们使用CRISPR/Cas9编辑T的表观基因组， 细胞，并使细胞对细胞因子释放综合征（CRS）具有抗性，同时采用工程 自动化CAR T细胞培养技术。项目2的目标是产生通用CAR T细胞 （UCART），然后将UCAR与自体CAR进行比较 在一个独特的犬类癌症模型中。在项目3中，我们将使用先进的蛋白质工程，细胞 在小鼠中测试合成细胞因子和细胞因子受体系统的工程化和溶瘤载体 和人类T细胞，长期目标是消除或减少淋巴细胞耗竭的需要， 在过继性细胞转移之前进行调节化疗。我们的方法是多学科和多- 体制性的。我们汇集了来自多个学科的优秀调查人员 他们合作出版了很多年最先进的基因编辑技术， 宾夕法尼亚大学的CRISPR/Cas9和细胞培养技术协同作用， 再加上斯坦福大学世界级的蛋白质工程和结构生物学。每个项目 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，并作为i3中心和IOTN数据管理之间的联络人， 资源共享中心（U24）和其他癌症登月联盟，包括儿科 免疫疗法发现和开发网络（PI-DDN）。此外，行政核心 将协调i3中心研究项目PD/PI之间的合作研究活动， IOTN（或其他）调查人员。U54的潜在范式转变影响是改变 第一代CAR T治疗白血病和淋巴瘤的经验教训对所有 恶性肿瘤。