Scaffolds mimicking antigen presenting cells

模拟抗原呈递细胞的支架

• 批准号: 10001355
• 负责人: David J Mooney
• 金额: $ 60万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001355
• 关键词: Scaffolds; mimicking; antigen; presenting; cells

Current approaches to expand T cells ex vivo for therapeutic applications are limited by low expansion rates and T-cell products of limited functionality. To address these issues, we have recently described a system that mimics natural antigen-presenting cells (APCs). These APC-mimetic scaffolds (APC-ms) consist of a fluid lipid bilayer supported by mesoporous silica micro-rods (MSRs). The lipid bilayer presents membrane-bound cues for T-cell receptor stimulation and costimulation at predefined densities, while the micro-rods enable sustained release of soluble paracrine cues. Using anti-CD3, anti-CD28 and controlled release of interleukin-2, we have shown that the APC-ms promotes ten-fold greater polyclonal expansion of primary mouse and human T cells than commercial beads (Dynabeads), and can be used to tune the phenotypic attributes of expanded T-cell products. APC-ms also support over 5-fold greater expansion of CD19 CAR-T cells than Dynabeads, with increased efficacy in a clinically-relevant xenograft lymphoma model. While APC-ms is a promising T cell expansion system, there are several development activities that would aid its clinical and commercial translation. The current MSR synthesis process has not been standardized for this application, and lacks established SOPs to yield material products with consistent properties. Currently, surface cues are presented on APC-ms using biotin-streptavidin, but the use of click chemistry in place of streptavidin could provide a number of advantages. While APC-ms is designed to completely degrade during the process of T cell culture period, obviating the need for its removal before cell delivery, we have not yet thoroughly explored the impact of any potential residual materials on the infused T cell products. These needs lead to the following specific objectives for this project (1) Establish SOPs for APC-ms synthesis. This will include identifying MSR critical quality attributes (CQAs) for functional APC-ms and understanding how critical process parameters (CPPs) in MSR synthesis affect those CQAs (2) Develop a process to directly and selectively conjugate surface cues onto lipid bilayers, via click chemistry, to simplify and modularity of APC-ms assembly and function. (3) Characterize residual APC-ms materials during T cell processing, and perform a thorough in vivo safety assessment. The successful achievement of these aims will immediately address key issues related to using APC-ms as an ex vivo T-cell expansion platform.

当前扩展T细胞用于治疗应用的T细胞的方法受到较低膨胀率的限制 和功能有限的T细胞产品。为了解决这些问题，我们最近描述了一个系统 模仿天然抗原的细胞（APC）。这些APC模拟支架（APC-MS）由液体脂质组成 介孔二氧化硅微杆（MSR）支持双层。脂质双层呈现膜结合的提示 用于在预定义的密度下进行T细胞受体刺激和共刺激，而微杆可实现持续 释放可溶性旁分泌线索。使用抗CD3，抗CD28和白介素-2的受控释放，我们有 表明APC-MS促进原代小鼠和人T细胞的多克隆扩张大十倍 而不是商业珠（Dynabeads），可以用来调整扩展的T细胞的表型属性 产品。 APC-MS还支持CD19 CAR-T细胞比Dynabeads大的5倍以上，并且具有 在临床上与异种移植淋巴瘤模型中的功效提高。虽然APC-MS是一个有希望的T细胞 扩展系统，有几项开发活动将有助于其临床和商业 翻译。当前的MSR合成过程尚未针对此应用进行标准化，并且缺乏 已建立的SOP生产具有一致特性的材料产品。目前，提出了表面提示 在APC-MS上使用生物素 - 链霉亲丁蛋白，但是使用点击化学代替链霉亲和素可以提供 优势的数量。虽然APC-MS旨在在T细胞培养过程中完全降解 时期，消除了在电池输送之前取消其去除的需求，我们尚未彻底探索影响 在注入T细胞产物上的任何潜在残留材料中。这些需求导致以下特定 该项目的目标（1）为APC-MS合成建立SOP。这将包括确定MSR关键 用于功能APC-MS的质量属性（CQA），并了解关键过程参数（CPP） MSR合成影响那些CQA（2）开发了一个直接和选择性结合表面提示的过程 通过单击化学，以简化APC-MS组件和功能的模块化，以简化和模块化。 （3） 在T细胞加工过程中表征残留的APC-MS材料，并进行彻底的体内安全性 评估。这些目标的成功成就将立即解决与使用有关的关键问题 APC-MS作为Ex Vivo T细胞扩展平台。