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

这个小企业创新(SBIR)第一阶段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)的治疗药物。这些免疫疗法的工作原理是利用携带TCR的T细胞，这种T细胞将识别和摧毁癌细胞，这些癌细胞自然会产生针对其表面癌症(例如，癌症突变)的特异性标记(抗原)。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。该项目可能会通过发现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。潜在的商业影响是巨大的。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。该方案所描述的平台具有发现许多基于TCR的治疗方法的潜力，为患者和整个社会创造价值。这一平台对于开发针对实体瘤的新免疫疗法以及了解TCR-抗原相互作用的生物学基础至关重要。由于很难跟踪数十万个独特细胞之间的相互作用，因此筛选数千个TCR针对数千个抗原的功能激活是具有挑战性的。建议的平台和方法使用工程化T-巨噬细胞和抗原提呈细胞(APC)系将T细胞激活与吞噬功能联系起来。T-巨噬细胞根据TCR激活的指示吞噬APC，捕捉到T-巨噬细胞内相互作用的证据。由此产生的相互作用可以通过单细胞测序从T-巨噬细胞中读出。该项目的目标是为TCR和抗原建立大型细胞文库，并鉴定相互作用的TCR-抗原对。抗原库将包括数百个临床相关的癌症靶点，如KRAS和TP53。这些结果将证明我们平台的可行性。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.