KRAS G12V neoantigen-specific TCR identification in non-small cell lung cancer patients and healthy donors and immunogenicity assessment in vitro and in vivo

Non-small cell lung cancer (NSCLC) is one of the most common and deadliest cancers with about 1.5 million associated deaths per year worldwide. The treatment for metastatic NSCLC advanced tremendously in the last decade with the entrance of new efficient targeted treatments for specific patients, and for the rest the addition of immunotherapy to the chemotherapy backbone improved response and survival. Nevertheless, many patients respond for a short while or not at all and the mortality rates are high. The immune response against tumor cells is thought to be driven by neoantigen presentation, thus the identification of recurrent and immunogenic neoantigens could be a potential target for new immunotherapy treatments as cancer vaccines and T-Cell Receptor (TCR)-engineered T cells, especially in cancers that have previously proved response to immunotherapy as NSCLC.

Using a data-driven approach, we identified a recurrent neoantigen derived from the KRAS G12V mutation (prevalent in ~6% of NSCLC patients). Next, by applying physically interacting cells sequencing and TCR-sequencing, we will molecularly characterize the immuno-reactivity of the neoantigen on T-B cell crosstalk, and identify the neoantigen-specific TCR in cohorts of NSCLC patients and healthy donors with matched HLA allotype. Next, we will functionally characterize the immuno-reactivity of the detected TCRs in vitro and in vivo.

The success of this project could be utilized for future clinical trials of personalized TCR therapies relevant for thousands of NSCLC patients but also for many other patients with solid tumors harboring the KRAS G12V mutation as colon and pancreas cancer patients.