Progress of immune checkpoint inhibitors in treatment of advanced hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YIN Peng ^1,2 ,  HU Chaoquan ²

1. School of Clinical Medicine, Guizhou Medical University, Guiyang 550000, P. R. China;
2. Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, P. R. China;

Corresponding author：

HU Chaoquan, Email: kevinhucn@yahoo.com

Keywords：

advanced hepatocellular carcinoma; immune checkpoint inhibitor; immunotherapy; review

DOI：

10.7507/1007-9424.202006125

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To review the present situation of immune checkpoint inhibitors in treatment of advanced hepatocellular carcinoma (HCC), and discuss the advance of combined immunotherapy.Methods The relevant literatures on researches of immune checkpoint inhibitors in the treatment of advanced HCC were retrieved to make an review.Results Immunotherapy intervention had been becoming a novel and promising therapeutic approach for HCC, which could suppress the progression of aggressive tumor and could inhibit tumor recurrence and metastasis shown in some pre-clinical trials. Other studies had found that the combined strategy of specific immunotherapy and conventional therapies could significantly improve the clinical outcomes of HCC patients.Conclusion Combined immunotherapy can significantly improve the clinical outcomes of HCC and benefit more patients with advanced HCC.

Citation： YIN Peng, HU Chaoquan. Progress of immune checkpoint inhibitors in treatment of advanced hepatocellular carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(4): 524-529. doi: 10.7507/1007-9424.202006125 Copy

