Primary Resistance to Immunotherapy-Based Regimens in Hepatocellular Carcinoma

Primary Resistance to Immunotherapy-Based Regimens in Hepatocellular Carcinoma: Comparison

Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Francesca Salani.

Immune checkpoint inhibitors (ICIs) had been explored extensively in patients affected by unresectable hepatocellular carcinoma. These agents were expected to be the keystones of the disease’s first-line treatment because they were theoretically able to revert the immune suppressive tumor microenvironment of the cancerous liver, and because of their manageable safety profile.

immune-checkpoint inhibitors (ICIs)
advanced hepatocellular carcinoma (aHCC)
first line
primary resistance
primary progressors
TIGIT
LAG3
IL-27
GPC3-CAR T
GPC3-CIRP

1. Introduction

Regarding advanced hepatocellular carcinoma (aHCC), the role of immune checkpoint inhibitors (ICIs) have changed. The common thread of these strategies is the attempt to overcome the intrinsic primary resistance that HCC shows against ICIs. However, two upstream factors, other than resistance, limit the feasibility of such treatments: the uneven worldwide access to ICIs due to their high costs, and the contraindication to ICIs constituted by orthotopic liver transplant (OLT). The HCC population undergoing OLT is increasing due to the extension of its indication ^[1], as is the number of patients experiencing disease recurrence afterward ^[2]. In an attempt to not exclude these patients from ICIs, their absolute contra-indications in the setting of OLT have been debated. Of the 29 case reports of HCC recurrence treated with salvage ICIs, 68% failed to respond and 32% experienced rejection, even though rejection-specific mortality was far less frequent than cancer-specific one ^[3]. More promising results in terms of efficacy and safety seem to be provided by ICIs’ employment as down-staging/bridging agents to OLT. Indeed most treated patients experienced a nearly complete response to ICIs neoadjuvant treatment, while very few witnessed reversible non-lethal adverse events [3,4]^[3][4]. Nonetheless, these data are supported by low numerosity observations mainly collected as case reports, thus they might only suggest a change in paradigm from absolute to relative contra-indications.

Supported by the promising results of anti-PD-1 agents at sorafenib failure and by the need for less toxic agents than tyrosine kinase inhibitors (TKIs), nivolumab ^[5] and pembrolizumab [6,7]^[6][7] were the first ones to be tested as first-line treatments through the CheckMate 459 ^[8] and Keynote 224 -cohort2 ^[9] trials, respectively.

The multicenter, randomized, open-label, international, phase 3 CheckMate 459 trial randomly assigned 743 patients to either sorafenib or nivolumab as first lines choices, with the aim to demonstrate a 26% decrease in the risk of death with the latter. The study’s negative result (HR for OS: 0.85) should be read in the context of key achievements by nivolumab: higher survival rates at landmark time-points (47% vs. 44% at 18 months, 37% vs. 33% at 24 months), greater depth of response (8% difference in objective response rate -ORR), higher dose-intensity (83% vs. 38%), lower dose delays because of treatment emergent toxicities (57% vs. 89%), more favorable physical and functional well-being and longer time-to-deterioration of these indexes. Despite being limited by the low sample size (51 patients enrolled) and the absence of a formal statistical design, the results from cohort 2 of the single-arm open-label phase 2 Keynote 224 drove similar observations. The reported ORR of 16%, the disease control rate of 57%, the median OS of 17 months, and the OS rate at 12 months of 58% supported those of CheckMate 459, respectively equal to 15%, 55%, 16.6 months, and 60%.

In this context, recent evidence on the impact of HCC etiology on the immune characterization of TME deserves a mention since it might represent a tailoring tool for ICIs administration in aHCC. Indeed, NASH-induced HCC led to the expansion of exhausted CD8+PD1+ T cells in pre-clinical models and human hepatic biopsies, suggesting the mechanism behind a reduced sensitivity to anti PD(L)1 mono-therapies in this subgroup of patients [18]^[10]. A focus on the biological role of some of the most studied ICIs’ resistance determinants is summarized in Table 1 along with their implication in ICIs’ sensitivity.

Table 1.

Most-studied determinants of ICIs resistance in HCC.

