Biomaterial Scaffolds for Ex Vivo and In Situ CAR-T Cell Production

项目摘要 尽管嵌合抗原受体（CAR）-T细胞疗法在临床上取得了前所未有的成功， 广泛的应用受到冗长且劳动密集型的体外制造程序的限制，所述体外制造程序导致： (i)高达50万美元的治疗成本非常高;（ii）输注CAR-T细胞的延迟数周或数月 快速进展疾病的患者;和（iii）异质组成和终末分化 输注的CAR-T细胞作为离体培养的结果限制了CAR-T细胞的植入和持久性。尽管 尽管在这一领域取得了重大成就，但减少时间、成本和监管负担仍然是一个深层次的问题 CAR-T细胞疗法的需求以及显著减少或消除离体程序仍然是一个关键的未满足的问题。 需要的该提案中概述的研究开发了新的生物材料方法，以减少时间和精力 在体外产生CAR-T细胞，以增强CAR-T细胞的表型和功能。我们建议短时间（~小时） 用抗-CD 3/CD 28抗体的预活化步骤之后可以立即进行转导和递送 使用生物材料支架。这种多样性补充将支持特雷·戴维斯博士，并允许他参加 新的实验，以扩大目标1的研究范围，并将使他能够接受强大的培训，在相关的 技术，专业发展和职业规划。我们希望我们的研究结果将为 一般的细胞治疗策略，并促进广泛的患者访问，特别是对人群， 成为健康差距的受害者。

PROJECT SUMMARY Despite unprecedented clinical success of chimeric antigen receptor (CAR)-T cell therapy against tumors, widespread application is limited by lengthy and labor-intensive ex vivo manufacturing procedures that result in: (i) very high costs of therapy of up to half of a million dollars; (ii) delays of weeks or months to infuse CAR-T cells to patients with rapidly progressing disease; and (iii) heterogeneous composition and terminal differentiation of infused CAR-T cells as a result of ex vivo culture that limit CAR-T cell engraftment and persistence. Despite significant achievements in this space, reducing the time, costs and regulatory burden remains a deep unmet need in CAR-T cell therapy and significant reducing or eliminating ex vivo procedures remains a critical unmet need. The research outlined in this proposal develops new biomaterials approaches to reduce the time and effort to produce CAR-T cells in vitro, to enhance CAR-T cell phenotype and function. We propose that a short (~hour) pre-activation step with anti-CD3/CD28 antibodies can be immediately followed by transduction and delivery using a biomaterial scaffold. This diversity supplement will support Dr. Trey Davis and allow him to participate in new experiments to extend the scope of Aim 1 studies and will allow him to receive robust training in associated techniques, professional development, and career planning. We expect that our results will provide a basis for a general cellular therapeutic strategy and promote widespread patient access, especially to populations that have been the victims of health disparities.