EAGER: Biomanufacturing: Towards Reproducible and Scalable Biomanufacturing of Tumor-Specific T Cells with Optimal Phenotype and Function for Personalized Immunotherapy

EAGER：生物制造：实现具有最佳表型和功能的肿瘤特异性 T 细胞的可重复和可扩展的生物制造，用于个性化免疫治疗

• 批准号: 1645229
• 负责人: Fei Wen
• 金额: $ 30万
• 依托单位: Regents of the University of Michigan - Ann Arbor
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1645229&HistoricalAwards=false
• 关键词: EAGER; Biomanufacturing; Towards; Reproducible; Scalable

1645229 - Wen Cancer is responsible for about 25% of deaths in the US. Developing an effective adoptive T-cell therapy (ACT), a promising and highly personalized cancer immunotherapy, holds significant benefits for society. However, it remains a significant challenge to develop reproducible and scalable manufacturing processes to reliably generate T cells with high anti-tumor activity. This project aims to address this challenge by developing a rapid, simple, and comprehensive T-cell profiling method. It represents a novel and radically different approach with transformative potential by addressing multiple roadblocks to the commercialization of ACT, including manufacturing reproducibility, therapeutic effectiveness and patient-to-patient variability. Research findings will also be used to strengthen undergraduate and graduate curricula, to power engineering outreach endeavors that encourage early exposure of K-12 students to science and engineering, and to increase public scientific literacy. Innovative pedagogies will be developed that can be readily incorporated by educators at all levels to improve their students' learning. These efforts will collectively help create a new generation of engineers with skills and fundamental knowledge in both engineering and life sciences. Adoptive T-cell therapy (ACT) is a highly personalized cancer immunotherapy that involves the infusion into patients of their natural or genetically engineered tumor-reactive T cells manufactured ex vivo. Expansion of a single naïve human T cell yields a heterogeneous population exhibiting a range of phenotype and function. While this diversity helps T cells acquire specialized responses to different types of pathogens and cancers at different stages, it represents a significant technical challenge to reproducible, large-scale manufacturing of T cells for therapeutic purposes. Therefore, it is critical to have a high performance T-cell profiling method to closely monitor their phenotype, function and specificity. Unfortunately, the current standard technology requires several sample runs, adding complexity, variability and workload to the manufacturing process. To address this issue, a T-cell profiling method will be developed to enable simultaneous detection of dozens of parameters on single T cells in a heterogeneous population in a single run. Visualization methods of the resulting high-dimensional data will be developed to facilitate objective data-analysis automation in the quality control steps of the manufacturing process. In parallel, by developing and applying an innovative artificial antigen presentation system, T cells specific to a range of subdominant tumor-associated antigens found in breast cancer will be expanded from human donors. Coupled with the T-cell profiling method developed here, these T cells provide valuable opportunities to systematically screen for optimal expansion conditions of subdominant T cells and define their molecular metrics that correlate with the best anti-tumor activity. The definition of such metrics will further simplify the quality control protocol and facilitate the standardization of the ACT manufacturing process.

1645229 -在美国，癌症占死亡人数的25%。 开发有效的过继性T细胞疗法（ACT），这是一种有前途的高度个性化的癌症免疫疗法，对社会有重大利益。然而，开发可重复和可扩展的制造工艺以可靠地产生具有高抗肿瘤活性的T细胞仍然是一个重大挑战。该项目旨在通过开发一种快速，简单和全面的T细胞分析方法来应对这一挑战。它代表了一种全新的、完全不同的方法，通过解决ACT商业化的多个障碍（包括制造重现性、治疗有效性和患者间差异性），具有变革潜力。研究结果还将用于加强本科和研究生课程，以动力工程推广工作，鼓励K-12学生早期接触科学和工程，并提高公众的科学素养。将制定创新的教学方法，供各级教育工作者随时采用，以改善学生的学习。这些努力将共同帮助创造新一代工程师，他们在工程和生命科学方面都具有技能和基础知识。免疫性T细胞疗法（ACT）是一种高度个性化的癌症免疫疗法，其涉及将离体制造的天然或基因工程肿瘤反应性T细胞输注到患者体内。单个幼稚人类T细胞的扩增产生了表现出一系列表型和功能的异质群体。虽然这种多样性有助于T细胞在不同阶段获得对不同类型病原体和癌症的专门反应，但它代表了用于治疗目的的T细胞的可重复，大规模制造的重大技术挑战。因此，关键是要有一个高性能的T细胞分析方法，以密切监测其表型，功能和特异性。不幸的是，目前的标准技术需要几个样品运行，增加了制造过程的复杂性，可变性和工作量。为了解决这个问题，将开发一种T细胞分析方法，以在单次运行中同时检测异质群体中单个T细胞上的数十个参数。将开发所得高维数据的可视化方法，以促进制造过程质量控制步骤中的客观数据分析自动化。同时，通过开发和应用创新的人工抗原呈递系统，将从人类供体中扩增对乳腺癌中发现的一系列亚显性肿瘤相关抗原具有特异性的T细胞。再加上这里开发的T细胞分析方法，这些T细胞提供了宝贵的机会，系统地筛选亚显性T细胞的最佳扩增条件，并定义与最佳抗肿瘤活性相关的分子指标。这些指标的定义将进一步简化质量控制方案，并促进ACT生产工艺的标准化。

项目成果

Rapid microsphere‐assisted peptide screening (MAPS) of promiscuous MHCII‐binding peptides in Zika virus envelope protein

寨卡病毒包膜蛋白中混杂的 MHCII 结合肽的快速微球辅助肽筛选 (MAPS)

• DOI: 10.1002/aic.16697
• 发表时间: 2019
• 期刊: AIChE Journal
• 影响因子: 3.7
• 作者: Smith, Mason R.;Bugada, Luke F.;Wen, Fei
• 通讯作者: Wen, Fei

The female-biased factor VGLL3 drives cutaneous and systemic autoimmunity

• DOI: 10.1172/jci.insight.127291
• 发表时间: 2019-04-18
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Billi, Allison C.;Gharaee-Kermani, Mehrnaz;Gudjonsson, Johann E.
• 通讯作者: Gudjonsson, Johann E.

Engineering Spatially Organized Multienzyme Assemblies for Complex Chemical Transformation

• DOI: 10.1021/acscatal.8b01883
• 发表时间: 2018-09-01
• 期刊: ACS CATALYSIS
• 影响因子: 12.9
• 作者: Bugada, Luke F.;Smith, Mason R.;Wen, Fei
• 通讯作者: Wen, Fei