Advanced Rigidity-based Material for Enhanced Immunotherapy

描述(由申请人提供)：适应性免疫系统是开发一系列疾病的有针对性、健壮和持久治疗的强大平台。在许多形式的过继T细胞免疫治疗中，一个核心步骤是在体外扩增开始的T细胞群体。该项目的重点是开发一个新的细胞培养平台，将 利用最近的发现，T细胞对提供CD3和CD28激活抗体的材料的机械刚性敏感，这两种抗体分别提供抗原性和共刺激信号，从而加强T细胞的扩增过程。特别是，T细胞的增殖和CD62L的保留率随着支架材料硬度的降低而增加。这项拟议工作的目标是将最初研究中使用的平面聚二甲基硅氧烷(PDMS)弹性体平台转变为与当代T细胞扩增更兼容的系统；目前，这是使用聚合物珠形式来诱导T细胞激活。具体地说，我们建议在PAR-13-137 BRG计划下开发一种基于纤维的PDMS格式，该格式将在紧凑的体积中为T细胞刺激提供增强的表面积，也很容易整合到现有的生物反应器系统中。这些研究分为三个相辅相成的特定目标：SA1)通过使用静电纺丝将PDMS纤维开发成细胞培养形式，SA2)开发一种将激活的生物分子共价固定在PDMS纤维上的化学系统，该系统将解决预期的调控和操作挑战，以及SA3)确定对使用该平台生成的细胞的数量和表型分布提供最佳控制的纤维形态和组成。这些研究的成功完成将为随后的动物研究提供所需的关键信息，以测试使用该平台扩增的T细胞的安全性和有效性。

DESCRIPTION (provided by applicant): The adaptive immune system is a powerful platform for development of targeted, robust, and persistent treatment of a range of diseases. A central step in many forms of adoptive T cell immunotherapy is the ex vivo expansion of a starting population of T cells. This project focuses on development of a new cell culture platform that will enhance the process of T cell expansion, leveraging the recent discovery that T cells are sensitive to the mechanical rigidity of the material presenting activating antibodies to CD3 and CD28, which provide antigenic and costimulatory signals, respectively. Specifically, T cell proliferation and retention of CD62L increased with decreasing stiffness of the support material. The goal of this proposed work is to transform the planar polydimethylsiloxane (PDMS) elastomer platform used in those initial studies into a system more compatible with contemporary T cell expansion; this is currently carried out using a polymer bead format to induce T cell activation. Specifically, we propose to develop, under the PAR-13-137 BRG program, a fiber-based format for PDMS that will offer enhances surface area for T cell stimulation in a compact volume that is also easy to incorporate into existing bioreactor systems. These studies are organized into three complementary Specific Aims: SA1) develop PDMS fibers into a cell culture format through the use of electrospinning, SA2) develop a chemical system for covalent immobilization of activating biomolecules onto the PDMS fibers, which would address anticipated regulatory and handling challenges, and SA3) determine the fiber morphologies and compositions that provide the best control over the number and phenotypic profile of cells generated using this platform. Successful completion of these studies will provide key information required for subsequent animal studies testing the safety and efficacy of T cells expanded using this platform.