Adoptive cell therapies (ACTs) including CAR-T, TCR-T, and TIL therapies have shown strong clinicalresponses for the treatment of cancer patients for hematological cancers and solid tumors. However, only anti-CD19 CAR-T cell therapies have been FDA approved and commercialized for the treatment of hematologicalcancers. Numerous TCR-T cell clinical trials are ongoing for the treatment of solid tumors, but these trialstarget only a handful of well-known cancer-testis and over expressed tumor antigens. Thus, there is a need todevelop TCR-T cell therapies that target novel tumor antigens.Recurrent cancer driver mutations and fusion events in genes like KRAS, EGFR, and ALK drive tumorigenesisin numerous cancers including non-small cell lung cancer (NSCLC). Importantly, these mutations arehomogenously present within the tumor and the generated neoantigens have shown immunogenicity in cancerpatients and healthy individuals across common HLA types. This suggests that TCR-T cell therapies targetingdriver mutations would be a safe and effective treatment for NSCLC.The Specific Aim of this Phase I SBIR project is to develop a catalog of natural human TCRs that targetrecurrent cancer driver gene mutations present in NSCLC patients for use in TCR-engineered autologous orallogeneic ACTs (TCR-T cells). GigaMune's unique technology uses microfluidics, genomics, and mammaliandisplay to generate millions-diverse, natively paired TCRab repertoire libraries. The TCRab libraries areimmortal, enabling repeated experimentation with a panel of antigens. This will expedite discovery of rare anti-driver mutation TCRs.The project is led by Dr. Matthew J. Spindler, an expert in immunogenomics and inventor of the GigaMunetechnology and supported by leading NSCLC oncologists Justin Gainor and Alice Shaw (Mass General). Aftercompleting this Phase I SBIR project, GigaMune will further develop promising TCRs as TCR-T cell therapies,through in vivo efficacy studies, in vitro safety studies, and manufacturing development. PROJECT NARRATIVE Project Title: Engineered TCR-T Cell Therapy Targeting Driver Mutations in NSCLC Organization: GigaMune Inc. PI: Matthew J Spindler, Ph.D. Cancer remains an intractable disease, but doctors have been achieving incredible results with new therapies that rely on genetic engineering of T cells. We are using microfluidics and DNA sequencing to capture disease- modulating T cells from patients. Antitumor genes from these T cells are then engineered into healthy T cells to create a TCR-engineered T cell therapy. 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