Adoptive T cell therapy cures mice from active hemophagocytic lymphohistiocytosis (HLH)

Primary hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome caused by impaired lymphocyte cytotoxicity. First‐line therapeutic regimens directed against activated immune cells or secreted cytokines show limited efficacy since they do not target the underlying immunological problem: defective lymphocyte cytotoxicity causing prolonged immune stimulation. A potential rescue strategy would be the adoptive transfer of ex vivo gene‐corrected autologous T cells. However, transfusion of cytotoxicity‐competent T cells under conditions of hyperinflammation may cause more harm than benefit. As a proof‐of‐concept for adoptive T cell therapy (ATCT) under hyperinflammatory conditions, we transferred syngeneic, cytotoxicity‐competent T cells into mice with virally triggered active primary HLH. ATCT with functional syngeneic trigger‐specific T cells cured Jinx mice from active HLH without life‐threatening side effects and protected Perforin‐deficient mice from lethal HLH progression by reconstituting cytotoxicity. Cured mice were protected long‐term from HLH relapses. A threshold frequency of transferred T cells with functional differentiation was identified as a predictive biomarker for long‐term survival. This study is the first proof‐of‐concept for ATCT in active HLH.