In Vivo Murine Models Core

摘要 体内小鼠模型核心的首要功能是提供人体安全性和有效性测试。 在小鼠模型中的细胞疗法。这一体内步骤是人体临床试验的关键先导。我们将用我们 丰富的经验，提供最先进的鼠实验模型，是针对研究 项目的目标，并以几种方式简化项目： (1)它根据需要为多个繁殖群体和小鼠种群提供集中的动物护理， 项目1、2和3，以及核心C（目标1）中的验证研究。(2)通过集中研究老鼠 在核心D中，每个项目都同样得到高质量实验室性能和创造性的支持。 实验方法（目标2）、知识伙伴关系和数据报告的一致性。(3)在一个迅速 在不断发展的领域中，能够将从一个项目中学到的知识应用于所有模型是一个优势， needed.该核心的具体目标如下： 目的1：研究经操作的人造血细胞群的功能、效力和安全性 使用最先进的小鼠模型支持每个项目中概述的实验研究， 核心C。具体来说，我们计划建立T祖细胞（Tprog）的概念验证和安全性数据 （项目1）、药物调节嵌合抗原受体（CAR）修饰的T干细胞记忆（Tsm）细胞（项目2） 2）和适应性自然杀伤（NK）细胞（项目3）。 目标2：提供独特的专门知识和新技术，以加强功能评估和分析 细胞的分布和存活。我们将定制动物模型和评估方法，以满足以下需求： 具体的项目，从使用氘标记人类Tprog细胞（项目1），以评估 从制造的人Tsm衍生的诱导多能干细胞（iPSC）（项目2）的多能性， 评估组成型和药物调节的CAR+ T细胞和适应性NK细胞定向的抗 主要白血病靶点（项目2和3）。 应用免疫细胞作为特殊递送剂Treg抑制移植物抗宿主病的能力， Tprog在免疫重建期间起“免疫桥”的作用，Tsm延长CAR+ T的寿命 细胞，并作为可再生的细胞治疗来源，药物调节的CAR+ T细胞，以尽量减少副作用， 基于CAR的疗法，以及预防和治疗白血病复发的适应性NK细胞，将使 这些先进的免疫重建和抗白血病疗法。 我们的目标是继续以最大的通用性来应对实验性的变化和挑战。因此，在本发明中， 核心D将与所有三个项目一起工作，为它们提供一个支持平台。这种协调 这将反过来为细胞制造和未来临床试验的设计提供信息。

Abstract The foremost function of the In Vivo Murine Models Core is to provide safety and efficacy testing of human cell therapies in a murine model. This in vivo step is a critical precursor to human clinical trials. We will use our extensive experience to provide state-of-the-art murine experimental modeling that is tailored to the research objectives of the Projects and streamlines the Projects in several ways: (1) It provides centralized animal care for multiple breeding colonies and the stock of mice as needed by Projects 1, 2, and 3, as well as the validation studies in Core C (Aim 1). (2) By focusing the murine research into Core D, each of the Projects is equally supported by high-quality laboratory performance and inventive experimental approaches (Aim 2), intellectual partnership, and consistent reporting of data. (3) In a rapidly evolving field, it is an advantage to be able to apply knowledge learned from one Project to all the models as needed. The Specific Aims of this Core are as follows: Aim 1: Investigate the function, potency, and safety of manipulated human hematopoietic cell populations using state-of-the-art murine models in support of the experimental studies outlined in each of the Projects and Core C. Specifically, we plan to establish proof-of-concept and safety data for T progenitor (Tprog) cells (Project 1), drug-regulated chimeric antigen receptor (CAR)-modified T stem cell memory (Tsm) cells (Project 2), and adaptive Natural Killer (NK) cells (Project 3). Aim 2: Provide unique expertise and new technologies that will enhance functional assessments and analysis of cell distribution and survival. We will tailor animal models and methods of assessment to fit the needs of specific projects, ranging from the use of deuterium labeling of human Tprog cells (Project 1), to the evaluation of pluripotency from manufactured human Tsm-derived induced pluripotent stem cells (iPSC) (Project 2), to the assessment of constitutive and drug-regulated CAR+ T cells and adaptive NK cell-directed responses against primary leukemia targets (Projects 2 and 3). The ability to apply immune cells as special delivery agents—Treg to suppress graft-versus-host disease, Tprog to function as an “immune bridge” during immune reconstitution, Tsm to improve longevity of CAR+ T cells and to serve as renewable cell therapy source, drug-regulated CAR+ T cells to minimize side effects of CAR-based therapies, and adaptive NK cells to prevent and treat leukemia relapse—will enable translation of these advanced immune reconstitution and anti-leukemia therapies to humans. Our ambition is to continue to meet experimental changes and challenges with the utmost versatility. Thus, Core D will work in synthesis with all three Projects to provide a support platform for them. This coordination will in turn inform the cell manufacturing and the design of future clinical trials.