Engineering the next generation of T cells

设计下一代 T 细胞

• 批准号: 10064451
• 负责人: CARL H. JUNE
• 金额: $ 23.31万
• 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/10064451
• 关键词: Adoptive Cell Transfers; Autologous; Biocompatible Materials; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; Canis familiaris; Cell Culture Techniques; Cell surface; Cells; Childhood; Computer Models; Coupled; Cytokine Receptors; Data Management Resources; Development; Discipline; Effectiveness; Engineering; Ensure; Evaluation; Gene Deletion; Generations; Genes; Genetic; Genetic Engineering; Goals; HLA-A gene; HLA-DR Antigens; Hematopoietic Neoplasms; Histocompatibility; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Human; Immune; Immune system; Immunoglobulin Constant Region; Immunologic Memory; Immunotherapy; Light; MHC Class I Genes; MHC Class II Genes; MHC class II transactivator protein; Malignant Neoplasms; Modeling; Modification; Mus; Nanotechnology; Natural Killer Cells; Normal tissue morphology; Patients; Pennsylvania; Prior Chemotherapy; Procedures; Protein Engineering; Proteins; Publishing; Research Activity; Research Personnel; Research Project Grants; Resistance; Resource Sharing; Risk; Safety; Solid; System; Systems Biology; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Theophylline; Therapeutic; Toxic effect; Universities; Vaccine Production; anti-cancer; authority; beta-2 Microglobulin; cell killing; cellular engineering; chimeric antigen receptor T cells; conditioning; cost; cytokine release syndrome; design; epigenome editing; gene product; immunoengineering; improved; in vivo; leukemia/lymphoma; mathematical model; multidisciplinary; neoplastic cell; next generation; oncolytic vector; response; structural biology; transcription factor; tumor

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 immune-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 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 offtarget 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.

这个U 54“免疫工程改善免疫治疗（i3）中心”是在 回复RFA-CA-19-013。这个U 54的目的是利用免疫工程 设计更持久、更容易获得、毒性更小的免疫预防的原则， 免疫治疗策略。癌症登月计划设定的国家优先事项是支持 结合下一代基因工程，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， 下一代免疫疗法的设计、实施和评估，重点是 克服免疫抑制屏障，靶向肿瘤细胞进行杀伤，并产生长 持久的抗癌免疫记忆。我们的U 54的重点是题为“工程的未来 T细胞的产生”是关于开发下一代基因编辑或免疫修饰， 细胞，以提高体内持久性，控制和操纵免疫系统，以减少脱靶 毒性和增强过继细胞疗法的抗肿瘤有效性。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U 54中心有三个科学项目。这些项目的共同目标是 使这种强大的治疗能够达到更广泛的血液癌症患者和固体 癌的在项目1中，我们使用CRISPR/Cas9编辑T细胞的表观基因组， 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。项目2的目标是产生通用CAR T细胞（UCART） 使用先进的基因编辑技术，然后将UCAR与自体CAR T进行比较， 一种独特的犬类癌症模型在项目3中，我们将使用先进的蛋白质工程，细胞 工程化和溶瘤载体，以测试合成的细胞因子和细胞因子受体系统， 小鼠和人类T细胞，长期目标是消除或减少对 在过继性细胞转移之前进行淋巴细胞清除预处理化疗。我们的做法是 多学科和多机构。我们召集了一批杰出的 来自多个学科的研究人员合作并共同发表了许多 年利用CRISPR/Cas9和细胞培养技术进行基因编辑的最新技术水平 宾夕法尼亚大学与世界一流的蛋白质工程协同作用， 斯坦福大学的结构生物学每个项目都由该领域公认的权威领导。 U 54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 和资源共享中心（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中心研究项目之间的合作研究活动 PD/PI和IOTN（或其他）研究者。范式转变的可能性对U 54的影响 是将第一代CAR-T治疗白血病和淋巴瘤的经验转化为有意义的 对所有恶性肿瘤的疗效。