*Purpose: Although liver transplantation (LT) is a preferred treatment for selected patients with Hepatocellular carcinoma (HCC), HCC-recurrence would be a still important medical problem. Most immunosuppressants reduce the proportion of adaptive components of cellular immunity while maintaining innate components. Natural killer (NK) cells play a central role in innate immunity against neoplastic cells; therefore, their augmentation is a promising immunotherapeutic approach against HCC recurrence after LT. We propose that adoptive transfer of IL-2-stimulated TRAIL⁺ NK cells extracted from donor liver graft perfusate can mount an anti-tumor response without causing toxicity to intact recipient tissues.

*Methods: Since 2006, we have successfully performed NK-cell immunotherapy in 39 living donor LT (LDLT) recipients with HCC in Japan. The median follow-up period is 65 months. We also applied the proposed approach to the deceased donor LT (DDLT) recipients in collaboration with the US since 2009.

*Results: This phase I study included 17 subjects with a median follow-up of 43 months. No study-related adverse events were noted in either of the studies. In the series of LDLT with HCC, among the 98 patients who met the Milan criteria (MC) on preoperative imaging (NK group n=33; control group n=65), 37 patients (38%) had HCC exceeding MC on postoperative pathology. Of these 37 patients, the recurrent free survival (RFS) rates were significantly improved in the NK group (n=15) as compared to those in the control group (n=22). Their 5 year-RFS were 79% and 45%, respectively (p=0.034). A sub-analysis showed that the incidence of bacteremia significantly decreased in the NK group (p=0.012). After infusion of NK cells, the NK cytotoxicity and the proportion of TRAIL⁺ NK cells in the peripheral blood of patients increased significantly (p<0.05). The inoculated donor NK cells could be confirmed up to 1 month through the analysis of peripheral blood chimerism. In the series of DDLT with HCC, among the 17 patients who met MC on preoperative imaging, 9 patients (53%) had HCC exceeding MC on postoperative pathology. None of the patients have shown any symptom of HCC recurrence.

*Conclusions: In conclusions, the administration of IL-2-stimulated NK cells derived from both living and deceased donor liver allografts was safely applied and is, therefore, a potential novel adjuvant immune treatment after LT in HCC patients.

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