Thermal ablation and immunotherapy for hepatocellular carcinoma: Recent advances and future directions

Table 1 Immunotherapy drugs used in hepatocellular carcinoma

Drugs	Trade name	Targets	Approved/ongoing	Company	Indications
Nivolumab	Opdivo	PD-1	Approved by FDA in 2017; Approved by China NMPA in 2018	Bristol-Myers Squibb	HCC progression after first-line therapy with sorafenib (second-line treatment)
Pembrolizumab	Keytruda	PD-1	Approved by FDA in 2018; Approved by China NMPA in 2018	Merck Sharp & Dohme	HCC progression or high toxicity after first-line therapy with sorafenib (second-line treatment)
Atezolizumab	Tecentriq	PD-L1	Approved by China NMPA in 2020	Roche Pharmaceutical Ltd	Advanced HCC
Camrelizumab	Erika	PD-1	Approved by China NMPA in 2020	Jiangsu Hengrui medicine	Advanced HCC after therapy with sorafenib or oxaliplatin
Tislelizumab	Baizean	PD-1	Ongoing	BeiGene (Shanghai)	/
Sintilimab	Daboshu	PD-1	Ongoing	Innovent	/
Toripalimab	Toi	PD-1	Ongoing	Shanghai Junshi Biosciences	/
Durvalumab	Imfinzi	PD-L1	Ongoing	AstraZeneca	/
Avelumab	BAVENCIO	PD-L1	Ongoing	Pfizer & Merck	/
Tremelimumab	Tremelimumab	CTLA-4	Ongoing	AstraZeneca	/

PD-1: Programmed cell death protein-1; PD-L1: Programmed cell death 1 ligand 1; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; FDA: Food and Drug Administration; NMPA: National Medical Products Administration; HCC: Hepatocellular carcinoma.

Table 2 Clinical studies of thermal ablation combined with immunotherapy for patients with hepatocellular carcinoma

Ref.	Location	No. (combination group vs control group)	Tumor size (cm)	Number of tumor nodules (single/multiple)	Combination group	Control group	Follow-up period (mo)	Recurrence rates	OS, RFS, PFS or DFS	Adverse events in the combination group
Weng et al[73], 2008	China	45 vs 40	2-13	NR	RFA + TACE + CIK cells	RFA + TACE	18	1-year (8.9% vs 30.0%), 18-mo (15.6% vs 40.0%) (both P < 0.05)	RFS rates: 68.9% (31/45) vs 20.0% (8/40)	A light feverand shiver (24.4%, 11/45)
Ma et al[75], 2010	China	7	1-3.5	6/1	RFA + RAK cells	/	7	No recurrence	NR	A slight fever (14.3%, 1/7)
Huang et al[74], 2013	China	85 vs 89	1-26	41/44 vs 40/49	RFA + TACE + CIK cells	RFA + TACE	median 78 (5–173)	NR	OS: 56 mo vs 31 mo (P = 0.001); PFS: 17 mo vs 10 mo (P = 0.001)	Fever (37.5–39.3℃) and chills (3.5%)
Cui et al[76], 2014	China	30 vs 32	2-8	12/18 vs 18/14	RFA + CIT	RFA	Median 12 (10–28)	NR	OS rates: 1-year (100% vs 92.6%), 2-yr (100% vs 76.6%); PFS: not reached vs 12 mo (P < 0.0001)	Fever (38.5℃) (3.3%)
Bian et al[77] , 2014	China	62 vs 65	BCLC stage 0-B	35/27	RFA + 131I metuximab	RFA	NR	1-year (31.8% vs 56.3%), 2-year (58.5% vs 70.9%)	NR	No serious adverse events
Tu et al[78], 2015	China	12 vs 22	< 5 (66.7%)	10/2 vs 16/6	RFA + 131I-chTNT	RFA	Median 31 (5–48)	83.3% (10/12) vs 86.4% (19/22)	OS: 43 mo vs 35 mo (P = 0.052); PFS: 23 mo vs 7 mo (P = 0.047)	The counts of white blood cells increased
Yu et al[82], 2015	China	14 vs 15	2.4 ± 0.7 vs 2.5 ± 0.8	NR	MWA + immunotherapy	MWA	16 vs 19	7.1% vs 40%	OS rates: 100% vs 80% (P = 0.126); DFS rates: 92.86% vs 66.67% (P = 0.076)	Fever (< 39℃) (42.9%)
Duffy et al[72], 2017	United States	32	BCLC stage C or B	NR	RFA + anti-CTLA-4 (tremelimumab)	/	NR	median time to tumor progression: 7.4 mo	Median OS: 12.3 mo; PFS rate: 6-m (57.1%), 12-mo (33.1%)	Pruritus
Huang et al[83] , 2020	China	43 vs 57	Median 9 (5–26)	19/24 vs 30/27	TACE + MWA + CIK	TACE + MWA	Median 31 (1–163)	NR	OS: 41 mo vs 24 mo (P = 0.002); DFS: 17 mo vs 10 mo (P = 0.023)	No severe adverse events

BCLC: Barcelona Clinic Liver Cancer; RFA: Radiofrequency ablation; TACE: transarterial chemo-embolization; MWA: Microwave ablation; CIK: Cytokine-induced killer; RAK: RetroNectin activated killer; CIT: Cellular immunotherapy; ¹³¹I-chTNT: Iodine-131-labeled chimeric tumor necrosis therapy; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; OS: Overall survival; RFS: Recurrence-free survival; PFS: Progression-free survival; DFS: Disease-free survival; NR: Not reported.