1.	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2.	Pawlotsky JM. Pathophysiology of hepatitis C virus infection and related liver disease. Trends Microbiol, 2004, 12(2): 96-102.
3.	Trépo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet, 2014, 384(9959): 2053-2063.
4.	Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology, 2004, 127(5 Suppl 1): S87-S96.
5.	Zhang DY, Friedman SL. Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology, 2012, 56(2): 769-775.
6.	Bugianesi E, Vanni E, Marchesini G. NASH and the risk of cirrhosis and hepatocellular carcinoma in type 2 diabetes. Curr Diab Rep, 2007, 7(3): 175-180.
7.	Yang JD, Hainaut P, Gores GJ, et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol, 2019, 16(10): 589-604.
8.	Sangro B, Carpanese L, Cianni R, et al. Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology, 2011, 54(3): 868-878.
9.	Giannini EG, Farinati F, Ciccarese F, et al. Prognosis of untreated hepatocellular carcinoma. Hepatology, 2015, 61(1): 184-190.
10.	Meyer T. Treatment of advanced hepatocellular carcinoma: beyond sorafenib. Lancet Gastroenterol Hepatol, 2018, 3(4): 218-220.
11.	Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol, 2015, 12(12): 681-700.
12.	Nishida N, Kudo M. Immunological microenvironment of hepatocellular carcinoma and its clinical implication. Oncology, 2017, 92 Suppl 1: 40-49.
13.	Cheng H, Sun G, Chen H, et al. Trends in the treatment of advanced hepatocellular carcinoma: immune checkpoint blockade immunotherapy and related combination therapies. Am J Cancer Res, 2019, 9(8): 1536-1545.
14.	Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis, 2015, 6(6): e1792.
15.	Umemoto Y, Okano S, Matsumoto Y, et al. Prognostic impact of programmed cell death 1 ligand 1 expression in human leukocyte antigen class Ⅰ-positive hepatocellular carcinoma after curative hepatectomy. J Gastroenterol, 2015, 50(1): 65-75.
16.	Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol, 2013, 59(1): 81-88.
17.	Huang M, He M, Guo Y, et al. The influence of immune heterogeneity on the effectiveness of immune checkpoint inhibitors in multifocal hepatocellular carcinomas. Clin Cancer Res, 2020, 26(18): 4947-4957.
18.	Kuang DM, Zhao Q, Peng C, et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med, 2009, 206(6): 1327-1337.
19.	Zhou G, Sprengers D, Boor PPC, et al. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating T cells in hepatocellular carcinomas. Gastroenterology, 2017, 153(4): 1107-1119.e10.
20.	Hato T, Goyal L, Greten TF, et al. Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions. Hepatology, 2014, 60(5): 1776-1782.
21.	Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res, 2013, 19(19): 5300-5309.
22.	Tarhini AA, Kirkwood JM. CTLA-4-blocking immunotherapy with ipilimumab for advanced melanoma. Oncology (Williston Park), 2010, 24(14): 1302, 1304.
23.	Kähler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. J Dtsch Dermatol Ges, 2011, 9(4): 277-286.
24.	Waidmann O. Recent developments with immunotherapy for hepatocellular carcinoma. Expert Opin Biol Ther, 2018, 18(8): 905-910.
25.	Huz JI, Melis M, Sarpel U. Spontaneous regression of hepatocellular carcinoma is most often associated with tumour hypoxia or a systemic inflammatory response. HPB (Oxford), 2012, 14(8): 500-505.
26.	Cheng AL, Hsu C, Chan SL, et al. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J Hepatol, 2020, 72(2): 307-319.
27.	Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature, 2006, 439(7077): 682-687.
28.	Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med, 2009, 206(13): 3015-3029.
29.	Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3-potential mechanisms of action. Nat Rev Immunol, 2015, 15(1): 45-56.
30.	El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet, 2017, 389(10088): 2492-2502.
31.	Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol, 2018, 19(7): 940-952.
32.	Segal NH, Ou SI, Balmanoukian A, et al. Safety and efficacy of durvalumab in patients with head and neck squamous cell carcinoma: results from a phase Ⅰ/Ⅱ expansion cohort. Eur J Cancer, 2019, 109: 154-161.
33.	Rexer H, Steiner T, Bergmann L. Nivolumab combined with ipilimumab versus sunitinib monotherapy-SUNNIFORECAST AN 41/16of the AUO: a phase 2, randomized, open-label study in subjects with previously untreated and advanced (unresectable or metastatic) non-clear cell renal cell carcinoma. Urologe A, 2017, 56(6): 802-803.
