Role of immunotherapy in downsizing hepatocellular carcinoma prior to liver transplantation

Table 1 Clinical trials assessing the effectiveness of immunotherapy in patients with advanced hepatocellular carcinoma

Trial name	Phase	Intervention	Status
Single-agent immunotherapy
NCT02576509	III	Nivolumab vs sorafenib	Completed
NCT02702414	II	Pembrolizumab (single-arm study)	Completed
NCT02702401	III	Pembrolizumab vs BSC	Completed
NCT03062358	III	Pembrolizumab and BSC vs BSC and placebo	Not yet completed; estimated completion date: June 2023
NCT03412773	III	Tislelizumab vs sorafenib	Not yet completed; estimated completion date: May 2022
NCT02989922	II/III	Camrelizumab (single-arm study)	Not yet completed
NCT01008358	II	Tremelimumab (single-arm study)	Completed
Combination of immunotherapy with other treatment modalities1
NCT02423343	I/II	Galunisertib and nivolumab (dose escalation and cohort expansion study)	Completed
NCT03893695	I/II	Ascrinvacumab and nivolumab (single-arm study)	Not yet completed; estimated completion date: June 2022
NCT03059147	I	PI3 kinase/BRD4 inhibitor small molecule and nivolumab (single-arm study)	Not yet completed; estimated completion date: October 2022
NCT03211416	I/II	Pembrolizumab and sorafenib	Not yet completed; estimated completion date: December 2022
NCT03713593	III	Lenvatinib and pembrolizumab vs Lenvatinib and placebo	Not yet completed; estimated completion date: December 2023
NCT03316872	II	Pembrolizumab and SBRT (single-arm study)	Not yet completed; estimated completion date: December 2023
NCT03099564	I	Pembrolizumab and Radioembolization (single-arm study)	Not yet completed; estimated completion date: June 2022
NCT03939975	II	Pembrolizumab or nivolumab or toripalimab with thermal ablation, RFA or MWA	Completed
NCT02715531	I	Atezolizumab with bevacizumab or other chemotherapy agents	Completed
NCT03434379	III	Atezolizumab and bevacizumab vs Sorafenib	Not yet completed; estimated completion date: June 2022
NCT03755791	III	Atezolizumab and cabozantinib vs sorafenib vs cabozantinib	Not yet completed; estimated completion date: December 2023
NCT04310709	II	Reforafenib and Nivolumab (single-arm study)	Not yet completed; estimated completion date: May 2023
NCT03869034	II	HAIC and sintilimab vs HAIC	Completed
NCT03794440	II/III	Anti-VEGF monoclonal antibody and sintilimab vs sorafenib	Not yet completed; estimated completion date: December 2022
NCT03764293	III	Apatinib and PD1 monoclonal antibody vs sorafenib	Not yet completed; estimated completion date: June 2022
NCT03755739	II/III	Pembrolizumab and/or ipilimumab administered via arterial infusion or intra-tumor fine needle injection vs pembrolizumab and/or ipilimumab administered via vein infusion	Not yet completed; estimated completion date: November 2033
NCT04273100	II	PD1 monoclonal antibody and TACE and lenvatinib (single-arm study)	Not yet completed
NCT03857815	II	PD1 monoclonal antibody and SBRT (single-arm study)	Not yet completed
NCT01853618	I/II	Tremelimumab and/or TACE and/or RFA (sequential assignment)	Completed
NCT04124991	I/II	Durvalumab and TARE (single-arm study)	Not yet completed
NCT03475953	I/II	Regorafenib and avelumab (sequential assignment)	Not yet completed; estimated completion date: December 2022

¹Combination therapy includes using two or more ICIs, an ICI plus systemic therapy and/or ICI plus LRT. BSC: Best supportive care; TACE: Transarterial chemoembolization; TAE: Transarterial embolization; PI3 kinase: Phosphoinositide 3 kinase; BRD4 inhibitor: Bromodomain-containing protein 4 inhibitor; SBRT: Stereotactic body radiotherapy; RFA: Radiofrequency ablation; MWA: Microwave ablation; HAIC: Hepatic arterial infusion chemotherapy; VEGF: Vascular endothelial growth factor; PD1: Programmed cell death receptor; ICI: Immune checkpoint inhibitor; LRT: Locoregional therapy.

Table 2 Summary of case reports assessing immune checkpoint inhibitors as a downstaging and/or bridging therapy prior to liver transplantation in patients with hepatocellular carcinoma

Sex	Age, yr	Underlying liver disease	ICI	Cycles (d)	Washout period	Post-LT outcome
M	66	ALD	Nivolumab	34	105	No rejection
M	65	HCV	Nivolumab	44	8	Fatal rejection
M	39	HBV	Toripalimab	10	93	Fatal rejection
M	69	None	Nivolumab	21	18	No rejection
F	56	HCV	Nivolumab	8	22	No rejection
M	58	HBV	Nivolumab	32	1	No rejection
M	63	HCV	Nivolumab	4	2	No rejection
M	30	HBV	Nivolumab	25	22	Mild rejection1
M	63	HBV	Nivolumab	4	13	No rejection
M	66	HBV	Nivolumab	9	253	No rejection
F	55	HBV	Nivolumab	12	7	No rejection
F	53	NASH	Nivolumab	2	30	No rejection
M	61	HBV	Durvalumab	NA	> 90	No rejection
M	53 ± 12.1	NA	Camrelizumab and/or Pembrolizumab	3 ± 2	870 on average	1 rejection in the cohort1

¹The rejection was appropriately treated and the patient suffered no major adverse outcomes. ICI: Immune checkpoint inhibitor; HCC: Hepatocellular carcinoma; M: Male; F: Female; LT: Liver transplantation; ALD: Alcoholic liver disease; HCV: Hepatitis C virus; HBV: Hepatitis B virus; NASH: Non-alcoholic steatohepatitis; NA: Not available.

Table 3 Clinical trials assessing immune checkpoint inhibitor use in the neoadjuvant setting prior to liver resection in patients with hepatocellular carcinoma

Trial name	Phase	Intervention	Status
NCT03510871	II	Nivolumab and ipilimumab (single-arm study)	Not yet completed; estimated completion date: December 2022
NCT03682276	I/II	Nivolumab and ipilimumab (single-arm study)	Not yet completed; estimated completion date: September 2022
NCT03299946	I	Nivolumab and cabozantinib (single-arm study)	Completed
NCT04615143	II	Tislelizumab or tislelizumab and Lenvatinib (sequential assignment)	Not yet completed; estimated completion date: December 2025
NCT03916627	II	Cemiplimab (parallel assignment)	Not yet completed; estimated completion date: September 2029
NCT03867370	I/II	Toripalimab or toripalimab and Lenvatinib (sequential assignment)	Not yet completed; estimated completion date: October 2022
NCT03630640	II	Nivolumab (single-arm study)	Not yet completed; estimated completion date: November 2023
NCT04123379	II	Nivolumab vs nivolumab and CCR2/5 inhibitor vs nivolumab and anti-IL-8 antibody (parallel assignment)	Not yet completed; estimated completion date: October 2024
NCT04297202	II	SHR-1210 (anti-PD1 inhibitor) and apatinib (single-arm study)	Completed

CCR2/5: Chemokine receptors type 2 and 5; IL-8: Interleukin-8; PD1: Programmed cell death receptor 1; NA: Not applicable.