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

这个小企业创新研究（SBIR）第二阶段项目的更广泛的影响/商业潜力是开发基于患者自身细胞的癌症和其他疾病的个性化疗法的新技术。 这种疗法在治疗以前难治性癌症方面显示出巨大的潜力。 然而，制造这些完全个性化的疗法的挑战是实现其在治疗效果和成本方面的全部社会潜力的能力的重大障碍。 该项目旨在消除基于树突状细胞的疗法的主要制造障碍，树突状细胞是人类免疫系统的重要组成部分，可以进行修改以针对特定疾病。 目前没有可用的制造系统可以执行制造个性化树突状细胞疗法的所有所需步骤。 该项目将通过利用工程和生物学的先进概念来解决这一主要未满足的需求，以设计一个具有成本效益的树突状细胞治疗制造集成系统。 鉴于目前在临床试验中和最近批准的大量基于细胞的个性化疗法，这种系统有望满足主要的社会需求，并具有巨大的商业潜力。 该SBIR II期项目将推进一种先进的生物反应器系统的商业化，用于自体树突状细胞疗法的封闭系统生产。 必须克服多种技术挑战，以自动化和集成与这些疗法的制造相关的单元操作。 由于树突状细胞在血液和组织中的丰度低，因此它们通常由白细胞减少症衍生的单核细胞产生。 粘附的单核细胞必须首先通过在IL 4和GM-CSF中孵育转化为非粘附的未成熟树突状细胞，然后成熟并用肿瘤特异性抗原刺激。为了在单个平台上实现这些步骤的自动化和集成，所提出的系统将建立在基于灌注的树突状细胞培养的成功I期工作的基础上，该工作能够减少与细胞因子输注相关的工艺步骤，并在简单且具有成本效益的一次性生物反应器设计中实现灌注。 此外，敏捷产品开发方法将与计算建模结合使用，以快速迭代地创建原型并在潜在客户手中进行测试。 从这些用户获得的反馈将被纳入预生产测试系统的组装中，该系统将在第二阶段结束时投入商业使用。该奖项反映了NSF的法定使命，并被认为值得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来支持。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project is in the development of new technologies to manufacture personalized therapies for cancer and other diseases, based on a patient's own cells. Such therapies have shown tremendous potential in the treatment of previously intractable cancers. However, challenges in manufacturing these completely personalized therapies are a significant impediment to the ability to realize their full societal potential both in terms of therapeutic efficacy and cost. This project aims to remove major manufacturing barriers for therapies based on dendritic cells, which are an important part of the human immune system and can be modified to target specific diseases. No manufacturing systems currently available can perform all the required steps of manufacturing personalized dendritic cell therapies. This project will address this major unmet need by leveraging advanced concepts in engineering and biology to design an integrated system for cost-effective dendritic cell therapy manufacturing. Given the large number of personalized cell-based therapies currently in clinical trials and recently approved, such a system is expected to address a major societal need and have significant commercial potential. This SBIR Phase II project will advance to commercialization an advanced bioreactor system for closed-system manufacturing of autologous dendritic cell therapies. Multiple technological challenges must be overcome to automate and integrate the unit operations associated with the manufacturing of these therapies. Because of their low abundance in blood and tissue, dendritic cells are typically generated from leukapheresis-derived monocytes. Adherent monocytes must first be converted into nonadherent immature dendritic cells via incubation inIL4 and GM-CSF, prior to maturation and stimulation with tumor specific antigens. In order to achieve automation and integration of these steps on a single platform, the proposed system will build on successful Phase I work in perfusion-based dendritic cell culture that enables reduction of process steps associated with cytokine infusion and achievement of perfusion in a simple and cost-effective single-use bioreactor design. In addition, an agile product development methodology will be utilized in conjunction with computational modeling to rapidly and iteratively create prototypes and test them in the hands of potential customers. Feedback obtained from these users will be incorporated into the assembly of a pre-production beta system to be launched commercially at the end of Phase II.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.