Fibrolamellar carcinoma (FLC) is a rare and lethal liver cancer that has no effective systemic therapy. It occurs primarily in young patients, and nearly all of the tumors are driven by the oncogenic fusion protein DNAJ-PKAc. The fusion of any two cellular proteins should create a unique and novel antigen at the fusion point. The Thomas lab hypothesizes that engineered antigen receptors directed at this fusion neoantigen could form the basis for an effective adoptive cell therapy in FLC. The group has preliminary data suggesting that patients can mount a T-cell response against the fusion antigen in FLC. The goal of the project is to identify endogenous T-cell receptors (TCRs) targeting the fusion antigen that could be used for adoptive T-cell therapy. One potential obstacle is that a TCR must be matched to an appropriate human leukocyte antigen (HLA) molecule in each patient for the therapy to be effective. A suite of different fusion-specific TCRs will need to be identified to cover the diverse array of HLA molecules found in patients. Using patient-derived FLC samples of multiple HLA types, researchers in the Thomas lab aim to identify and clone TCRs capable of mediating a therapeutic response. Candidate TCRs will be taken forward for functional testing in vitro to ascertain their impact on HLA restriction in models of different HLA types. This research is a critical first step in developing a cellular immunotherapy that relies on native, patient-derived TCRs, which could one day change the landscape of immunotherapy for FLC and other solid tumors.