SBIR Phase I: Automated Closed Systems for Manufacturing Autologous Dendritic Cell Therapies

这项小型企业创新研究项目的更广泛影响/商业潜力在于开发新技术，以制造基于患者自身细胞的针对癌症和其他疾病的个性化疗法。近年来，这种疗法取得了显著的成功，然而，制造这些疗法具有挑战性，因为当每位患者接受独特的治疗时，无法采用大规模生产技术。事实上，对于基于树突状细胞的治疗，树突状细胞是人类免疫系统的重要组成部分，目前还没有可用的制造系统可以执行所有必需的步骤。该项目将通过利用工程和生物学的先进概念，设计一个具有成本效益的树突状细胞疗法制造的集成系统，解决这一主要未满足的需求。鉴于目前临床试验中大量的个性化细胞疗法，以及最近批准的疗法，这样的系统有望满足主要的社会需求，并具有巨大的商业潜力。这个SBIR一期项目建议开发一个制造系统，以涵盖制造自体树突状细胞疗法所涉及的步骤。由于这些细胞在血液中的丰度较低，树突状细胞通常由血液来源的单核细胞产生。单核细胞分化为树突状细胞后，这些细胞成熟并受到肿瘤特异性抗原的刺激。这些步骤代表了离散的单元操作，需要一个能够处理贴壁和非贴壁细胞类型的系统，每个步骤使用不同的试剂，并且能够以最小的细胞损失从一个步骤过渡到另一个步骤。此外，所有步骤必须在一次性使用的外壳中进行。为了实现这些步骤的自动化和集成，所提出的系统将利用基于灌注的树突状细胞培养和新颖且具有成本效益的生物反应器设计策略的创新。计算建模和快速原型技术的结合将用于原型的快速迭代和潜在用户参与治疗开发的测试。该项目的成功完成将导致集成制造系统的可行性论证，并获得重要的最终用户反馈。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) project is in the development of new technologies to manufacture personalized therapies for cancer and other diseases that are based on a patient's own cells. Such therapies have shown remarkable success in recent years, however, manufacturing these therapies is challenging because mass production techniques cannot be employed when each patient receives a unique therapy. Indeed, for therapies based on dendritic cells, which are an important part of the human immune system, there are no manufacturing systems currently available that can perform all of the required steps. This project will address this major unmet need by leveraging advanced concepts in engineering and biology to design an integrated system for cost-effective manufacturing of dendritic cell therapies. Given the large number of personalized cell-based therapies currently in clinical trials, and recently approved therapies, such a system is expected to address a major societal need and have significant commercial potential. This SBIR Phase I project proposes to develop a manufacturing system to cover the steps involved in the manufacturing of autologous dendritic cell therapies. Because of the low abundance of these cells in blood, dendritic cells are typically generated from blood-derived monocytes. Following differentiation of monocytes into dendritic cells, these cells are then matured and stimulated with tumor-specific antigens. These steps represent discrete unit operations that require a system capable of handling both adherent and non-adherent cell types, different reagents for each step, and the ability to transition from one step to another with minimal loss of cells. Further, all steps must be performed in a disposable single-use enclosure. In order to achieve automation and integration of these steps, the proposed system will leverage innovations in perfusion-based dendritic cell culture and novel and cost-effective bioreactor design strategies. A combination of computational modeling and rapid-prototyping techniques will be employed for rapid iteration of prototypes and testing with potential users involved in therapeutic development. Successful completion of this project will result in feasibility demonstration of an integrated manufacturing system developed with significant end user feedback.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.