34.	Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol, 2015, 33(17): 1974-1982.
35.	Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med, 2016, 375(19): 1823-1833.
36.	Kudo M. Immuno-oncology in hepatocellular carcinoma: 2017 update. Oncology, 2017, 93 Suppl 1: 147-159.
37.	Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer, 2016, 54: 139-148.
38.	Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science, 2018, 359(6382): 1350-1355.
39.	Lin Z, Lu D, Wei X, et al. Heterogeneous responses in hepatocellular carcinoma: the achilles heel of immune checkpoint inhibitors. Am J Cancer Res, 2020, 10(4): 1085-1102.
40.	Kuo HY, Chiang NJ, Chuang CH, et al. Impact of immune checkpoint inhibitors with or without a combination of tyrosine kinase inhibitors on organ-specific efficacy and macrovascular invasion in advanced hepatocellular carcinoma. Oncol Res Treat, 2020, 43(5): 211-220.
41.	Cui H, Dai G, Guan J. Programmed cell death protein-1 (PD-1)-targeted immunotherapy for advanced hepatocellular carcinoma in real world. Onco Targets Ther, 2020, 13: 143-149.
42.	Chen Y, Ramjiawan RR, Reiberger T, et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology, 2015, 61(5): 1591-1602.
43.	Zamarin D, Holmgaard RB, Subudhi SK, et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med, 2014, 6(226): 226ra32.
44.	Duffy AG, Ulahannan SV, Makorova-Rusher O, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol, 2017, 66(3): 545-551.
45.	Cui J, Wang N, Zhao H, et al. Combination of radiofrequency ablation and sequential cellular immunotherapy improves progression-free survival for patients with hepatocellular carcinoma. Int J Cancer, 2014, 134(2): 342-351.
46.	Lee JH, Tak WY, Lee Y, et al. Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase Ⅱ study. Oncoimmunology, 2017, 6(7): e1328335.
47.	Shi L, Lin H, Li G, et al. Cisplatin enhances NK cells immunotherapy efficacy to suppress HCC progression via altering the androgen receptor (AR)-ULBP2 signals. Cancer Lett, 2016, 373(1): 45-56.
48.	Qin S, Bai Y, Lim HY, et al. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol, 2013, 31(28): 3501-3508.
49.	Murawski M, Weeda VB, Maibach R, et al. Hepatocellular carcinoma in children: does modified platinum- and doxorubicin-based chemotherapy increase tumor resectability and change outcome? Lessons learned from the SIOPEL 2 and 3 studies. J Clin Oncol, 2016, 34(10): 1050-1056.
50.	Burki TK. Palbociclib improves survival in advanced breast cancer. Lancet Oncol, 2017, 18(1): e1.
51.	Zhou J, Liu M, Sun H, et al. Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy. Gut, 2018, 67(5): 931-944.
52.	Bollard J, Miguela V, Ruiz de Galarreta M, et al. Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma. Gut, 2017, 66(7): 1286-1296.
53.	Takayama T, Sekine T, Makuuchi M, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet, 2000, 356(9232): 802-807.
54.	Lee JH, Lee JH, Lim YS, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology, 2015, 148(7): 1383-1391.e6.
55.	Wang H, Liu A, Bo W, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma patients after curative resection, a systematic review and meta-analysis. Dig Liver Dis, 2016, 48(11): 1275-1282.
56.	Nakagawa H, Mizukoshi E, Kobayashi E, et al. Association between high-avidity T-cell receptors, induced by α-fetoprotein-derived peptides, and anti-tumor effects in patients with hepatocellular carcinoma. Gastroenterology, 2017, 152(6): 1395-1406.e10.
57.	Butterfield LH, Ribas A, Meng WS, et al. T-cell responses to HLA-A*0201 immunodominant peptides derived from alpha-fetoprotein in patients with hepatocellular cancer. Clin Cancer Res, 2003, 9(16 Pt 1): 5902-5908.
58.	Shao YY, Liu TH, Hsu C, et al. Early alpha-foetoprotein response associated with treatment efficacy of immune checkpoint inhibitors for advanced hepatocellular carcinoma. Liver Int, 2019, 39(11): 2184-2189.
59.	Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature, 2014, 515(7528): 577-581.
60.	Heo J, Reid T, Ruo L, et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med, 2013, 19(3): 329-336.
61.	Chon HJ, Lee WS, Yang H, et al. Tumor microenvironment remodeling by intratumoral oncolytic vaccinia virus enhances the efficacy of immune-checkpoint blockade. Clin Cancer Res, 2019, 25(5): 1612-1623.

