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

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.