DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma

Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in this disease is its highly conserved driver mutation: a gene fusion between DNAJB1 and PRKACA, which is expressed in all FLC tumors and could be an ideal neoantigen target for immunotherapy. In this study, we aimed to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) as candidates for novel cellular immunotherapies. Although fusion-specific T cells in FLC appear to be difficult to detect, we nevertheless defined an endogenous functional T cell response in an FLC patient. We further identified two fusion-specific TCRs, validated their specificity and function in vitro, and showed that one has strong anti-fusion activity in an in vivo xenograft model. Together, our results provide compelling support for clinical development of immunotherapies for FLC.