Sustained efficacy of adjuvant immunotherapy with cytokineinduced killer cells for hepatocellular carcinoma: an extended 5-year follow-up

Abstract

Our earlier multicenter randomized controlled trial showed that adjuvant immunotherapy with cytokine-induced killer (CIK) cells resulted in longer recurrence-free survival (RFS) and overall survival (OS) as well in patients who received curative treatment for hepatocellular carcinoma (HCC). In the present study, we determined if the efficacy of CIK cell therapy continued after end of repeated CIK cell injections. We performed a follow-up study of our preceding trial. We included 226 patients: 114 patients in the immunotherapy group (injection of 6.4 × 10 9 CIK cells, 16 times during 60 weeks) and 112 patients in the control group (no treatment) after potentially curative treatment for HCC. In total, 162 patients (89 of the immunotherapy group and 73 of controls) underwent an extended follow-up for 60 months after randomization of the last patient. The primary endpoint was RFS, and secondary endpoints included OS. During follow-up time of median 68.5 months (interquartile range 45.0-82.2 months), the immunotherapy group continued to show a significantly lower risk of recurrence or death [hazard ratio (HR) 0.67; 95% confidence interval (CI) 0.48-0.94; P = 0.009 by one-sided log-rank test]. At 5 years, RFS rate was 44.8% in the immunotherapy group and 33.1% in the control group. The risk of all-cause death was also lower in the immunotherapy group compared to the control group (HR 0.33; 95% CI 0.15-0.76; P = 0.006). In patients who received curative treatment for HCC, the significant improvement in RFS and OS as a result of adjuvant CIK cell immunotherapy lasted over 5 years without boosting. Keywords Hepatocellular carcinoma • Cytokine-induced killer cell • Adjuvant immunotherapy • Recurrence-free survival • Overall survival Abbreviations AFP Alpha-fetoprotein AJCC American Joint Committee on Cancer CI Confidence interval CIK Cytokine-induced killer CSS Cancer-specific survival HBV Hepatitis B virus HCC Hepatocellular carcinoma HCV Hepatitis C virus HR Hazard ratio The results of the present extended follow-up study were previously presented as an oral presentation at the European Association of the Study of the Liver (EASL) International Liver Congress (ILC) 2018, France, Paris, April 11-15, 2018 [1]. The details of the original clinical trial were reported before in 2015 in an article in "Gastroenterology" titled "Adjuvant Immunotherapy with Autologous Cytokine-Induced Killer Cells for Hepatocellular Carcinoma" [2].

2018 Korean Liver Cancer Association–National Cancer Center Korea Practice Guidelines for the Management of Hepatocellular Carcinoma

“…In a recent Korean phase III RCT,541 adjuvant therapy with CIK cells significantly improved RFS (HR, 0.63; 95% CI, 0.43 to 0.94) and OS (HR, 0.21; 95% CI, 0.06 to 0.75) in AJCC stage I or II HCC patients after curative resection or local ablative therapy (RFA or PEI). An extended follow-up study (median, 68.5 months) also showed a sustained improvement in both RFS (HR, 0.67; 95% CI, 0.48 to 0.94; p=0.009) and OS (HR, 0.67; 95% CI, 0.48 to 0.94; p=0.009) and the 5-year RFS rate was 44.8% in the CIK cell group and 33.1% in the control group 545. In a phase III RCT in China, CIK cell treatment showed significantly prolonged time-to-recurrence (13.6 months in the CIK group and 7.8 months in the control group, p=0.01).…”

Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells

“…46,47 Adoptive cell therapy using autologous, ex vivo-expanded cytotoxic cells termed cytokine-induced killer cells (CIK), is also being tested for HCC. 48,49 DC vaccines or peptide vaccines aim to exploit the strong capacities of innate immune cells to present antigens to cells involved in adaptive immunity to subsequently boost the tumorspecific immune response. [50][51][52][53][54][55][56] Oncolytic viruses represent a novel therapeutic approach in cancer treatment due to their ability to selectively infect, replicate in, and (onco-)lyse tumor cells.…”

Targeted and Immune-Based Therapies for Hepatocellular Carcinoma

“…Administration of the CIK cells increased odds of recurrence-free survival by 33%, and reduced the risk of all-cause death by 67%, in a study of 226 patients with a median follow-up time of 68.5 months. 81…”