EAGER: Biomanufacturing: BATON: Bioreactor System for Autologous T-Cell Stimulation

1645205-癌症治疗的下一个主要前沿涉及使用患者自己的细胞来靶向并摧毁癌细胞和肿瘤。几十年的基础研究以完全个性化的新疗法的形式取得了突破。最常被用于靶向癌症的细胞类型是T细胞，这是一种白细胞。这些细胞可以通过几种不同的方式之一进行修饰，以赋予它们靶向能力。一种方法是使用身体对感染等威胁做出反应的自然机制。树突状细胞是存在于身体多个部位的细胞；这些细胞能够识别威胁并将其基本特征传递给T细胞，然后T细胞可以摧毁感染性病原体。这种方法也可以用于靶向癌症，方法是从患者身上获取树突状细胞，将这些细胞暴露在肿瘤衍生材料中，然后利用这些细胞刺激从患者血液中获得的T细胞。这一过程还会导致T细胞在数量上显著扩张或增殖。然后，这些T细胞被重新注入患者体内，以靶向患者的癌症。这种方法在多个早期临床试验中被发现在癌症治疗中非常有效。然而，这种治疗方法的一个主要挑战是治疗的个性化性质。每个患者的治疗由他/她自己的细胞组成，根据他/她自己的癌症特征准备。目前的方法需要超过4600个手动步骤来为一个患者准备一个治疗剂，这在治疗全国大量患者方面既不实用，也不划算。该项目以跨学科的方法解决与T细胞刺激相关的制造挑战，以设计一次性刺激系统，该系统可以接受树突状细胞和T细胞样本，以及时和有效的方式完成所需的刺激，并产生足够的治疗剂量的T细胞。预计与T细胞刺激过程相关的步骤数量将显著减少。此外，该过程将基本上自动化，以最大限度地减少人工处理。该项目的教育影响将是对一名博士后科学家和多名学生进行学术和产业合作的培训。最近成功的临床演示了免疫系统调节大型和已建立的肿瘤排斥反应的能力，这代表了癌症治疗的范式转变，这将给医学带来革命性的变化。从肿瘤测序数据中预测候选新抗原和监测患者中新抗原特异性T细胞反应的能力为设计个性化的人类治疗方法提供了基础，最近几个小组已经有效地证明了这种方法。在这种方法中，从患者血液中获得的T细胞通过与抗原呈递细胞共培养来刺激和扩增，其中最有效的是来自同一患者的单核细胞来源的树突状细胞。在几项临床研究中，已经取得了深刻而持久的临床反应。然而，人们普遍认识到，目前制造这种疗法的方法远远不够，也不会让这些疗法的真正潜力在我们整个社会得到广泛实现。人工细胞培养技术仍然是生产的中流砥柱，这既不实用，也不划算。该项目旨在通过将自动化和下一代生物反应器设计相结合来解决对高效T细胞刺激技术的未满足需求。用于自体T细胞刺激(BASON)系统的生物反应器将利用流体系统以及质量传输方面的最新进展，并将由Neon治疗公司的免疫学家和东北大学的工程师紧密合作进行设计。接力棒系统采用高度模块化设计，具有完全一次性的部件，包括一次性泵和机载试剂存储。这种设计将使大量这样的单元能够并行使用，以处理来自多个患者的样本，用户只需要在每个患者剂量下执行总共约180个步骤。该项目解决了个性化T细胞疗法制造过程中的一个关键需求。封闭式系统处理对于此类疗法的可扩展制造是非常必要的，但这种处理系统很难设计，因为与T细胞治疗生产相关的复杂生物过程以及与自体细胞处理相关的生物过程和监管要求。T细胞和树突状细胞之间的相互作用是一个精确的过程，受到生化和物理参数的严格限制。这些条件必须在拟议的自动化系统的设计中重复，需要仔细的实验设计和计算模型的补充。该项目有望克服有效制造治疗癌症的自体T细胞疗法的主要障碍。

1645205 - MurthyThe next major frontier in the treatment of cancer involves the use of a patient's own cells to target and destroy cancer cells and tumors. Decades of fundamental research has led to breakthroughs in the form of new therapies that are entirely personalized. The cell type that is most commonly used to target cancers is the T cell, a type of white blood cell. These cells can be modified in one of several different ways to endow them with targeting capability. One way is to use the natural mechanism by which the body responds to threats such as infections. Dendritic cells are cells that are present in multiple locations of the body; these cells are capable of identifying threats and communicating their essential characteristics to T cells, which can then destroy the infectious agents. This type of approach can also be utilized to target cancer by obtaining dendritic cells from a patient, exposing these cells to tumor-derived material, and then utilizing these cells to stimulate T cells obtained from the patient's blood. This process also causes the T cells to expand, or multiply significantly in number. These T cells are then infused back into the patient to target the patient's cancer. This approach has been found to be highly effective in cancer treatment in multiple early-stage clinical trials. However, a major challenge with this therapeutic approach is the personalized nature of the treatment. Each patient's therapy consists of his/her own cells, prepared based on his/her own cancer characteristics. Current methods require over 4,600 manual steps to prepare one therapeutic dose for one patient, which is neither practical nor cost-effective in treating large numbers of patients across the nation. This project addresses the manufacturing challenge associated with T cell stimulation with an interdisciplinary approach to