Sustained efficacy of adjuvant immunotherapy with cytokine-induced 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 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.

Glycoengineering of NK cells with glycan ligands of CD22 and selectins for B-cell lymphoma therapy

“…To prepare CIK cells, peripheral blood precursors from healthy donors were activated with anti-CD3 and anti-CD28 antibodies, and maintained in IL-2 supplemented T-cell culture medium for 10-15 days. 24 After subjecting NK-92MI and CIK cells to Because most leukemia and lymphoma cells require a close relationship with the bone marrow microenvironment for their survival and disease progression. 37,38 We reasoned that NK cells may not be sufficiently trafficking to bone marrow to attack B lymphoma where they reside in situ.…”

“…20 Cytokine-Induced Killer (CIK) cells, generated by ex vivo incubation of human peripheral blood mononuclear cells (PBMC) or cord blood mononuclear cells, feature a mixed T-and natural killer (NK) cell-like phenotype. [21][22][23][24] Like NK-92MI cells, the intrinsic tumor killing ability of CIK is mainly mediated by the NKG2D receptor that recognizes, in MHC-independent manner, stress-inducible targets. 24 We hypothesize that by using high-affinity and specific CD22 ligands to functionalize NK-92MI and CIK cells, specific targeting and killing of tumor cells with CD22 over-expression can be achieved.…”

“…[21][22][23][24] Like NK-92MI cells, the intrinsic tumor killing ability of CIK is mainly mediated by the NKG2D receptor that recognizes, in MHC-independent manner, stress-inducible targets. 24 We hypothesize that by using high-affinity and specific CD22 ligands to functionalize NK-92MI and CIK cells, specific targeting and killing of tumor cells with CD22 over-expression can be achieved. 25,26 Here, we exploit chemoenzymatic glycan editing 27 to create high-affinity CD22 ligands on the cell surface of NK-92MI and CIK cells.…”

Cytotoxic immune cell-based immunotherapy for hepatocellular carcinoma

“…CIK cell adjuvant therapy also reduces the recurrence in HCC patients undergoing curative treatment [117] . Lee et al [118] found that the efficacy of CIK cells in patients with HCC lasted over 5 years. Chang et al [119] reported that the high number of PD-1 + tumor infiltrating lymphocytes could predict the response and clinical benefits of CIK cell adjuvant immunotherapy in HCC patients.…”

Recent Advances and Future Directions in Immunotherapeutics for Hepatocellular Carcinoma

“…22 In an extended 5-year follow-up study, patients who received an adjuvant CIK cell immunotherapy for HCC showed significant improvement in recurrence-free and OS that lasted for over 5 years without additional booster treatments. 23 A meta-analysis of eight randomized clinical trials and six prospective studies revealed that CIK treatment increased the rate of patient survival, but did not prolong progression-free survival. 24…”