Current Status and Future Direction of Immunotherapy in Hepatocellular Carcinoma: What Do the Data Suggest?

Hye Won Lee; Kyung Joo Cho; Jun Yong Park

doi:10.4110/in.2020.20.e11

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Lee, Cho, and Park: Current Status and Future Direction of Immunotherapy in Hepatocellular Carcinoma: What Do the Data Suggest?

Review Article

Immune Netw 2020;20(1):e11.

Published online: 4 February 2020

DOI: https://doi.org/10.4110/in.2020.20.e11

Current Status and Future Direction of Immunotherapy in Hepatocellular Carcinoma: What Do the Data Suggest?

Hye Won Lee^1,^2,³, Kyung Joo Cho^3,⁴, Jun Yong Park^1,^2,^3,^4,^*

¹Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea

²Institue of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea

³Yonsei Liver Center, Severance Hospital, Seoul 03722, Korea

⁴BK21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea

^*Correspondence to Jun Yong Park Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. E-mail: drpjy@yuhs.ac

Conflict of Interests The authors declare no potential conflicts of interest.

Received 15 January 2020 Revised 7 February 2020 Accepted 8 February 2020

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Most patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage of disease. Until recently, systemic treatment options that showed survival benefits in HCC have been limited to tyrosine kinase inhibitors, antibodies targeting oncogenic signaling pathways or VEGF receptors. The HCC tumor microenvironment is characterized by a dysfunction of the immune system through multiple mechanisms, including accumulation of various immunosuppressive factors, recruitment of regulatory T cells and myeloid-derived suppressor cells, and induction of T cell exhaustion accompanied with the interaction between immune checkpoint ligands and receptors. Immune checkpoint inhibitors (ICIs) have been interfered this interaction and have altered therapeutic landscape of multiple cancer types including HCC. In this review, we discuss the use of anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies in the treatment of advanced HCC. However, ICIs as a single agent do not benefit a significant portion of patients. Therefore, various clinical trials are exploring possible synergistic effects of combinations of different ICIs (anti-PD-1/PD-L1 and anti-CTLA-4 antibodies) or ICIs and target agents. Combinations of ICIs with locoregional therapies may also improve therapeutic responses.

Keywords: Carcinoma, hepatocellular, Immune checkpoint inhibitor, Therapeutics

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Figure 1.

Schematic diagram of T cell Interaction with hepatocellular tumor cells and dendritic cells.

Table 1.

Clinical trials associated with ICIs in hepatocellular carcinoma

Drug name	Trial name	Phase	Line of thera	apy Design	NCT number	Status
Anti-PD-1
Nivolumab	CheckMate 040	I/II	1L/2L	Nivolumab vs. sorafenib	NCT01658878	Completed
	CheckMate459	III	1L	Nivolumab vs. sorafenib	NCT02576509	Completed
	–	Ib/II	2L	Nivolumab+galunisertib (TGF-β receptor I kinase inhibitor)	NCT02423343	Recruiting
Pembrolizumab	KEYNOTE-224	II	2L	Pembrolizumab	NCT02702414	Completed
	KEYNOTE-240	III	2L	Pembrolizumab vs. placebo	NCT02702401	Recruiting
	–	I	2L	Pemrolizumab+lenvatinib	NCT03006926	Recruiting
Tislelizumab	RATIONALE-301	III	1L	Tislelizumab vs. sorafenib	NCT03412773	Recruiting
Camrelizumab	–	II/III	2L	Camrelizumab	NCT02989922	Recruiting
	–	II	1L/2L	Camrelizumab+apatinib vs. Camrelizumab+FOLFOX4	NCT03092895	Recruiting
Sintilimab	ORIENT-32	III	1L	Sintilimab+bevacizumab (VEGF Ab) vs. sorafenib	NCT03794440	Recruiting
Anti-PD-L1
Durvalumab	HIMALAYA	III	1L	Durvalumab+tremelimumab (CTLA-4 Ab) vs. durvalumab	NCT03298451	Recruiting
	–	II	1L/2L	Durvalumab; tremelimumab; durvalumab+tremelimumab	NCT02519348	Recruiting
	–	I	2L	Durvalumab+ramucirumab (VEGFR2 inhibitor)	NCT02572687	Recruiting
Atezolizumab	–	I	1L	Atezolizumab+bevacizumab	NCT02715531	Recruiting
	–	III	1L	Atezolizumab+bevacizumab vs. sorafenib	NCT03434379	Recruiting
Avelumab	–	I	1L	Avelumab+axitinib (tyrosine kinase inhibitor)	NCT03289533	Recruiting
Anti-CTLA-4
Tremelimumab	–	II	2L	Tremelimumab (HCV)	NCT01008358	Completed
Ipilimumab	–	II	Neoadjuvan	nt Ipilimumab+nivolumab vs. nivolumab	NCT03222076	Recruiting

