Novel Approach to High-Throughput Identification and Characterization of Neoantigen-Specific T-Cell Receptors to Guide Immunotherapy Development. - PROJECT SUMMARY Despite tremendous progress, a significant fraction of cancer patients will not benefit from the latest breakthroughs in immunotherapy development due to the characteristics of their tumor. T-cell Receptor engineered T-cells (TCR T-cells) targeting tumor specific neoantigens has arisen as a promising approach to improve efficacy, decrease toxicity and overcome acquired resistance. However, the highly personalized nature of such treatments that relies solely on the recognition of antigens expressed in specific cancers by corresponding T-Cell Receptors (TCRs) makes their development especially challenging. The identification and characterization of immunogenic neoantigen targets and their associated TCRs has been recognized as a major challenge due to the multiplicity of mutations in cancer and the lack of high-throughput methods to identify neoantigen-specific TCRs. Consequently, most current clinical developments have been focused on tumor mutations that have high prevalence among cancer patients, leaving many patients without therapeutic options. To increase the number of clinically relevant targets and candidates, thus the pool of eligible patients, Flexomics is developing a next generation of screening platform dedicated to the high-throughput discovery and characterization of antigen-specific TCRs. Our approach combines live cell analysis, gold-standard immunoassays and state-of-the-art single cell genomics in a unique platform specifically designed for the screening of neoantigen/T-cell interactions. Our proprietary platform is designed to identify T-cell activation in response to specific antigen exposure at single cell level for 100,000s T-cells while simultaneously capturing phenotypic and genotypic information in the form of expression of key marker genes and full-length TCR sequence identification. Building on our promising feasibility result, we propose to demonstrate the scalability and functional relevance of our method by: (1) increasing our screening capabilities by interrogating multiple antigens, (2) integrating, streamlining and automating all the different components of our process, (3) validate our workflow and generate proof-of-concept data for 100 select cancer targets. At the end of our Phase II grant, we will be ideally positioned to start engaging with external customers, strategic partners and investors to drive the adoption of our platform and the translation of the data generated into therapeutic developments.
