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2	format change	Peter Tang	Meta information modification	2466	2022-10-12 03:37:16	\|

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Salani, F.; Genovesi, V.; Vivaldi, C.; Massa, V.; Cesario, S.; Bernardini, L.; Caccese, M.; Graziani, J.; Berra, D.; Fornaro, L.; et al. Primary Resistance to Immunotherapy-Based Regimens in Hepatocellular Carcinoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/28947 (accessed on 17 July 2025).

Salani F, Genovesi V, Vivaldi C, Massa V, Cesario S, Bernardini L, et al. Primary Resistance to Immunotherapy-Based Regimens in Hepatocellular Carcinoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/28947. Accessed July 17, 2025.

Salani, Francesca, Virginia Genovesi, Caterina Vivaldi, Valentina Massa, Silvia Cesario, Laura Bernardini, Miriam Caccese, Jessica Graziani, Dario Berra, Lorenzo Fornaro, et al. "Primary Resistance to Immunotherapy-Based Regimens in Hepatocellular Carcinoma" Encyclopedia, https://encyclopedia.pub/entry/28947 (accessed July 17, 2025).

Salani, F., Genovesi, V., Vivaldi, C., Massa, V., Cesario, S., Bernardini, L., Caccese, M., Graziani, J., Berra, D., Fornaro, L., & Masi, G. (2022, October 11). Primary Resistance to Immunotherapy-Based Regimens in Hepatocellular Carcinoma. In Encyclopedia. https://encyclopedia.pub/entry/28947

Salani, Francesca, et al. "Primary Resistance to Immunotherapy-Based Regimens in Hepatocellular Carcinoma." Encyclopedia. Web. 11 October, 2022.

Primary Resistance to Immunotherapy-Based Regimens in Hepatocellular Carcinoma

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This entry is adapted from the peer-reviewed paper 10.3390/cancers14194896

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]. 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] 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 ^[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	Specificity to HCC	Putative Mechanism of Resistance	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.	Lower enrichment score of immune signatures: T-cell exclusion, and down-regulation of CCL4. Down-regulation of NKG2D ligand hampering NK-mediated response.	^[11]^[12]^[13]
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.	High correlation between its expression and immune-suppressive or exhausted tumor environment.	^[14]^[15]^[16]^[17]
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	High expression of FGL1 is correlated with higher density of LAG3+: blocking the FGL1/LAG3 can promote T cytotoxicity immunity.	^[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	^[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 ^[23] and tremelimumab/durvalumab (STRIDE regimen) being a more recent valuable competitor ^[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 ^[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 ^[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	Trial Name and/or CTC Identification	Recruitment	Phase	Comparator	Interventions ^targets
Anti-PD(L)1/anti CTLA4	NCT04720716	China	III	Sorafenib ^a	IBI-310 ^b (ipilimumab bio-similar) + sintilimab ^c
Anti-PD(L)1/anti CTLA4	NCT04039607/ CheckMate 9DW	global	III	Sorafenib or Lenvatinib ^d	Ipilimumab ^b + nivolumab ^c
Anti-PD(L)1/anti-VEGF	NCT04605796	China	II	-	JS001, toripalimab ^c + bevacizumab ^e
	NCT04560894	China	II/III	Sorafenib ^a	SCT-I10A^c + SCT510 (bevacizumab bio-similar) ^e
	NCT04741165	China	II	-	HX008 ^c + bevacizumab ^e
	NCT03973112, arm IV	China	II	-	HLX10, serplulimab ^c + HLX04 (bevacizumab biosimilar) ^e
Anti PD(L)1/TKIs	NCT04443309	China	I/II	-	Camrelizumab ^c + lenvatinib ^d
	NCT04401800	China	II	-	Tislelizumab ^c + Lenvatinib ^d
	NCT04183088	Taiwan	II	Regorafenib ^f	tislelizumab ^c + regorafenib ^f
	NCT04523493	global	III	Lenvatinib ^d	JS001, toripalimab ^c + lenvatinib ^d
	NCT03841201/IMMUNIB	Germany	II	-	Nivolumab ^c + lenvatinib ^d
	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 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	Study Phase	Treatment Arms	Targets	Primary End-Point
NCT05363722	Ib	IBI 310 (ipilimumab biosimilar) + bevacizumab + sintilimab	anti PD1 + anti CTLA4 + anti-VEGF	ORR
NCT04740307 MK-1308A-004	II	pembrolizumab/quavonlimab (MK-1308A) + lenvatinib	Coformulated anti PD1/anti CTLA4 + TKI	DLTs ORR
NCT05363722	III	Camrelizumab + Folfox4	anti PD1 + chemotherapy	OS
NCT05363722	III	Camrelizumab + placebo	anti PD1 + chemotherapy	OS
NCT04948697 AdvanTIG-206	II	ociperlimab + tislelizumab + BAT1706	Anti-TIGIT + anti PD1 + anti- VEGF	ORR
NCT04948697 AdvanTIG-206	II	tislelizumab + BAT1706	anti PD1 + anti- VEGF	ORR
NCT05337137 Relativity-106	I/II	Relatlimab + Nivolumab + Bevacizumab	Anti-LAG + anti PD1 + anti-VEGF	DLTs ad PFS
NCT05337137 Relativity-106	I/II	Placebo + Nivolumab + Bevacizumab	anti PD1 + anti-VEGF	DLTs ad PFS
NCT05359861	II	SRF388 + Atezolizumab + bevacizumab	Anti-IL27 + anti PDL1 + anti-VEGF	PFS
NCT05359861	II	Placebo + Atezolizumab + bevacizumab	anti PDL1 + anti-VEGF	PFS
NCT05249569	II	Axitinib + Avelumab + Bavituximab	Anti-VEGFR + anti PDL1 + anti-phosphatidylserine	RR

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.

Table 4. Ongoing clinical trials of CAR-T and vaccine for aHCC.

Treatment Strategy	Trial Identification	Study Phase	Treatment Arms	Primary End-Point
CAR-T cells therapy	NCT02905188 GLYCAR trial	I	GPC3-CAR (GLYCAR T cells) + lymphodepleting chemotherapy (Cyclophosphamide and Fludarabine)	DLT
	NCT03884751	I	CAR-GPC3 T Cells	DLT + MTD
	NCT03980288	I	CAR-GPC3 T Cells (in part II: combination with TKI or anti- PD(L)1)	DLT + MTD
	NCT04121273	I	CAR-GPC3 T Cells	DLT
	NCT03993743	I	CD147-CART hepatic artery infusion	AEs
Vaccine + RFA/surgery	NCT03067493 RAMEC trial	II	RFA or surgery +/− Neo-MASCT	DFS + immune response rate
Vaccine + ICIs	NCT04248569	I	DNAJB1-PRKACA peptide vaccine + Nivolumab + Ipilimumab	AEs + change in INF-producing DNAJB1-PRKACA-specific CD8/CD4 T cells

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

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Subjects: Oncology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Francesca Salani

Virginia Genovesi

Caterina Vivaldi

Valentina Massa

Silvia Cesario

Laura Bernardini

Miriam Caccese

Jessica Graziani

Dario Berra

Lorenzo Fornaro

Gianluca Masi

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Update Date: 12 Oct 2022

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