1L, first line; 2L, second line; HCV, hepatitis C virus.

Table 2.

Summary of clinical trials of ICIs-based combination treatment in hepatocellular carcinoma

Characteristic	Phase	Line of therapy	Treatment	No. of patients	Results
Combination of 2 ICIs
Nivolumab+ipilimumab (62)	II	2L	(A) Nivolumab 1 mg/kg+ipilimumab 3 mg/kg Q3W (4 doses) or (B) nivolumab 3 mg/kg+ipilimumab 1 mg/kg Q3W (4 doses), each followed by nivolumab 240 mg Q2W, or (C) nivolumab 3 mg/kg Q2W+ipilimumab 1 mg/kg Q6W	148	(A) ORR: 32%, CR: 8%, PR: 8%, DCR: 54%, mOS: 23 months or (B) ORR: 32%, CR: 6%, PR: 24%, DCR: 43%, mOS: 12 months or (C) ORR: 31%, CR: 0%, PR: 31%, DCR: 49%, mOS: 13 months
Durvalumab+tremelimumab (44)	I/II	1L/2L	11 HBV positive, 9 HCV positive, 20 uninfected	40	ORR: 15%, CR+PR: 20%, DCR16: 57.5%
ICIs+angiogenesis inhibitors
Atezolizumab+bevaxizumab (63)	III	1L	(A) Atezolizumab 1,200 mg IV Q3W+bevaxizumab 15 mg/kg IV Q3W or (B) sorafenib 400 mg BID	501	(A) mOS: NA, mPFS: 6.8 months (B) mOS: 13.2 months, mPFS: 4.3 months
Pembrolizumab+lenvatinib (64)	Ib	1L	Lenvatinib (BW ≥60 kg: 12 mg/day; <60 kg: 8 mg/ day QD) and pembrolizumab (200 mg IV Q3W)	67	ORR: 44.8%, CR: 6.0%, PR: 26%, SD: 37.3%, PD: 9.0%
Avelumab+axitinib (56)	I	1L	Avelumab 10 mg/kg IV Q2W+axitinib 5 mg orally BID	22	ORR: 31.8%, mPFS: 3.8 months, 6-month PFS: 30.9% (mRECIST)
Camrelizumab+apatinib (57)	Ib	2L	Camrelizumab 200 mg every 2 wk and apatinib 125–500 mg once daily	16	PR: 44.4%, ORR: 50%, DCR: 93.8%, mPFS: 5.8 months
ICIs+locoregional therapy
Tremelimumab+tumor ablation (49)	III	1L/2L	Tremelimumab (3.5 and 10 mg/kg IV) every 4 wk for 6 doses, followed by 3-monthly infusions. On day 36, patients underwent ablation	32	6-month PFS: 57.1%, 12-month PFS: 33.1%, mTTP: 7.4 months, mOS: 12.3 months
ICIs+yttrium-90 radioembolizationn (65)	NA	1L/2L	Nivolumab alone or ipilimumab and nivolumab or ipilimumab and nivolumab following nivolumab	26	TTP: 5.7 months, PFS: 5.7 months

1L, first line; 2L, second line; Q3W, every 3 weeks; Q2W, every 2 weeks; Q6W, every 6 weeks; ORR, objective response rate; CR, complete response; PR, partial response; DCR, disease control rate; mOS, median overall survival; HBV, hepatitis B virus; HCV, hepatitis C virus; IV, intravenously; PFS, progression free survival; mPFS, median progression free survival; TTP, time to tumor progression; mTTP, median time to tumor progression; NA, not available; mRECIST, median Response Evaluation Criteria in Solid Tumors; BID, twice a day; SD, standard deviation; BW, body weight; QD, once daily.

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