Determinant	Biological Role	Trial Name and/or CTC Identification Specificity to HCC	Recruitment Putative Mechanism of Resistance	Phase Ref.
WNT/CTNNTB1	Evolutionary conserved transcriptional pathway, cell-cell adhesion, pivotal hepatic functions since embryonal life.	Its activating mutation relates to over-expression of wnt-target genes, enrichment in beta-catenin, and PTK2-related immune exclusion. More represented in viral etiology.
Anti-PD(L)1/anti CTLA4	Lower enrichment score of immune signatures: T-cell exclusion, and down-regulation of CCL4. Down-regulation of NKG2D ligand hampering NK-mediated response.

Determinant

Biological Role

Trial Name

and/or

CTC Identification

Specificity

to HCC

Recruitment

Putative Mechanism

of Resistance

Phase

Ref.

Comparator

Interventions

^targets

WNT/CTNNTB1

Evolutionary conserved transcriptional pathway, cell-cell adhesion, pivotal hepatic functions since embryonal life.

Its activating mutation relates to over-expression of wnt-target genes, enrichment in beta-catenin, and PTK2-related immune exclusion. More represented in viral etiology.

Anti-PD(L)1/anti CTLA4

Lower enrichment score of immune signatures: T-cell exclusion, and down-regulation of CCL4. Down-regulation of NKG2D ligand hampering NK-mediated response.

FGFR4.

3. Triplets: A Strategy under Investigation

Triplet systemic regimens under study (Table 3) comprise the combination of: (i) the three already proved-active compounds anti PD1 + anti-CLTA4 + anti-angiogenics (i.e., anti-VEGF or TKIs); (ii) ICIs + chemotherapy (restricted to Asiatic population); (iii) the anti PD1 + anti-VEGF + alternative immunity targets TIGIT, LAG3 or IL-27. As a whole, these strategies aim at targeting simultaneously different pathways which are synergically involved in aHCC pathology. The different strategies’ specific rationales are hereafter recapitulated.

Table 3.

Ongoing clinical trials of the triplet systemic strategy as first line for aHCC.

Trial Identification

Table 4.

Ongoing clinical trials of CAR-T and vaccine for aHCC.

Treatment Strategy	Study Phase	Trial Identification Treatment Arms	Study Phase Targets	Treatment Primary End-Point
	Arms			Primary End-Point
	NCT04720716		[	19	China ,	III 20,21]^[11][12][13]
	Sorafenib	^a			IBI-310 ^b (ipilimumab bio-similar) + sintilimab ^c
NCT05363722	Ib	LAG-3	Type-I trans-membrane protein acts as a negative immune counterweight during prolonged exposure to tumor antigens and is constitutively expressed by T-regs.	More expressed and more frequently mutated (15%) in HCC tissues than non-malignant livers in TGCA samples; positively correlated with the oncogenic transcription factor E2F1.
CAR-T cells therapy	NCT02905188 GLYCAR trial	IBI 310 (ipilimumab biosimilar) + bevacizumab + sintilimab	anti PD1 + anti CTLA4 + anti-VEGF
	NCT04039607/ CheckMate 9DW		High correlation between its expression and immune-suppressive or exhausted tumor environment.		global	III	Sorafenib or Lenvatinib ^d [17,22,23,24]^[14][15][16]	Ipilimumab ^b + nivolumab ^c^[^17]
		I		GPC3-CAR (GLYCAR T cells) + lymphodepleting chemotherapy (Cyclophosphamide and Fludarabine)	ORR		FGL1	Liver-secreted protein and main functional ligand to LAG-3 inhibiting antigen-specific T cell activation	Significantly down-regulated in HCC samples and correlated with higher grades, presence of metastases and poorer outcomes. FGL1-positive CTC patients showed resistance to ICIs treatment in a limited retrospective case-series
	Anti-PD(L)1/anti-VEGF	NCT04605796		High expression of FGL1 is correlated with higher density of LAG3+: blocking the FGL1/LAG3 can promote T cytotoxicity immunity.
			DLT		NCT04740307 MK-1308A-004		China [14,25,26]^[18][19][20]
		TIGIT	Co-inhibitor receptor expressed on T cells and NK, functionally similar to PD-1	Co-factor for T cells functional exhaustion in chronic viral hepatotropic infections; hallmark of immune suppressed HCC TGCA sub-group.	TIGIT, CTLA4 and ICOS are co-regulated and co-expressed; TIGIT interaction with NECTIN2 shapes a cancer-promoting immune suppressive environment	[14,27,28]^[18][21][22]

Abbreviations: LAG3, lymphocyte-activation gene 3; FGL1, fibrinogen-like protein1; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; NK, natural killers; CTLA4, Cytotoxic T-Lymphocyte Antigen 4; ICOS, Inducible T-cell costimulator.

