Engineering the Next Generation of T Cells

总体总结 这个U54“免疫工程以改进免疫治疗(I3)中心”是为了响应 RFA-CA-19-013。这款U54的目的是利用免疫工程原理设计更多 持久、可获得且毒性较低的免疫预防和免疫治疗策略。国家优先事项 由癌症登月计划设立的目的是支持结合下一代基因的研究 工程学、工程生物材料、纳米技术、计算和数学模型，或 系统生物学方法在下一代网络的设计、实施和评估中的应用 免疫疗法的重点是克服免疫抑制障碍，靶向肿瘤细胞以杀死肿瘤细胞， 并产生持久的抗癌免疫记忆。我们的U54的焦点是 “设计下一代T细胞”是关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 目的：降低过继细胞治疗的ff靶向毒性，提高ff的抗肿瘤活性。我们的中央 假设下一代工程可以提高CAR T细胞的安全性和有效性 同时降低了商品的成本。我们的U54中心有三个科学项目。共享的 这些项目的目标是使这种强大的疗法能够接触到更广泛的 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，并使细胞抵抗细胞因子释放综合征(CRS)，同时使用工程学 自动化汽车T细胞培养的技术。项目2的目标是生成通用的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 在一种独特的犬癌模型中。在项目3中，我们将使用先进的蛋白质工程，细胞 工程载体和溶瘤载体在小鼠体内测试合成的细胞因子和细胞因子受体系统 和人类T细胞，其长期目标是消除或减少淋巴消耗的需要 在过继细胞移植之前进行条件化疗。我们的方法是多学科和多领域的 制度性的。我们聚集了一支来自多个学科的特殊调查人员队伍 他们多年来一直合作并共同出版。使用最先进的基因编辑 CRISPR/CAS9和宾夕法尼亚大学的细胞培养技术是协同的 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。 该U54的管理核心旨在管理和协调所有i3中心研究 作为i3中心与物联网数据管理和数据中心之间的联络人 资源共享中心(U24)和其他癌症登月联盟，包括儿科 免疫疗法发现和发展网络(PI-DDN)。此外，行政核心 将协调i3中心研究项目PD(S)/Pi(S)和 IOTN(或其他)调查人员。改变范式的潜在影响这款U54将改变 第一代CAR T治疗白血病和淋巴瘤的经验教训是对ALL有意义的疗效 恶性肿瘤。

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.