Adjuvant therapy using ex vivo-expanded allogenic natural killer cells in hepatectomy patients with hepatitis B virus related solitary hepatocellular carcinoma: MG4101 study

다국어 초록 (Multilingual Abstract)

Backgrounds/Aims: Fewer reports have been published regarding hepatectomy patients with solitary hepatocellular carcinoma (HCC) who received immunotherapeutic agents as adjuvant therapy. We evaluated the safety and efficacy of ex vivo-expanded allogenic natural killer (NK) cells in those patients with modified International Union Against Cancer (UICC) stage T3. Methods: From August 2014 to October 2015, five patients who underwent hepatic resection received ex vivo-expanded allogenic NK cells. Patients received five rounds of NK cells (2-3×10<SUP>7</SUP> cells/kg) at postoperative 4, 6, 8, 12, and 16 weeks. This study is registered with ClinicalTrials.gov, number NCT02008929. Results: The median age of the five patients (three men and two women) was 44.8 years (range, 36-54 years). All had hepatitis B virus-related HCC, and the median tumor size was 2.2 cm (range, 2.1-8.2 cm). None of the patients had any adverse events. HCC recurrence developed in two patients at one year after hepatic resection, but four patients were alive at 3 years. The two recurrence-free patients showed a higher ratio of CD8+ T lymphocyte populations before and after administration of ex vivo-expanded allogenic NK cells compared with the three patients who experienced recurrence. Conclusions: Immunotherapy using ex vivo-expanded allogenic NK cells in hepatectomy patients can be used safely. Further studies should be investigated for efficacy.

목차 (Table of Contents)

• INTRODUCTION
• MATERIALS AND METHODS
• RESULTS
• DISCUSSION
• REFERENCES

참고문헌 (Reference)

1 Lee JH, "Sustained efficacy of adjuvant immunotherapy with cytokine-induced killer cells for hepatocellular carcinoma : an extended 5-year follow-up" 68 : 23-32, 2019

2 Imamura H, "Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy" 38 : 200-207, 2003

3 Zarour HM, "Reversing T-cell dysfunction and exhaustion in cancer" 22 : 1856-1864, 2016

4 Lim O, "Present and future of allogeneic natural killer cell therapy" 6 : 286-, 2015

5 Yang Y, "Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors" 4 : 215-224, 2016

6 Kim JM, "PIVKA-II is a useful marker in patients with modified UICC T3stage hepatocellular carcinoma" 60 : 1456-1462, 2013

7 Kim JM, "Outcomes after curative hepatectomy in patients with non-B non-C hepatocellular carcinoma and hepatitis B virus hepatocellular carcinoma from non-cirrhotic liver" 110 : 976-981, 2014

8 Samuel M, "Neoadjuvant and adjuvant therapy for surgical resection of hepatocellular carcinoma" 2009 : CD001199-, 2009

9 Lim KC, "Microvascular invasion is a better predictor of tumor recurrence and overall survival following surgical resection for hepatocellular carcinoma compared to the Milan criteria" 254 : 108-113, 2011

10 Ungefroren H, "Interaction of tumor cells with the microenvironment" 9 : 18-, 2011

11 Harding JJ, "Immunotherapy in hepatocellular carcinoma: primed to make a difference?" 122 : 367-377, 2016

12 Hong YP, "Immunotherapy for hepatocellular carcinoma : from basic research to clinical use" 7 : 980-992, 2015

13 Grivennikov SI, "Immunity, inflammation, and cancer" 140 : 883-899, 2010

14 Korangy F, "Immune responses in hepatocellular carcinoma" 28 : 150-154, 2010

15 Lim O, "GMP-compliant, large-scale expanded allogeneic natural killer cells have potent cytolytic activity against cancer cells in vitro and in vivo" 8 : e53611-, 2013

16 European Association for the Study of the Liver, "Electronic address : easloffice@easloffice. eu; European Association for the Study of the Liver. EASL Clinical Practice Guidelines : Management of hepatocellular carcinoma" 69 : 182-236, 2018

17 Yu R, "Efficacy of cytokine-induced killer cell infusion as an adjuvant immunotherapy for hepatocellular carcinoma : a systematic review and meta-analysis" 11 : 851-864, 2017

18 Jong Man Kim, "Early disseminated recurrence after liver resection in solitary hepatocellular carcinoma" 대한외과학회 94 (94): 129-134, 2018

19 Zamarron BF, "Dual roles of immune cells and their factors in cancer development and progression" 7 : 651-658, 2011

20 Kim JM, "Differences between hepatocellular carcinoma and hepatitis B virus infection in patients with and without cirrhosis" 21 : 458-465, 2014

21 Aerts M, "Current status and perspectives of immune-based therapies for hepatocellular carcinoma" 22 : 253-261, 2016

22 Chew V, "Chemokine-driven lymphocyte infiltration : an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma" 61 : 427-438, 2012

23 Jung SM, "Characteristics of early recurrence after curative liver resection for solitary hepatocellular carcinoma" 23 : 304-311, 2019

24 Bruix J, "Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation(STORM) : a phase 3, randomised, doubleblind, placebo-controlled trial" 16 : 1344-1354, 2015

25 Lee JH, "Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma" 148 : 1383.e6-1391.e6, 2015

26 Moretta A, "Activating and inhibitory killer immunoglobulin-like receptors(KIR)in haploidentical haemopoietic stem cell transplantation to cure high-risk leukaemias" 157 : 325-331, 2009

27 Heimbach JK, "AASLD guidelines for the treatment of hepatocellular carcinoma" 67 : 358-380, 2018

28 Yu SJ, "A concise review of updated guidelines regarding the management of hepatocellular carcinoma around the world : 2010-2016" 22 : 7-17, 2016

29 한국 간 암 스터디그룹, "2014 KLCSG-NCC Korea Practice Guideline for the Management of Hepatocellular Carcinoma" 거트앤리버 소화기연관학회협의회 9 (9): 267-317, 2015