2. Doublets: The Current Strategy

In the attempt to improve ICIs’ efficacy in aHCC, three different combination strategies have been so far developed based on the concept of treatment intensification: (a) double ICIs blockade, namely anti PD(L)1/anti CTLA4; (b) anti PD(L)1/anti-VEGF; (c) anti PD(L)1/multi-target tyrosine kinase inhibitors (TKIs). Of these strategies, (a) and (b) have already proven superior to sorafenib, with atezolizumab/bevacizumab representing one of the current standards of care in this setting [29]^[23] and tremelimumab/durvalumab (STRIDE regimen) being a more recent valuable competitor [10]^[24]. As for (c), reported data are conflicting. If camrelizumab/rivoceranib showed survival benefit over sorafenib supporting another new first-line treatments option for aHCC [LBA35, ESMO 2022], lenvatinib/pembrolizumab [LBA34, ESMO 2022] and cabozantinib/atezolizumab failed to show an overall significant benefit over TKIs alone.

IMbrave and Himalaya were the first phase 3 clinical trials to demonstrate the superiority of a doublet strategy over sorafenib. As a global, open-label study, IMbrave enrolled 501 patients, randomly allocated 2:1 to atezolizumab/bevacizumab or sorafenib, to test the superiority of the experimental arm in terms of OS and progression-free survival (PFS). Both primary analysis and updated results performed beyond expectations: not only efficacy endpoints showed clinically sound improvement with mOS of 19.2 months (HR 0.66) and mPFS of 6.8 months, but the benefit of the strategy was maintained during the follow-up time, with upfront and progressive separation of Kaplan-Meier curves and duration of response >6 months in 87.6%. The activity enhancement was equally remarkable, with 73.6% of DCR, 29.8% of ORR, and 7.7% of complete responses (CR), despite unfavorable prognostic features of the study population, such as macro-vascular invasion of the main portal trunk or the portal vein branch contralateral to the primarily involved lobe, bile duct invasion, or at least 50% hepatic involvement. Quite simultaneously designed, the Himalaya phase 3, global, open-label trial aimed at proving the OS superiority of tremelimumab single-dose priming combined with subsequent durvalumab administration (the so-called STRIDE regimen) over sorafenib, as a primary endpoint. In addition to improved mOS (16.43 vs. 13.77 months, HR 0.78), the key secondary endpoints of durvalumab non-inferiority to sorafenib, prolonged duration of response (65.8% at 12 months), and the increased survival benefit after 9 months of treatment proved the strength of this strategy. As for activity, in contrast to an mPFS superimposed to sorafenib’s one, DCR (60.1%), ORR (20.1%), and CR (3.1%) greatly favored STRIDE. Key differences between the two regimens lay in their safety profile and consequently their feasibility. The addition of an anti-VEGF drug caused 7% upper gastrointestinal bleeding, higher G3-4 hypertension rate (15.2%), and proteinuria (3%), making the evaluation of the presence of gastro-esophageal varices a compulsory up-front screening before treatment administration and a possible limitation of this doublet application. The rate of G3-5 hemorrhagic events in the real-world population is being investigated as the primary endpoint of the phase 3b Amethista trial, whose results will help to tailor patient selection for this regimen [30]^[25]. Conversely, the addition of a single anti CTLA4 priming led to an overall lower incidence of any G3-4 treatment-emergent adverse events (50.5% vs. 56.5% with atezolizumab/bevacizumab), but to a higher rate of immune-mediated ones (12.6%), 20.1% of which requiring high-dose steroids.