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2. Pawlotsky JM. Pathophysiology of hepatitis C virus infection and related liver disease. Trends Microbiol, 2004, 12(2): 96-102.
3. Trépo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet, 2014, 384(9959): 2053-2063.
4. Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology, 2004, 127(5 Suppl 1): S87-S96.
5. Zhang DY, Friedman SL. Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology, 2012, 56(2): 769-775.
6. Bugianesi E, Vanni E, Marchesini G. NASH and the risk of cirrhosis and hepatocellular carcinoma in type 2 diabetes. Curr Diab Rep, 2007, 7(3): 175-180.
7. Yang JD, Hainaut P, Gores GJ, et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol, 2019, 16(10): 589-604.
8. Sangro B, Carpanese L, Cianni R, et al. Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology, 2011, 54(3): 868-878.
9. Giannini EG, Farinati F, Ciccarese F, et al. Prognosis of untreated hepatocellular carcinoma. Hepatology, 2015, 61(1): 184-190.
10. Meyer T. Treatment of advanced hepatocellular carcinoma: beyond sorafenib. Lancet Gastroenterol Hepatol, 2018, 3(4): 218-220.
11. Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol, 2015, 12(12): 681-700.
12. Nishida N, Kudo M. Immunological microenvironment of hepatocellular carcinoma and its clinical implication. Oncology, 2017, 92 Suppl 1: 40-49.
13. Cheng H, Sun G, Chen H, et al. Trends in the treatment of advanced hepatocellular carcinoma: immune checkpoint blockade immunotherapy and related combination therapies. Am J Cancer Res, 2019, 9(8): 1536-1545.
14. Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis, 2015, 6(6): e1792.
15. Umemoto Y, Okano S, Matsumoto Y, et al. Prognostic impact of programmed cell death 1 ligand 1 expression in human leukocyte antigen class Ⅰ-positive hepatocellular carcinoma after curative hepatectomy. J Gastroenterol, 2015, 50(1): 65-75.
16. Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol, 2013, 59(1): 81-88.
17. Huang M, He M, Guo Y, et al. The influence of immune heterogeneity on the effectiveness of immune checkpoint inhibitors in multifocal hepatocellular carcinomas. Clin Cancer Res, 2020, 26(18): 4947-4957.
18. Kuang DM, Zhao Q, Peng C, et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med, 2009, 206(6): 1327-1337.
19. Zhou G, Sprengers D, Boor PPC, et al. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating T cells in hepatocellular carcinomas. Gastroenterology, 2017, 153(4): 1107-1119.e10.
20. Hato T, Goyal L, Greten TF, et al. Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions. Hepatology, 2014, 60(5): 1776-1782.
21. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res, 2013, 19(19): 5300-5309.
22. Tarhini AA, Kirkwood JM. CTLA-4-blocking immunotherapy with ipilimumab for advanced melanoma. Oncology (Williston Park), 2010, 24(14): 1302, 1304.
23. Kähler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. J Dtsch Dermatol Ges, 2011, 9(4): 277-286.
24. Waidmann O. Recent developments with immunotherapy for hepatocellular carcinoma. Expert Opin Biol Ther, 2018, 18(8): 905-910.
25. Huz JI, Melis M, Sarpel U. Spontaneous regression of hepatocellular carcinoma is most often associated with tumour hypoxia or a systemic inflammatory response. HPB (Oxford), 2012, 14(8): 500-505.
26. Cheng AL, Hsu C, Chan SL, et al. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J Hepatol, 2020, 72(2): 307-319.
27. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature, 2006, 439(7077): 682-687.
28. Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med, 2009, 206(13): 3015-3029.
29. Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3-potential mechanisms of action. Nat Rev Immunol, 2015, 15(1): 45-56.
30. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet, 2017, 389(10088): 2492-2502.
31. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol, 2018, 19(7): 940-952.
32. Segal NH, Ou SI, Balmanoukian A, et al. Safety and efficacy of durvalumab in patients with head and neck squamous cell carcinoma: results from a phase Ⅰ/Ⅱ expansion cohort. Eur J Cancer, 2019, 109: 154-161.
33. Rexer H, Steiner T, Bergmann L. Nivolumab combined with ipilimumab versus sunitinib monotherapy-SUNNIFORECAST AN 41/16of the AUO: a phase 2, randomized, open-label study in subjects with previously untreated and advanced (unresectable or metastatic) non-clear cell renal cell carcinoma. Urologe A, 2017, 56(6): 802-803.
34. Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol, 2015, 33(17): 1974-1982.
35. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med, 2016, 375(19): 1823-1833.
36. Kudo M. Immuno-oncology in hepatocellular carcinoma: 2017 update. Oncology, 2017, 93 Suppl 1: 147-159.
37. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer, 2016, 54: 139-148.
38. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science, 2018, 359(6382): 1350-1355.
39. Lin Z, Lu D, Wei X, et al. Heterogeneous responses in hepatocellular carcinoma: the achilles heel of immune checkpoint inhibitors. Am J Cancer Res, 2020, 10(4): 1085-1102.
40. Kuo HY, Chiang NJ, Chuang CH, et al. Impact of immune checkpoint inhibitors with or without a combination of tyrosine kinase inhibitors on organ-specific efficacy and macrovascular invasion in advanced hepatocellular carcinoma. Oncol Res Treat, 2020, 43(5): 211-220.
41. Cui H, Dai G, Guan J. Programmed cell death protein-1 (PD-1)-targeted immunotherapy for advanced hepatocellular carcinoma in real world. Onco Targets Ther, 2020, 13: 143-149.
42. Chen Y, Ramjiawan RR, Reiberger T, et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology, 2015, 61(5): 1591-1602.
43. Zamarin D, Holmgaard RB, Subudhi SK, et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med, 2014, 6(226): 226ra32.
44. Duffy AG, Ulahannan SV, Makorova-Rusher O, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol, 2017, 66(3): 545-551.
45. Cui J, Wang N, Zhao H, et al. Combination of radiofrequency ablation and sequential cellular immunotherapy improves progression-free survival for patients with hepatocellular carcinoma. Int J Cancer, 2014, 134(2): 342-351.
46. Lee JH, Tak WY, Lee Y, et al. Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase Ⅱ study. Oncoimmunology, 2017, 6(7): e1328335.
47. Shi L, Lin H, Li G, et al. Cisplatin enhances NK cells immunotherapy efficacy to suppress HCC progression via altering the androgen receptor (AR)-ULBP2 signals. Cancer Lett, 2016, 373(1): 45-56.
48. Qin S, Bai Y, Lim HY, et al. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol, 2013, 31(28): 3501-3508.
49. Murawski M, Weeda VB, Maibach R, et al. Hepatocellular carcinoma in children: does modified platinum- and doxorubicin-based chemotherapy increase tumor resectability and change outcome? Lessons learned from the SIOPEL 2 and 3 studies. J Clin Oncol, 2016, 34(10): 1050-1056.
50. Burki TK. Palbociclib improves survival in advanced breast cancer. Lancet Oncol, 2017, 18(1): e1.
51. Zhou J, Liu M, Sun H, et al. Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy. Gut, 2018, 67(5): 931-944.
52. Bollard J, Miguela V, Ruiz de Galarreta M, et al. Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma. Gut, 2017, 66(7): 1286-1296.
53. Takayama T, Sekine T, Makuuchi M, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet, 2000, 356(9232): 802-807.
54. Lee JH, Lee JH, Lim YS, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology, 2015, 148(7): 1383-1391.e6.
55. Wang H, Liu A, Bo W, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma patients after curative resection, a systematic review and meta-analysis. Dig Liver Dis, 2016, 48(11): 1275-1282.
56. Nakagawa H, Mizukoshi E, Kobayashi E, et al. Association between high-avidity T-cell receptors, induced by α-fetoprotein-derived peptides, and anti-tumor effects in patients with hepatocellular carcinoma. Gastroenterology, 2017, 152(6): 1395-1406.e10.
57. Butterfield LH, Ribas A, Meng WS, et al. T-cell responses to HLA-A*0201 immunodominant peptides derived from alpha-fetoprotein in patients with hepatocellular cancer. Clin Cancer Res, 2003, 9(16 Pt 1): 5902-5908.
58. Shao YY, Liu TH, Hsu C, et al. Early alpha-foetoprotein response associated with treatment efficacy of immune checkpoint inhibitors for advanced hepatocellular carcinoma. Liver Int, 2019, 39(11): 2184-2189.
59. Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature, 2014, 515(7528): 577-581.
60. Heo J, Reid T, Ruo L, et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med, 2013, 19(3): 329-336.
61. Chon HJ, Lee WS, Yang H, et al. Tumor microenvironment remodeling by intratumoral oncolytic vaccinia virus enhances the efficacy of immune-checkpoint blockade. Clin Cancer Res, 2019, 25(5): 1612-1623.

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