UNS: Tunable and Scalable Protein Assemblies for Personalized Cancer Immunotherapy

UNS：用于个性化癌症免疫治疗的可调节和可扩展的蛋白质组件

• 批准号: 1511720
• 负责人: Fei Wen
• 金额: $ 34万
• 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: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1511720&HistoricalAwards=false
• 关键词: UNS; Tunable; Scalable; Protein; Assemblies

1511720 (Wen)Cancer is projected to cause well over half-a-million deaths in the US in 2015, and is expected to surpass heart diseases as the leading cause of death in the next few years. While T-cell-based immunotherapy holds great potential to cure cancer, there are multiple roadblocks including therapeutic effectiveness, patient individuality, biomanufacturing, and cost. This proposal aims to tackle these limitations by making nanoscale assemblies of proteins that can collectively program a patient's own immune system to seek out and destroy the cancer cells. The modular nature and the inexpensive production system of the protein assemblies hold promise to make personalized cancer immunotherapy both effective and affordable. The successful completion of this work will provide an enabling strategy for developing personalized immunotherapy to treat cancer and help define the metrics of effective anti-tumor immune cell responses.T-cell based immunotherapy holds great promise to treat cancer, as recognized by the recent approval of sipuleucel-T to treat advanced prostate cancer. The key to a successful T-cell immunotherapy is to elicit a potent anti-tumor response by presenting the right signals (i.e. protein ligands) in the right spatial pattern to T cells as observed in the immunological synapse. While artificial presenting systems represent an affordable alternative to adoptive transfer of patient's own immune cells, their existing designs lack the spatial control of the protein ligands, resulting in limited beneficial clinical outcome. The investigator proposes a novel approach of synthesizing tunable and scalable protein assemblies (TSPAs), which consist of multiple T-cell-activating protein ligands of choice that self-assemble into defined supramolecular patterns on an addressable scaffold. Coupled with high dimensional single-cell phenotyping, the availability of the proposed TSPAs opens up the possibility to engineer personalized and affordable immunotherapy. Specifically, using breast cancer as a model system, the investigators will establish the relationship between the composition of the T-cell-activating ligands in the TSPA, the pattern of the ligands, and the anti-tumor activity of the activated T cells. This will further enable the identification of the optimal TSPA configuration to mount an effective anti-tumor T-cell response. The successful completion of this work will provide an enabling strategy for developing personalized immunotherapy to treat other types of cancer, and help define the metrics of effective anti-tumor T-cell responses. The definition of such a standard will significantly improve the ability to predict T-cell therapeutic outcome and help provide guidelines for designing better cancer therapeutics and vaccines. To generate a broader impact, protein and life science research-based learning platform will be established at different academic levels to foster students' interest in engineering and manufacturing therapeutic molecules, increase their knowledge in the emerging field of personalized medicine, and provide new opportunities for women and underrepresented minorities to pursue careers in engineering and medicinal science. These efforts will collectively help create a new generation of engineers with a multi-disciplinary skillset ready to make an impact on human health.

2015年，癌症预计将在美国造成50多万人死亡，预计在未来几年内，癌症将超过心脏病成为导致死亡的主要原因。虽然基于t细胞的免疫疗法在治愈癌症方面具有巨大的潜力，但存在多种障碍，包括治疗效果、患者个性、生物制造和成本。这项提议旨在通过制造纳米级蛋白质组件来解决这些限制，这些蛋白质组件可以共同编程患者自身的免疫系统，以寻找并摧毁癌细胞。蛋白质组装的模块化性质和廉价的生产系统有望使个性化的癌症免疫治疗既有效又负担得起。这项工作的成功完成将为开发个性化的免疫疗法来治疗癌症提供一个有利的策略，并有助于确定有效的抗肿瘤免疫细胞反应的指标。基于t细胞的免疫疗法在治疗癌症方面有着巨大的希望，正如最近批准的sipuleucel-T治疗晚期前列腺癌所认识到的那样。成功的T细胞免疫治疗的关键是通过在免疫突触中观察到的以正确的空间模式向T细胞提供正确的信号（即蛋白质配体）来引发有效的抗肿瘤反应。虽然人工呈递系统是患者自身免疫细胞过继转移的一种经济实惠的替代方案，但其现有设计缺乏对蛋白质配体的空间控制，导致有益的临床结果有限。研究者提出了一种合成可调节和可扩展的蛋白质组件（tspa）的新方法，tspa由多种t细胞激活蛋白配体组成，这些配体可以在可寻址的支架上自组装成定义的超分子模式。再加上高维单细胞表型，所提出的tspa的可用性为设计个性化和负担得起的免疫疗法提供了可能性。具体来说，以乳腺癌为模型系统，研究者将建立TSPA中T细胞活化配体的组成、配体的模式和活化T细胞的抗肿瘤活性之间的关系。这将进一步确定最佳的TSPA配置，以建立有效的抗肿瘤t细胞反应。这项工作的成功完成将为开发个性化免疫疗法来治疗其他类型的癌症提供一个有利的策略，并有助于确定有效的抗肿瘤t细胞反应的指标。这样一个标准的定义将显著提高预测t细胞治疗结果的能力，并有助于为设计更好的癌症治疗方法和疫苗提供指导。为了产生更广泛的影响，将在不同的学术水平上建立基于蛋白质和生命科学研究的学习平台，以培养学生对工程和制造治疗分子的兴趣，增加他们在个性化医疗新兴领域的知识，并为女性和未被充分代表的少数民族追求工程和医学科学的职业提供新的机会。这些努力将共同帮助培养具有多学科技能的新一代工程师，他们随时准备对人类健康产生影响。