Moreover, the influence of HCC etiology on these doublets’ efficacy is an intriguing difference that warrants further confirmation: compared to either HBV- or HCV-related HCC, the non-viral etiology seems to derive less benefit from atezolizumab/bevacizumab, while a greater one with STRIDE, even though no interaction tests were carried out.

Phase III trials exploring the addition of TKIs to an anti PD(L)1 have been recently reported. In particular, the randomized phase 3, open-label, multicenter COSMIC-312 trial is the first published one to explore the combination of cabozantinib plus atezolizumab over sorafenib, with regard to OS and PFS dual primary endpoints. Despite mOS results from the combination revealing no improvement [31]^[26], PFS was significantly improved (6.8 vs. 4.2 months, HR 0.63). Moreover, some interesting observations are prompted by the trial’s results: comparable DCR (78%) and ORR (11%) to the other tested doublets, low rates of PP (14%), the enhanced PFS benefit in the Asiatic and HBV-positive population, and the higher PFS of cabozantinib monotherapy over sorafenib’s one (5.8 vs. 4.3 months) underpinning the contribution of this TKI to the combination’s efficacy. During ESMO 2022 congress, the results of the LEAP 002 and SHR-1210-III-310 trials were presented. Unfortunately, the lenvatinib/pembrolizumab combination did not meet its primary dual endpoint of OS and PFS, despite showing a trend toward improvement over lenvatinib monotherapy. On the contrary, in the SHR-1210-III-310 trial camrelizumab/rivoceranib significantly improved in OS and PFS versus sorafenib. Despite similar endpoint results (21.2 and 221.1 months of mOS for lenvatinib/pembrolizumab and camrelizumab/rivoceranib, respectively), the SHR-1210-III-310 trial was successful, while LEAP-002 trial was statistically negative. Putative contributing factors to such a difference were study design and enrolled population. LEAP-002 trial set lenvatinib plus placebo as a control arm, while the SHR-1210-III-310 trial used sorafenib: using a placebo control arm, the drop-out rate and/or investigator-assessed progression events might have been lowered and both lenvatinib and sorafenib OS outperformed those of the original pivotal trials. In this regard, more stringent eligibility criteria with fitter enrolled patients, improvement of supportive care and earlier initiation of systemic therapy due to multidisciplinary decisions might have improved control arms’ OS. As for the study population, in both trials patients with HBV etiology had better OS: thus, the higher proportion of HBV positivity in the SHR-1210-III-310 trial (75%) might partially explain the differences in outcome between the studies, along with a higher proportion of Asian subjects (83% vs. 31%, respectively).

Seeking to consolidate the results derived from the aforementioned strategies, test bio-similar compounds, and extend these results to the HBV-positive Chinese population, many clinical trials on doublets are currently ongoing, as reported in Table 2.

Table 2. Ongoing phase II/III trials of the following first-line combination strategies in aHCC setting, registered to Clinical Trial.gov: anti-PD(L)1/anti CTLA4; anti-PD(L)1/anti-VEGF; anti-PD(L)1/multi-target TKIs.

Strategy

NCT03884751	II		I pembrolizumab/quavonlimab (MK-1308A) + lenvatinib	CAR-GPC3 T Cells Coformulated anti PD1/anti CTLA4 + TKI		DLT + MTD DLTs ORR
NCT05363722	III	Camrelizumab + Folfox4	II
NCT05363722	III	NCT03980288	I		anti PD1 + chemotherapy	-	OS	JS001, toripalimab ^c + bevacizumab ^e
					anti PD1 + chemotherapy		OS
	CAR-GPC3 T Cells (in part II: combination with TKI or anti- PD(L)1)		DLT + MTD	NCT04560894		Camrelizumab + placebo China
NCT04121273	I	II/III	CAR-GPC3 T Cells Sorafenib ^a	DLT SCT-I10A^c + SCT510 (bevacizumab bio-similar) ^e
NCT04741165	NCT04948697 AdvanTIG-206	China
NCT03993743	NCT04948697 AdvanTIG-206		II	I II	ociperlimab + tislelizumab + BAT1706		CD147-CART hepatic artery infusion -	Anti-TIGIT + anti PD1 + anti- VEGF HX008 ^c + bevacizumab	AEs ^e
	ORR		II	NCT03973112, arm IV
	tislelizumab + BAT1706 China	anti PD1 + anti- VEGF
Vaccine + RFA/surgery	NCT03067493	II	ORR -

