Engineered TCR-T Cell Therapy Targeting Driver Mutations in NSCLC

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PROJECT SUMMARY Project Title: Engineered TCR-T Cell Therapy Targeting Driver Mutations in NSCLC Organization: GigaMune Inc. PI: Matthew J Spindler, Ph.D. Adoptive cell therapies (ACTs) including CAR-T, TCR-T, and TIL therapies have shown strong clinical responses 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 hematological cancers. Numerous TCR-T cell clinical trials are ongoing for the treatment of solid tumors, but these trials target only a handful of well-known cancer-testis and over expressed tumor antigens. Thus, there is a need to develop TCR-T cell therapies that target novel tumor antigens. Recurrent cancer driver mutations and fusion events in genes like KRAS, EGFR, and ALK drive tumorigenesis in numerous cancers including non-small cell lung cancer (NSCLC). Importantly, these mutations are homogenously present within the tumor and the generated neoantigens have shown immunogenicity in cancer patients and healthy individuals across common HLA types. This suggests that TCR-T cell therapies targeting driver 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 target recurrent cancer driver gene mutations present in NSCLC patients for use in TCR-engineered autologous or allogeneic ACTs (TCR-T cells). GigaMune's unique technology uses microfluidics, genomics, and mammalian display to generate millions-diverse, natively paired TCRab repertoire libraries. The TCRab libraries are immortal, 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 GigaMune technology and supported by leading NSCLC oncologists Justin Gainor and Alice Shaw (Mass General). After completing 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.