Specific recognition of anFGFR2fusion by tumor infiltrating lymphocytes from a patient with metastatic cholangiocarcinoma

Abstract

BackgroundMetastatic cholangiocarcinoma (CC), a form of gastrointestinal cancer that originates from the bile ducts, cannot be cured by currently available therapies, and is associated with dismal prognosis. In a previous case report, adoptive transfer of autologous tumor infiltrating lymphocytes (TILs), the majority of which recognized a tumor-specific point mutation, led to a profound and durable cancer regression in a patient with metastatic CC. Thus, more effective treatment for patients with this disease may be developed by using TILs that target cancer-specific mutations, but also other genetic aberrations such as gene fusions. In this context, fusions that involvefibroblast growth factor receptor 2(FGFR2) and function as oncogenes in a subset of patients with intrahepatic CC (ICC) represent particularly attractive targets for adoptive cell therapy. However, no study to date has explored whetherFGFR2fusions can be recognized by patients’ T cells.MethodTo address whetherFGFR2fusions can be recognized by patients’ T cells, we tested TILs from four patients withFGFR2fusion-positive ICC for recognition of peptides and minigenes that represented the breakpoint regions of these fusions, which were unique to each of the four patients.ResultsWe found that CD4+TILs from one patient specifically recognized the breakpoint region of a uniqueFGFR2-TDRD1 (tudor domain-containing 1)fusion, and we isolated a T-cell receptor responsible for its recognition.ConclusionsThis finding suggests thatFGFR2fusion-reactive TILs can be isolated from some patients with metastatic ICC, and thus provides a rationale for future exploration of T cell-based therapy targetingFGFR2fusions in patients with cancer. Furthermore, it augments the rationale for extending such efforts to other types of solid tumors hallmarked by oncogenic gene fusions.