Clinical Studies Applying Cytokine-Induced Killer Cells for the Treatment of Gastrointestinal Tumors

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
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 1.85×10^6 to 1.41×10^5 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
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
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 × 10^3	CIK therapy can prolong the recurrence-free time and fight HBV; CIK therapy after TACE/RFA is an effective therapeutic strategy for HCC
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
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 × 10^3 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
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
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
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
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
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.