Is cytokine‑induced killer (CIK) cell therapy a viable adjuvant treatment for adult patients with hepatocellular carcinoma, chronic hepatitis B or C infection, and cirrhosis who have undergone curative resection, liver transplantation, or locoregional therapy?

Cytokine-Induced Killer (CIK) Cell Therapy for Hepatocellular Carcinoma

Adjuvant CIK cell immunotherapy can be considered after curative treatment (resection, radiofrequency ablation, or percutaneous ethanol injection) in patients with HCC ≤2 cm without lymph node or distant metastasis, based on Korean guideline recommendations. 1

Evidence Quality and Geographic Considerations

The recommendation for CIK cell therapy comes primarily from Korean and Asian clinical practice guidelines, while European guidelines explicitly recommend against adjuvant therapy after resection or ablation (strong recommendation, Level of Evidence 2). 1, 2 This geographic divergence reflects fundamental differences in the evidence base:

• Korean Phase 3 RCT data demonstrated significant improvements in recurrence-free survival (HR 0.63; 95% CI 0.43–0.94) and overall survival (HR 0.21; 95% CI 0.06–0.75) in patients with AJCC stage I or II HCC after curative treatment. 1
• Extended follow-up (median 68.5 months) showed sustained benefit with RFS HR 0.67 (95% CI 0.48–0.94, P=0.009) and OS HR 0.33 (95% CI 0.15–0.76, P=0.006). 1
• Real-world Korean propensity score analysis confirmed these findings with RFS HR 0.42 (95% CI 0.22–0.80, P=0.006). 1, 3

However, a Chinese Phase 3 RCT showed conflicting results—prolonged time-to-recurrence (13.6 vs 7.8 months, P=0.01) but no statistically significant differences in RFS or OS. 1

Patient Selection Criteria

CIK cell therapy should only be considered for highly selected patients meeting ALL of the following criteria: 1

• Tumor size ≤2 cm (subgroup analysis showed benefit only in AJCC stage I HCC)
• No lymph node involvement
• No distant metastasis
• After curative treatment (resection, RFA, or PEI—not after TACE or transplantation)
• Adequate liver function to tolerate the therapy

Mechanism and Treatment Protocol

CIK cells are autologous peripheral blood mononuclear cells expanded ex vivo with interferon-gamma, anti-CD3 monoclonal antibody, and IL-2. 4, 5 The dominant effector population is CD3+CD56+ cells, which increase from 0.1-0.13% to 19.0-20.5% after 21 days of culture. 4 These cells demonstrate higher cytotoxic activity against autologous HCC cells compared to lymphokine-activated killer cells. 4

Safety Profile

CIK cell therapy has an acceptable safety profile with adverse event rates of 16-27% and no grade 3 or 4 adverse events reported in clinical studies. 1, 3, 5 The therapy can improve immunological status by increasing DC1 and DC2 dendritic cell subsets without major side effects. 5

Meta-Analysis Evidence

Meta-analyses of RCTs demonstrate: 1, 6, 7

• Improved 1-year (RR=1.23, P<0.001), 2-year (RR=1.37, P<0.001), and 3-year (RR=1.35, P=0.004) disease-free survival 6
• Improved 1-year (RR=1.08, P=0.001), 2-year (RR=1.14, P<0.001), and 3-year (RR=1.15, P=0.02) overall survival 6
• No benefit for 4-year and 5-year outcomes (P>0.05) 6
• Pooled HR for overall survival of 0.594 (95% CI 0.501-0.703, P<0.001) 7

Cost-Effectiveness

Incremental cost-effectiveness ratios were $33,077/QALY based on RCT data and $25,107/QALY based on real-world data, suggesting reasonable cost-effectiveness in the Korean healthcare context. 1

Critical Limitations and Contraindications

Do not use CIK cell therapy in the following situations: 1, 2

• Tumors >2 cm (no proven benefit in subgroup analysis)
• AJCC stage II or higher (benefit only demonstrated in stage I)
• After liver transplantation (not studied in this context)
• Presence of vascular invasion or extrahepatic disease
• Western patient populations (evidence predominantly from Asian studies with hepatitis B/C-related HCC—85.9% of patients in meta-analyses) 6

Comparison to Modern Immunotherapy

Immune checkpoint inhibitors have uniformly failed as adjuvant therapy in three major trials (Checkmate-9DX, KEYNOTE-937, EMERALD-2), and the IMbrave050 trial showed updated RFS HR of 0.90 (95% CI 0.72–1.12, not statistically significant) with unfavorable OS trend (HR 1.26; 95% CI 0.85–1.87). 2 This makes CIK cell therapy a potentially viable alternative in the specific patient population where it has been studied, though surveillance remains the standard of care in Western guidelines. 2

Practical Algorithm for Decision-Making

For patients with HCC after curative treatment:

1. Assess tumor characteristics: Size ≤2 cm, AJCC stage I, no nodal/distant metastasis → proceed to step 2; otherwise → surveillance only 1
2. Evaluate geographic/institutional context: Korean or Asian center with CIK cell program → consider CIK therapy; Western center → surveillance per EASL guidelines 1, 2
3. Confirm hepatitis B or C etiology: 85.9% of evidence base involves viral hepatitis-related HCC 6
4. Ensure adequate liver function and patient willingness to undergo leukapheresis and multiple infusions 1, 5
5. Counsel regarding limited long-term benefit beyond 3 years 6

Common Pitfalls to Avoid

• Do not extrapolate CIK cell data to Western populations without recognizing the evidence comes almost entirely from Asian patients with viral hepatitis-related HCC 6
• Do not use CIK cells for tumors >2 cm despite guideline language stating "≤2 cm"—the benefit was only proven in stage I disease 1
• Do not combine CIK therapy with other adjuvant treatments like TACE or sorafenib, which have failed to show benefit 1
• Do not delay surveillance imaging while pursuing CIK therapy, as early detection of recurrence remains critical 2