Journal List > Immune Netw > v.20(1) > 1148274

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

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.

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Figure 1.
Schematic diagram of T cell Interaction with hepatocellular tumor cells and dendritic cells.
in-20-e11f1.tif
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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