Long-acting IL-7 restores T-cell reconstitution in a humanized mouse model of lymphopenia

BACKGROUND: Idiopathic CD4 lymphocytopenia (ICL) is a clinical syndrome characterized by low CD4 T-cell counts (<300/μL blood), occasionally accompanied by CD8 lymphopenia. ICL, which is associated with serious opportunistic infections, cancers and autoimmune diseases, has no established treatment. OBJECTIVE: We tested NT-I7 (efineptakin alfa), a long-acting form of recombinant human Interleukin (rhIL)-7, as a potential immunotherapy for ICL in a pre-clinical mouse model. METHODS: Mice received peripheral blood mononuclear cells (PBMC) from 15 individuals; five healthy donors (HD) and ten persons with ICL (pICL). Mice receiving ICL PBMC were either untreated or treated with one NT-I7 dose. Blood was sampled at different times and spleens were collected on day 28 to compare lymphocyte reconstitution, IL-7Rα expression, and TCR clonality, while weight was monitored to detect potential graft versus host disease (GvHD). In a single patient study, NT-I7 was administered, and blood lymphocytes were enumerated up to 98 days. RESULTS: In mice that phenocopied their donors' lymphopenia, NT-I7 treatment restored CD4 T-cell counts to the levels observed in mice receiving HD lymphocytes. A single NT-I7 dose downregulated IL-7Rα on CD4-T cells for 2-3 weeks, and increased T-cell counts with preserved polyclonality in three out of four patients tested, without causing GvHD. The lymphopenic NT-I7 treated patient experienced a two- and three-fold rise in CD4 and CD8-T cell numbers, respectively, two months after a single dose of NT-I7. CONCLUSION: A single dose of NT-I7 restored T-cell numbers in a mouse model of ICL and improved lymphocyte counts in a single-patient study.