SBIR Phase I: High throughput and antigen specific T-cell receptor discovery through engineered macrophages

这个小型企业创新（SBIR）I期项目的更广泛影响是为治疗选择有限的晚期癌症患者发现所需的基于T细胞受体（TCR）的治疗方法。这些免疫疗法通过利用用TCR工程化的T细胞来起作用，所述TCR将识别并破坏在其表面上天然呈递对癌症特异性的标志物（抗原）的癌细胞（例如，癌症突变）。该项目将开发一个高通量平台，能够针对数千种抗原筛选数千种TCR，以识别临床相关的TCR。该项目可以通过发现TCR来影响社会的健康，这些TCR将作为治疗目前无法治愈的癌症的基础。商业影响可能很大。2018年，T细胞疗法的总市场规模为24亿美元，预计到2027年将达到85亿美元。本项目所描述的平台有可能发现许多基于TCR的治疗方法，为患者和整个社会创造价值。拟议的项目是开发一个用于识别具有临床价值的TCR的平台。该平台对于开发针对实体瘤的新免疫疗法和理解TCR-抗原相互作用的生物学基础至关重要。由于难以追踪数十万个独特细胞之间的相互作用，筛选数千个TCR以针对数千种抗原进行功能活化是具有挑战性的。所提出的平台和方法使用工程化的T-巨噬细胞和抗原呈递细胞（APC）系将T-细胞活化与吞噬作用联系起来。T-巨噬细胞如TCR活化所指导的那样吞噬APC，捕获T-巨噬细胞内相互作用的证据。所产生的相互作用可以通过单细胞测序从T-巨噬细胞读取。该项目的目标是产生TCR和抗原的大型细胞库，并鉴定相互作用的TCR-抗原对。该抗原库将包括数百个临床相关的癌症靶标，如KRAS和TP 53。这个奖项反映了NSF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 of this Small Business Innovation (SBIR) Phase I project is to enable discovery of needed T-cell receptor (TCR) based therapeutics for late-stage cancer patients who have limited treatment options. These immunotherapies work by leveraging T-cells engineered with TCRs that will identify and destroy cancer cells that naturally present a marker (antigen) specific to the cancer on their surface (e.g., cancer mutations). This project will develop a high-throughput platform capable of screening many thousands of TCRs against many thousands of antigens to identify clinically relevant TCRs. This project could impact society’s health by discovering TCRs that will serve as the basis for treatments against currently incurable cancers. The commercial impacts are potentially large. The total market size of T-cell therapeutics was $2.4 billion in 2018 and is estimated to reach $8.5 billion by 2027. The platform described by this proposal has the potential to discover many TCR based therapeutics, creating value for patient and society at large.The proposed project is to develop a platform for identifying clinically valuable TCRs. This platform could be critical for developing new immunotherapies against solid tumors and for understanding the biology that underlies TCR-antigen interaction. Screening thousands of TCRs for functional activation against thousands of antigens is challenging due to the difficulty of tracking interactions between hundreds of thousands of unique cells. The proposed platform and method links T-cell activation with phagocytosis using engineered T-macrophage and antigen presenting cell (APC) lines. T-macrophages engulf APCs as directed by TCR activation, capturing evidence of an interaction within the T-macrophage. The resulting interactions can be read from the T-macrophages via single-cell sequencing. The objective of this project is to produce large cell-based libraries for TCR and antigens and to identify interacting TCR-antigen pairs. The antigen library will include hundreds of clinically relevant cancer targets, such as KRAS and TP53. These results will demonstrate the feasibility of our platform.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.