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 × 109, 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.