Advanced Rigidity-based Material for Enhanced Immunotherapy

描述（由申请人提供）：适应性免疫系统是一个强大的平台，用于开发一系列疾病的靶向、稳健和持久治疗。在许多形式的过继性T细胞免疫疗法中的中心步骤是起始T细胞群的离体扩增。该项目的重点是开发一种新的细胞培养平台， 增强T细胞扩增的过程，利用了最近的发现，即T细胞对呈递活化抗体的材料的机械刚性敏感，所述活化抗体分别针对CD 3和CD 28提供抗原和共刺激信号。具体地，T细胞增殖和CD 62 L的保留随着支撑材料刚度的降低而增加。这项拟议工作的目标是将这些初步研究中使用的平面聚二甲基硅氧烷（PDMS）弹性体平台转化为与当代T细胞扩增更相容的系统;目前使用聚合物珠形式诱导T细胞活化。具体而言，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提供增强的T细胞刺激表面积，该体积也易于纳入现有的生物反应器系统。这些研究分为三个互补的具体目标：SA 2）开发用于将活化生物分子共价固定到PDMS纤维上的化学系统，这将解决预期的监管和处理挑战，和SA 3）确定对使用该平台产生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后续动物研究提供关键信息，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.