RAMEC trial		II		HLX10, serplulimab ^c	RFA or surgery +/− Neo-MASCT + HLX04 (bevacizumab biosimilar) ^e
	DFS +		immune response rate		Anti PD(L)1/TKIs	NCT04443309	NCT05337137 Relativity-106	I/II	China		Relatlimab + Nivolumab + Bevacizumab I/II		Anti-LAG + anti PD1 + anti-VEGF -	DLTs ad PFS	Camrelizumab ^c + lenvatinib ^d
NCT04401800	China	II					NCT05337137 Relativity-106	I/II						DLTs ad PFS
Placebo + Nivolumab + Bevacizumab	anti PD1 + anti-VEGF		-	Tislelizumab ^c + Lenvatinib ^d
NCT04183088
	Taiwan	II	SRF388 + Atezolizumab + bevacizumab	Anti-IL27 + anti PDL1 + anti-VEGF		PFS
	Placebo + Atezolizumab + bevacizumab	II	anti PDL1 + anti-VEGF			PFS

Vaccine + ICIs	NCT04248569	I	DNAJB1-PRKACA peptide vaccine + Nivolumab + Ipilimumab	AEs + change in INF-producing DNAJB1-PRKACA-specific CD8/CD4 T cells		NCT05359861		II	Regorafenib ^f	tislelizumab ^c + regorafenib ^f
NCT04523493	global	III	Lenvatinib ^d	JS001, toripalimab ^c + lenvatinib ^d		NCT05359861
NCT03841201/IMMUNIB	NCT05249569 Germany		II II	Axitinib + Avelumab + Bavituximab -		Anti-VEGFR + anti PDL1 + anti-phosphatidylserine Nivolumab ^c + lenvatinib ^d	RR	NCT04741165	China	II	-	HX008 ^c + lenvatinib ^d
NCT05441475, part b	China	II	-	Atezolizumab ^g + ABSK-011 ^h
NCT03439891	USA	II	-	nivolumab ^c + sorafenib ^a
NCT04443322	China	II	-	Durvalumab ^h + lenvatinib ^d

Interventions’ targets: ^a BRAF, VEGFR1-3, FLT3, PDGFR-beta, FGFR1, RET, KIT; ^b CTLA4; ^c PD-1; ^d VEGFR1-3, FGFR1-4, PDGFR alfa, RET, KIT; ^e VEGF-A; ^f VEGFR1- 3, KIT, PDGFR alfa, PDGFR beta, FGFR 1-2, angiopoietin receptor, BRAF, MAPK 11, FRK, ABL1, RET; ^g PD-L1; ^h

Abbreviations: ORR, objective response rate; DLTs, dose limiting toxicities; OS, overall survival; PFS, progression free survival; RR, response rate.

4. Immunotherapy beyond ICIs: Future Perspectives

Since some of the discussed limitations to ICIs’ efficacy are intrinsic to their mechanism of action, a new paradigm of immunotherapy agents is being explored for aHCC patients. Functionally, they are complementary to ICIs, therefore they provide a sound rationale for being combined with known check-point inhibitors, rather than being tested as monotherapies, as discussed below. An overview of currently ongoing phase I trials of these new strategies is given in Table 4.

Abbreviations: DLT, dose limiting toxicity; MTD, maximum tolerated dose; AEs, adverse events.

