Safety and Therapeutic Outcomes of Adjuvant Immunotherapy With Autologous Cytokine-induced Killer Cells for Patients With Hepatocellular Carcinoma Beyond Milan Criteria After Liver Transplantation

Abstract

Background: Adjuvant immunotherapy with autologous cytokine-induced killer (CIK) cells for hepatocellular carcinoma (HCC) remains understudied in liver transplant patients because of potential risks of acute rejection and diminished efficacy by immunosuppression.

Methods: This study examined the safety and effectiveness of CIK therapy in patients with HCC exceeding the Milan criteria, treated at 2 Korean hospitals between 2019 and 2021. We analyzed clinical outcomes of 16 patients who underwent CIK therapy compared with 44 propensity-matched controls who did not receive CIK therapy. CIK cells were administered in 6 escalating doses, either 3 or 6 times over the course of weeks 4, 5, 6, 8, 10, and 12 posttransplantation.

Results: CIK therapy was well-tolerated without significant treatment-related adverse reactions. Maximal tolerated dose of CIK cells was 10 × 10 9 , which had been repeated 6 times. The CIK group exhibited higher 2-y HCC recurrence-free (87.5% versus 62.9%, P = 0.027) and patient survival (100% versus 81.5%, P = 0.002) rates, with no significant difference in rejection-free survival rates (92.9% versus 95.0%, P = 0.926) compared with the no-CIK group. Subgroup analysis showed that the CIK group in patients with high retreat scores, elevated R3-α-fetoprotein scores, and those beyond the University of California San Francisco criteria had improved HCC recurrence-free survival. Immunological evaluation showed elevated CD8 + T cells and polymorphonuclear myeloid-derived suppressor cells with transient increases in granzyme B and tumor necrosis factor-α levels in the CIK group.

Conclusions: These findings advocate CIK therapy as a safe and effective, potential adjuvant treatment for HCC beyond Milan criteria after transplantation, supporting further validation trials.