First-in-human evaluation of memory-like NK cells with an IL-15 super-agonist and CTLA-4 blockade in advanced head and neck cancer

Cytokine induced memory-like natural killer (CIML NK) cells combined with an IL-15 super-agonist (N-803) are a novel modality to treat relapsed/refractory head and neck cancer. We report data from a phase I trial of haploidentical CIML NK cells combined with N-803 with or without ipilimumab (IPI) in relapsed/refractory head and neck cancer patients after a median of 6 prior lines of therapy. The primary endpoint was safety, which was established, with dose-limiting toxicity in 1/10 patients. A promising though transient disease control rate of 70% correlated with donor NK cell expansion, the latter occurring irrespective of IPI. High-resolution immunophenotypic and transcriptional profiling characterized the NK cells and their interacting partners in vivo. IPI was associated with contraction of Treg:Tcon, rapid recovery of recipient CD8+ T cells, and accelerated rejection of donor NK cells. These results inform evaluation of CIML NK therapy for advanced malignancies, with considerations for combination with IPI.