Adoptive Immunotherapy With Deceased Donor Derived-Liver Natural Killer (NK) Cells Is Well Tolerated and Has the Potential to Become a Powerful Therapeutic Tool for Preventing Recurrence of Hepatocellular Carcinoma After Liver Transplantation.

Abstract

Introduction: Liver transplantation (LT) is currently one of the main treatment options for hepatocellular carcinoma (HCC). In spite of careful patient selection using the Milan Criteria (MC) which is the accepted standard, the recurrence rate of HCC following LT is 10-20%. Although the outcome of these patients with recurrence is poor, there is no established treatment to prevent HCC recurrence. In this situation, there is an urgent need for alternative therapies for these patients. Liver is a unique organ for NK cells. About 30- 50 % of lymphocytes in the liver are NK cells. IL-2-stimulated donor liver mononuclear cells (LMNC) contain extremely high amounts of TNF-related apoptosis inducing ligand (TRAIL)-expressing NK cells and exert potent cytotoxicity to hepatoma cells. Based on these results, we performed a phase I clinical study of adoptive immunotherapy with deceased donor derived-liver NK cells in patients with HCC from July 2010 to April 2013. Method: LMNC extracted from deceased donor were cultured in X-VIVO15 medium with IL-2 for 3-5 days. Anti-CD3 mAb was added one day before the cell administration in order to prevent Graft versus Host Disease (GVHD). The final product was administered to the recipients through IV infusion. We retrospectively compared 18 recipients who received adoptive immunotherapy (NK therapy group) and historical control in our center. Result: Eighteen LT recipients with HCC were enrolled in this study. Eight patients exceeded MC in the pathology of the explanted liver. We had completed administration of the activated liver NK cells without safety issues. No study patients suffered from GVHD. No severe post-operative adverse events related with this therapy were seen. All HCC patients in NK cell therapy group are alive and without evidence of recurrence (Median follow-up; 21 months), except for one patient (pathological diagnosis was embryonal sarcoma, which was suspected for HCC preoperatively). Focus on the recipients exceeding the MC in the pathology of the explanted liver, the recurrence free survival rate was better in NK cell therapy group when compared with historical control. Conclusion: We can feasibly and safely perform this therapy. This therapy has the potential to become a powerful therapeutic tool for preventing HCC recurrence after LT.