Advanced Rigidity-based Material for Enhanced Immunotherapy

用于增强免疫治疗的先进刚性材料

• 批准号: 9182814
• 负责人: Lance C Kam
• 金额: $ 39.26万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9182814
• 关键词: Adaptive Immune System; Address; Adopted; Adoptive Immunotherapy; Alpha Cell; Animal Model; Animals; Antibodies; Area; Back; Biomedical Engineering; Bioreactors; CD28 gene; CD3 Antigens; Caliber; Cell Culture System; Cell Culture Techniques; Cell Differentiation process; Cell Proliferation; Cell Surface Receptors; Cells; Chemicals; Chemistry; Clinical; Clinical Trials; Complement; Data; Development; Dimensions; Disease; Elastomers; Electrospinning; Engineering; Fiber; Formulation; Goals; Gold; Growth; Human; Immobilization; Immune system; Immunology; Immunotherapy; Individual; Measures; Mechanics; Methodology; Morphology; Outcome; Patients; Phenotype; Polymers; Polystyrenes; Population; Process; Proteins; Protocols documentation; Research Personnel; Research Project Grants; SELL gene; Signal Transduction; Structure; Surface; System; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Techniques; Technology; Testing; Work; base; cancer therapy; cell type; cytokine; efficacy testing; improved; mechanical properties; nano; polydimethylsiloxane; programs; public health relevance; response; safety testing; therapy development; tool

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.

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、稳健和持久的治疗方法。许多形式的过继性 T 细胞免疫疗法的核心步骤是离体扩增起始 T 细胞群。该项目的重点是开发一个新的细胞培养平台，该平台将 利用最近发现的 T 细胞对呈递 CD3 和 CD28 激活抗体的材料的机械刚性敏感（分别提供抗原和共刺激信号），增强 T 细胞扩增过程。具体来说，T 细胞增殖和 CD62L 保留随着支撑材料硬度的降低而增加。这项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。具体来说，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提供增强的 T 细胞刺激表面积，并且易于合并到现有的生物反应器系统中。这些研究分为三个互补的具体目标：SA1) 通过使用静电纺丝将 PDMS 纤维开发成细胞培养形式，SA2) 开发一种化学系统，用于将活化生物分子共价固定到 PDMS 纤维上，这将解决预期的监管和处理问题挑战和 SA3) 确定纤维形态和成分，从而对使用该平台生成的细胞的数量和表型特征提供最佳控制。这些研究的成功完成将为后续动物研究测试使用该平台扩增的 T 细胞的安全性和有效性提供所需的关键信息。