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

项目总结 尽管嵌合抗原受体(CAR)-T细胞疗法在抗肿瘤方面取得了前所未有的临床成功， 长时间和劳动密集型的体外制造程序限制了广泛的应用，导致： (一)治疗费用非常高，高达50万美元；。(二)延迟数周或数月输注CAR-T细胞。 对进展迅速的疾病的患者；以及(Iii)异质性成分和终末分化 输注CAR-T细胞是体外培养的结果，这限制了CAR-T细胞的植入和持久性。尽管 在这一领域取得重大成就，减少时间、成本和监管负担仍然是一个深层次的问题 CAR-T细胞治疗和显著减少或消除体外程序的需要仍然是一个关键的未得到满足的问题 需要。这项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 体外培养CAR-T细胞，增强CAR-T细胞的表型和功能。我们建议在短时间内(~小时) 抗CD3/CD28抗体的预激活步骤可以立即通过转导和传递来进行 使用生物材料支架。这一多样性补充将支持Trey Davis博士，并允许他参与 新的实验扩大了目标1的研究范围，并将使他能够在相关的 技术、职业发展和职业规划。我们预计，我们的结果将为 一般细胞治疗策略，并促进患者的广泛接触，特别是在有 一直是健康差距的受害者。

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.