Abstract
BACKGROUND: Recurrent hepatocellular carcinoma (HCC) after liver transplantation remains a formidable challenge. This Phase 1, dose-escalation trial had the primary objectives of evaluating the safety and tolerability of various natural killer (NK) cell infusion regimens in patients with recurrent HCC. As exploratory endpoints, the study also assessed preliminary antitumor activity, with progression-free survival (PFS) and overall survival (OS) being key measures of interest. METHODS: Between December 31, 2014, and March 29, 2017, 18 patients with recurrent HCC after liver transplantation were enrolled in this single-center, Phase I dose-exploration study. Patients were allocated to four treatment groups to receive different frequencies and doses of NK cell infusions alongside conventional treatment. Group A (n = 3) received four low-dose infusions, Group B (n = 5) received four normal-dose infusions, Group C (n = 6) received eight normal-dose infusions, and Group D (n = 4) followed an incremental dosing schedule. Treatment-related adverse events (AEs) and survival outcomes were systematically evaluated, with a maximum follow-up period of 9 years. RESULTS: The most common AE was Grade 1 pyrexia, which typically resolved within a day. The median PFS across the cohort was 4.8 months, with significant differences observed among the groups (log-rank P = 0.0008). Specifically, the PFS was 1.6 months for Group A, 2.5 months for Group B, 5.5 months for Group C, and 7.5 months for Group D. The median OS was 17.7 months, with notable differences among the groups (log-rank P = 0.0403). The OS durations were 12.6 months for Group A, 16.1 months for Group B, 18.4 months for Group C, and 31.3 months for Group D. CONCLUSION: NK cell infusions were well tolerated and associated with differences in both PFS and OS in patients with recurrent HCC after liver transplantation. Both the frequency and dosage of NK cell infusions are crucial factors influencing survival outcomes, suggesting a potential dose-frequency response relationship.These findings preliminarily underscore the potential of optimizing NK cell-based immunotherapies to enhance clinical outcomes in this challenging patient population. TRIAL REGISTRATION: Trial registration NCT, NCT02399735, Registered 23 March 2015 - Retrospectively registered, https://clinicaltrials.gov/study/NCT02399735. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-026-07725-x.