References

Reig, M.; Forner, A.; Rimola, J.; Ferrer-Fàbrega, J.; Burrel, M.; Garcia-Criado, Á.; Kelley, R.K.; Galle, P.R.; Mazzaferro, V.; Salem, R.; et al. BCLC Strategy for Prognosis Prediction and Treatment Recommendation: The 2022 Update. J. Hepatol. 2022, 76, 681–693.
Luo, Y.; Teng, F.; Fu, H.; Ding, G.-S. Immunotherapy in Liver Transplantation for Hepatocellular Carcinoma: Pros and Cons. World J. Gastrointest. Oncol. 2022, 14, 163–180.
Katariya, N.N.; Lizaola-Mayo, B.C.; Chascsa, D.M.; Giorgakis, E.; Aqel, B.A.; Moss, A.A.; Uson Junior, P.L.S.; Borad, M.J.; Mathur, A.K. Immune Checkpoint Inhibitors as Therapy to Down-Stage Hepatocellular Carcinoma Prior to Liver Transplantation. Cancers 2022, 14, 2056.
Abdelrahim, M.; Esmail, A.; Saharia, A.; Abudayyeh, A.; Abdel-Wahab, N.; Diab, A.; Murakami, N.; Kaseb, A.O.; Chang, J.C.; Gaber, A.O.; et al. Utilization of Immunotherapy for the Treatment of Hepatocellular Carcinoma in the Peri-Transplant Setting: Transplant Oncology View. Cancers 2022, 14, 1760.
El-Khoueiry, A.B.; Sangro, B.; Yau, T.; Crocenzi, T.S.; Kudo, M.; Hsu, C.; Kim, T.-Y.; Choo, S.-P.; Trojan, J.; Welling, T.H.; 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, 2492–2502.
Zhu, A.X.; Finn, R.S.; Cattan, S.; Edeline, J.; Ogasawara, S.; Palmer, D.H.; Verslype, C.; Zagonel, V.; Rosmorduc, O.; Vogel, A.; et al. KEYNOTE-224: Pembrolizumab in Patients with Advanced Hepatocellular Carcinoma Previously Treated with Sorafenib. JCO 2018, 36, 209.
Finn, R.S.; Ryoo, B.-Y.; Merle, P.; Kudo, M.; Bouattour, M.; Lim, H.Y.; Breder, V.; Edeline, J.; Chao, Y.; Ogasawara, S.; et al. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. JCO 2020, 38, 193–202.
Yau, T.; Park, J.-W.; Finn, R.S.; Cheng, A.-L.; Mathurin, P.; Edeline, J.; Kudo, M.; Harding, J.J.; Merle, P.; Rosmorduc, O.; et al. Nivolumab versus Sorafenib in Advanced Hepatocellular Carcinoma (CheckMate 459): A Randomised, Multicentre, Open-Label, Phase 3 Trial. Lancet Oncol. 2022, 23, 77–90.
Verset, G.; Borbath, I.; Karwal, M.; Verslype, C.; Van Vlierberghe, H.; Kardosh, A.; Zagonel, V.; Stal, P.; Sarker, D.; Palmer, D.H.; et al. Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial. Clin. Cancer Res. 2022, 28, 2547–2554.
Pfister, D.; Núñez, N.G.; Pinyol, R.; Govaere, O.; Pinter, M.; Szydlowska, M.; Gupta, R.; Qiu, M.; Deczkowska, A.; Weiner, A.; et al. NASH Limits Anti-Tumour Surveillance in Immunotherapy-Treated HCC. Nature 2021, 592, 450–456.
Sia, D.; Jiao, Y.; Martinez-Quetglas, I.; Kuchuk, O.; Villacorta-Martin, C.; de Moura, M.C.; Putra, J.; Camprecios, G.; Bassaganyas, L.; Akers, N.; et al. Identification of an Immune-Specific Class of Hepatocellular Carcinoma, Based on Molecular Features. Gastroenterology 2017, 153, 812–826.
Fujita, M.; Yamaguchi, R.; Hasegawa, T.; Shimada, S.; Arihiro, K.; Hayashi, S.; Maejima, K.; Nakano, K.; Fujimoto, A.; Ono, A.; et al. Classification of Primary Liver Cancer with Immunosuppression Mechanisms and Correlation with Genomic Alterations. eBioMedicine 2020, 53, 102659.
Shimada, S.; Mogushi, K.; Akiyama, Y.; Furuyama, T.; Watanabe, S.; Ogura, T.; Ogawa, K.; Ono, H.; Mitsunori, Y.; Ban, D.; et al. Comprehensive Molecular and Immunological Characterization of Hepatocellular Carcinoma. eBioMedicine 2019, 40, 457–470.
