*Purpose: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is an indication for liver transplantation (LT). Immunosuppressive regimens currently used after LT 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.

*Methods: 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.

*Results: We have successfully performed NK-cell immunotherapy in 45 living donor LT (LDLT) recipients with HCC in Japan. The median follow-up period is 68 months. In the series of LDLT with HCC, among the 101 patients who met the Milan criteria (MC) on preoperative imaging (NK group n=37; control group n=64), 38 patients (37%) had HCC exceeding MC on postoperative pathology. Of these 38 patients, the recurrent free survival (RFS) rates were significantly improved in the NK group (n=16) as compared to those in the control group (n=22). Their 5 year-RFS were 75% and 48%, respectively (p=0.042). 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 for up to 1 month through the analysis of peripheral blood chimerism. We also applied the proposed approach to the deceased donor LT (DDLT) recipients in collaboration with the US since 2009. This phase I study included 17 subjects with a median follow-up of 96 months. No study-related adverse events were noted in either of the studies. Regarding overall survival, the high-dose group had significantly better survival than the low-dose group (p = 0.0064). 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. Interestingly, the number of HLA mismatches between donor and recipient was associated with tumor recurrence after NK cell therapy.

*Conclusions: In conclusion, 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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