Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma.
OBJECTIVE
No adjuvant therapy has been shown to extend the survival of patients with hepatocellular carcinoma (HCC) receiving curative treatment. We investigated whether injections of activated cytokine-induced killer (CIK) cells (CD3+/CD56+ and CD3+/CD56- T cells and CD3-/CD56+ natural killer cells) prolongs recurrence-free survival of patients after curative therapy for HCC.


METHODS
We performed a multicenter, randomized, open-label, phase 3 trial of the efficacy and safety of adjuvant immunotherapy with activated CIK cells (created by incubation of patients' peripheral blood mononuclear cells with interleukin 2 and an antibody against CD3). The study included 230 patients with HCC treated by surgical resection, radiofrequency ablation, or percutaneous ethanol injection at university-affiliated hospitals in Korea. Patients were assigned randomly to receive immunotherapy (injection of 6.4 × 10(9) autologous CIK cells, 16 times during 60 weeks) or no adjuvant therapy (controls). The primary end point was recurrence-free survival; secondary end points included overall survival, cancer-specific survival, and safety.


RESULTS
The median time of recurrence-free survival was 44.0 months in the immunotherapy group and 30.0 months in the control group (hazard ratio with immunotherapy, 0.63; 95% confidence interval [CI], 0.43-0.94; P = .010 by 1-sided log-rank test). Hazard ratios also were lower in the immunotherapy than in the control group for all-cause death (0.21; 95% CI, 0.06-0.75; P = .008) and cancer-related death (0.19; 95% CI, 0.04-0.87; P = .02). A significantly higher proportion of patients in the immunotherapy group than in the control group had an adverse event (62% vs 41%; P = .002), but the proportion of patients with serious adverse events did not differ significantly between groups (7.8% vs 3.5%; P = .15).


CONCLUSIONS
In patients who underwent curative treatment for HCC, adjuvant immunotherapy with activated CIK cells increased recurrence-free and overall survival. ClinicalTrials.gov number: NCT00699816.
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Joon Hyeok
JH
Lee
Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Jeong-Hoon
JH
Lee
Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Young-Suk
YS
Lim
The Liver Center, Korea University Guro Hospital, Seoul, Korea.
Jong Eun
JE
Yeon
Department of Surgery, Korea University Ansan Hospital, Ansan, Gyeonggi-do, Korea.
Tae-Jin
TJ
Song
Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Su Jong
SJ
Yu
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Geum-Youn
GY
Gwak
Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Kang Mo
KM
Kim
Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Yoon Jun
YJ
Kim
Department of Statistics, Korea University, Seoul, Korea.
Jae Won
JW
Lee
Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea. Electronic address: yoonjh@snu.ac.kr.
Jung-Hwan
JH
Yoon
D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D017115:Catheter Ablation; D055612:Cytokine-Induced Killer Cells / Q000276:immunology / Q000637:transplantation*; D018450:Disease Progression; D018572:Disease-Free Survival; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D006498:Hepatectomy; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods*; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D016016:Proportional Hazards Models; D056910:Republic of Korea; D012307:Risk Factors; D013997:Time Factors; D014182:Transplantation, Autologous; D016896:Treatment Outcome
D000431:Ethanol
Clinical Trial; IL2; Liver Cancer; NK Cell