Sanceau, J.; Gougelet, A. Epigenetic Mechanisms of Liver Tumor Resistance to Immunotherapy. World J. Hepatol. 2021, 13, 979–1002.
Maruhashi, T.; Sugiura, D.; Okazaki, I.; Okazaki, T. LAG-3: From Molecular Functions to Clinical Applications. J. Immunother. Cancer 2020, 8, e001014.
Li, W.; Mei, M.; Liu, T.; Zhang, S.; Wang, Z.; Suo, Y.; Wang, S.; Liu, Y.; Zhang, N.; Lu, W. Identification of PDCD1 and PDCD1LG2 as Prognostic Biomarkers and Associated with Immune Infiltration in Hepatocellular Carcinoma. Int. J. Gen. Med. 2022, 15, 437–449.
Dong, W.; Zhan, C. Bioinformatic-Based Mechanism Identification of E2F1-Related CeRNA and E2F1 Immunoassays in Hepatocellular Carcinoma. J. Gastrointest. Oncol. 2022, 13, 1915–1926.
Xiong, J.; Wang, Q.-Q. Mechanisms and Strategies to Overcome Immunotherapy Resistance in Hepatobiliary Malignancies. Hepatobiliary Pancreat. Dis. Int. 2022, in press.
Hua, N.; Chen, A.; Yang, C.; Dong, H.; He, X.; Ru, G.; Tong, X.; Zhou, F.; Wang, S. The Correlation of Fibrinogen-like Protein-1 Expression with the Progression and Prognosis of Hepatocellular Carcinoma. Mol. Biol. Rep. 2022, 49, 7911–7919.
Yan, Q.; Lin, H.-M.; Zhu, K.; Cao, Y.; Xu, X.-L.; Zhou, Z.-Y.; Xu, L.; Liu, C.; Zhang, R. Immune Checkpoint FGL1 Expression of Circulating Tumor Cells Is Associated With Poor Survival in Curatively Resected Hepatocellular Carcinoma. Front. Oncol. 2022, 12, 810269.
Wei, Y.-Y.; Fan, J.; Shan, M.-X.; Yin, D.-D.; Wang, L.-L.; Ye, W.; Zhao, W. TIGIT Marks Exhausted T Cells and Serves as a Target for Immune Restoration in Patients with Chronic HBV Infection. Am. J. Transl. Res. 2022, 14, 942–954.
Wang, T.; Dang, N.; Tang, G.; Li, Z.; Li, X.; Shi, B.; Xu, Z.; Li, L.; Yang, X.; Xu, C.; et al. Integrating Bulk and Single-cell RNA Sequencing Reveals Cellular Heterogeneity and Immune Infiltration in Hepatocellular Carcinoma. Mol. Oncol. 2022, 16, 2195–2213.
Finn, R.S.; Qin, S.; Ikeda, M.; Galle, P.R.; Ducreux, M.; Kim, T.; Kudo, M.; Breder, V.; Merle, P.; Kaseb, A.O.; et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N. Engl. J. Med. 2020, 382, 1894–1905. Available online: https://www.nejm.org/doi/full/10.1056/nejmoa1915745 (accessed on 8 July 2022).
Abou-Alfa, G.K.; Lau, G.; Kudo, M.; Chan, S.L.; Kelley, R.K.; Furuse, J.; Sukeepaisarnjaroen, W.; Kang, Y.-K.; Van Dao, T.; De Toni, E.N.; et al. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022, 1.
A Phase IIIB, Single Arm, Multicenter Study of Atezolizumab (Tecentriq) in Combination With Bevacizumab to Investigate Safety and Efficacy in Patients With Unresectable Hepatocellular Carcinoma Not Previously Treated With Systemic Therapy-Amethista. clinicaltrials.gov; 2022. Available online: https://clinicaltrials.gov/ct2/show/NCT04487 (accessed on 1 August 2022).
Kelley, R.K.; Rimassa, L.; Cheng, A.-L.; Kaseb, A.; Qin, S.; Zhu, A.X.; Chan, S.L.; Melkadze, T.; Sukeepaisarnjaroen, W.; Breder, V.; et al. Cabozantinib plus Atezolizumab versus Sorafenib for Advanced Hepatocellular Carcinoma (COSMIC-312): A Multicentre, Open-Label, Randomised, Phase 3 Trial. Lancet Oncol. 2022, 23, 995–1008.