design disposable stimulation systems that can accept dendritic cell and T cell samples, accomplish the desired stimulation in a timely and efficient manner, and generate enough T cells for a therapeutic dose. It is expected that the number of steps associated with the T cell stimulation process will be reduced significantly. Furthermore the process will be substantially automated to minimize manual handling. The educational impact of this project will be in the form of training for a postdoctoral scientist and multiple students in an academic-industrial collaboration.The recent successful clinical demonstration of the immune system's ability to mediate rejection of large and established tumors represents a paradigm shift in cancer therapy that will revolutionize medicine. The ability to predict candidate neoantigens from tumor sequencing data and monitoring neoantigen-specific T-cell responses in patients provides a basis for designing personalized therapies in humans, and this approach has been effectively demonstrated by several groups recently. In this approach, T cells obtained from the patient's blood are stimulated and expanded by co-culture with antigen-presenting cells, the most potent of which are dendritic cells derived from monocytes obtained from the same patient. Deep and durable clinical responses have been achieved in several clinical studies. Yet it is widely recognized that current approaches to the manufacturing of such therapies are far from adequate and will not allow the true potential of these therapies to be broadly realized across our society. Manual cell culture techniques remain the mainstay of production, which is neither practical nor cost-effective. This project aims to address the unmet need for efficient T cell stimulation technologies by a combination of automation and next-generation bioreactor design. The Bioreactor for Autologous T Cell Stimulation (BATON) system will leverage recent advances in fluidic systems as well as mass transport and will be designed in a tight-knit collaborative effort by immunologists at Neon Therapeutics and engineers at Northeastern University. The BATON system features a highly modular design with fully disposable components including disposable pumps and on-board reagent storage. This design will enable large numbers of such units to be used in parallel to process samples from multiple patients, with the users only needing to perform a total of about 180 steps per patient dose. This project addresses a critical need in the manufacturing process of personalized T cell therapies. Closed system processing is highly desired for the scalable manufacturing of such therapies, but such processing systems are difficult to design because of the complex biological processes associated with T cell therapy production as well as the bioprocess and regulatory requirements associated with autologous cell processing. The interaction between T cells and dendritic cells is a precise process with tight constraints with respect to biochemical and physical parameters. These conditions must be replicated in the design of the proposed automated system, requiring careful experimental design supplemented by computational modeling. This project is expected to overcome a major impediment to effective manufacturing of autologous T cell therapies for cancer.