Table 2.
Clinical studies applying CIK cells for the treatment of HCC.
| Study | Number of patients | Therapy | Results | Conclusions |
|---|---|---|---|---|
| Takayama et al., 2000 [34] | 150 | Resection; Immunotherapy group: additional infusions of lymphocytes activated in vitro with rIL-2, and anti-CD3 | Recurrence: 59% in immunotherapy group versus 77% in control group; TTP: 2.8 yrs in immunotherapy group versus 1.6 yrs in control group | Immunotherapy lowered risk of recurrence by 41%; the difference in OS was not significant; safe and feasible treatment |
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| Shi et al., 2004 [35] | 13 | i.v. CIK transfusions | Increased proportions of CD3+CD8+, CD25+, and CD3+CD56+ cells in peripheral blood up to 108 d after immunotherapy; median HBV viral load decreased from 1.85 × 106 to 1.41 × 105 copies of DNA/mL in 3 months | CIK cells can efficiently improve the immunological status of HCC patients; CIK cells played important role in antiviral and antitumoral treatment |
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| Zhang et al., 2005 [38] | 17 | Resection; CIK cell transfusion | Only one case described: decreased ascites; improvement of nausea, and vomiting; large lymphocyte infiltration in tumor | Significant enhancement of antitumor immunity; perform CIK therapy to eradicate remaining tumor cells after operation |
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| Zhao et al., 2006 [39] | 64 | TACE/RFA; immunotherapy group: additional CIK infusions i.v. or via hepatic artery | After 1 yr followup: 29 of 33 patients in immunotherapy group and 23 of 31 patients in control group were recurrence-free; in 29 patients in the immunotherapy group and in only 1 patient in the control group the HBV DNA content was <1 × 103 | CIK therapy can prolong the recurrence-free time and fight HBV; CIK therapy after TACE/RFA is an effective therapeutic strategy for HCC |
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| Weng et al., 2008 [40] | 85 | TACE/RFA; immunotherapy group: additional CIK infusions via hepatic artery | Increased proportions of CD3+, CD4+, CD56+, and CD3+CD56+ cells and the CD4+/CD8+ ratio—percentages were lower in recurrent patients than in nonrecurrent patients; recurrence: 31.1% in immunotherapy group versus 85.0% in control group | CIK cell therapy can reduce recurrence and improve survival rates; CIK transfusions can boost immunity of HCC patients |
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| Pan et al., 2010 [41] | 83 | TACE/RFA; immunotherapy group: additional CIK cell transfusions i.v. or via common hepatic artery | Downtrend of AFP only in immunotherapy group; 1-yr recurrence rate 7.14% in immunotherapy group versus 23.1% in control group; percentage of patients with HBV DNA content <1 × 103 copies/mL was 73.5% in the immunotherapy group versus 9.1% in the control group | CIK cell transfusions can decrease the 1-yr recurrence rate of HCC patients and reduce serum AFP levels, which may serve as a useful marker to predict clinical outcome after immunotherapy and TACE/RFA |
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| Huang et al., 2013 [42] | 174 | TACE/RFA; immunotherapy group: additional i.v. CIK cell infusions | Significantly longer OS and PFS in immunotherapy group | Combination of TACE/RFA and CIK cell therapy is safe and can be an effective treatment modality |
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| Hao et al., 2010 [44] | 146 | TACE; immunotherapy group: additional i.v. CIK cell transfusions | 1-yr and 2-yr PFS rates: 40.4% and 25.3% in the immunotherapy group versus 7.7% and 2.6% in the control group; 1-yr and 2-yr OS rates: 71.9% and 62.4% in the immunotherapy group versus 42.8% and 18.8% in the control group; the times of TACE and CIK cell transfusions were independent prognostic factors for PFS and OS | Adjuvant CIK cell therapy can greatly improve the efficacy of TACE and prolong PFS and OS in HCC patients |
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| Wang et al., 2013 [45] | 31 | RF hyperthermia; i.p. CIK cell perfusions | Significant increases in levels of CD4+, CD3+CD8+, and CD3+CD56+ cells in peripheral blood; AFP and abdominal circumference decreased; median TTP: 6.1 mo; 1-yr survival rate: 17.4%; median OS: 8.5 months | I.p. perfusions of CIK cells combined with local RF hyperthermia are safe, can improve immunology, and prolong survival of HCC patients |
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| Hui et al., 2009 [46] | 127 | Resection; immunotherapy group I: additional 3 courses of CIK therapy; immunotherapy group II: additional 6 courses of CIK therapy | DFS rates significantly higher in CIK-treated groups than in control group; no statistical significance between immunotherapy group I and group II; no statistical significance in OS between the 3 groups | Postoperative CIK cell therapy can prolong DFS but not the OS rates; valuable therapeutic strategy for HCC patients to prevent recurrence |
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| Qiu et al., 2011 [47] | 18 | Resection, radio-, chemo-, and interventional therapies; immunotherapy group: additional transfusion of CIK cells previously cocultured with α-Gal epitope-pulsed DCs | Survival was significantly prolonged: 17.1 months in the immunotherapy group versus 10.1 months in the control group; all patients in the immunotherapy group had systemic cytotoxicity in response to tumor lysate, decreased serum AFP, and increased levels of CD8+, CD45RO+, and CD56+ cells in peripheral blood | CIK therapy was safe and effective; new therapeutic approach has great potential in tumor therapy |
CIK: cytokine-induced killer; HCC: hepatocellular carcinoma; rIL-2: recombinant Interleukin-2; anti-CD3: anti-CD3 antibody; TTP: time to progression; OS: overall survival; i.v.: intravenous; HBV: hepatitis B virus; TACE: transarterial chemoembolization; RFA: radiofrequency ablation; AFP: alpha fetoprotein; PFS: progression-free survival; i.p.: intraperitoneal; DFS: disease-free survival; α-Gal: α1,3-galactosyl; DC: dendritic cell.