The Fibrolamellar Cancer Foundation has awarded a new research grant to Paul Thomas, PhD, of the Fred Hutchinson Cancer Center in Seattle, Washington to advance the development of T-cell receptor-engineered T-cell (TCR-T) therapies for fibrolamellar carcinoma (FLC).

FLC is driven by the DNAJB1-PRKACA fusion protein, a unique cancer-specific target that is absent from healthy cells. Previous research has shown that the immune system can recognize protein fragments derived from this fusion, and recent clinical studies suggest that immune responses directed against this target can lead to meaningful patient benefits.

One promising emerging therapeutic strategy is TCR-T cell therapy, in which a patient’s immune cells are engineered to include receptors that recognize and attack cancer cells that display DNAJB1-PRKACA-derived peptides. For T cells to recognize these peptides, they must be presented by molecules called human leukocyte antigens (HLAs). Because HLA types vary from person to person, a T-cell receptor that is effective in one patient will only work in other patients who share the same HLA type.

The goal of this project is to identify and characterize a broad library of DNAJB1-PRKACA-specific T-cell receptors that function across many different HLA types. Building on samples collected from patients treated with FLC immunotherapy, Dr. Thomas and his team will use advanced high-throughput technologies to discover new fusion-specific T-cell receptors and determine which HLA types they recognize.

By expanding the repertoire of available T-cell receptors, the investigators will lay the groundwork for TCR-T therapies that could be applicable to most patients with FLC.