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This article has been accepted for publication and undergone full peer review but has not

been through the copyediting, typesetting, pagination and proofreading process, which may

lead to differences between this version and the Version of Record. Please cite this article as

doi: 10.1002/hep.30337

This article is protected by copyright. All rights reserved.

Article type : Review

Challenges and opportunities in the clinical development of immune checkpoint

inhibitors for hepatocellular carcinoma.

Michael J Flynn1, Anwar A. Sayed2,3, Rohini Sharma4, Abdul Siddique4, David J. Pinato4

1. Department of Medicine, The Royal Marsden NHS Foundation Trust, Fulham Road, SW3

6JJ London, UK

2. Centre for Haematology, Imperial College London, Hammersmith Campus, Du Cane

Road, W12 0NN, London, United Kingdom

3. Department of Medical Microbiology and Immunology, Taibah University, Janadah Bin

Umayyah Road, 42353, Medina, Saudi Arabia

4. Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du

Cane Road, W120HS London, UK.

Keywords: immune-checkpoint inhibitors, hepatocellular carcinoma, cirrhosis, biomarkers, loco-regional therapies, antiangiogenics

Running Head: Immune checkpoint inhibitors in HCC

To whom correspondence should be addressed:

Dr David J. Pinato, MD MRes MRCP PhD

NIHR Academic Clinical Lecturer in Medical Oncology

Imperial College London Hammersmith Campus,

Du Cane Road, W12 0HS, London (UK)

Tel: +44 020 83833720 E-mail: [email protected]

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Abstract.

After a decade of stagnation in drug development, therapeutic reversal of immune-exhaustion with

immune checkpoint inhibitors (ICPI) has been shown to be effective in advanced hepatocellular

carcinoma (HCC). The clinical development of novel ICPIs continues at a rapid pace, with more than 50

clinical trials of immunotherapeutic agents registered as of May 2018 for this indication. The

development of ICPI is particularly challenging in patients with HCC, a population with unique features

which impact on safety and efficacy of immune-modulating therapies. In this review, we discuss the

biologic foundations supporting the development of ICPI across the advancing stages of HCC, focusing in

particular on the proposal of a rational positioning of ICPI across the various Barcelona-Clinic Liver

Cancer stages of the disease. Translational studies should guide adequate prioritisation of those

therapeutic agents and combination strategies which are most likely to achieve patient benefit based on

solid mechanistic and clinical justifications.

Introduction.

The role of immune evasion as a pivotal mechanism in the progression of hepatocellular carcinoma (HCC)

has long been recognised, but has for many decades remained an “undruggable” domain due to the lack of

effective therapies capable of reversing cancer-related immunosuppression1. Clinical trials of immune

checkpoint inhibitors (ICPI) have ascribed HCC to the widening list of tumours characterised by intrinsic

sensitivity to immunotherapy. In particular, these agents have been proven effective in advanced

melanoma, renal cell carcinoma and non-small cell lung cancer (NSCLC), with a widening number of

studies demonstrating response rates of up to 25% across haematological and solid malignancies.

However, despite the unprecedented efficacy of ICPI, patients with HCC represent a population with

distinct features. The concomitant presence of cirrhosis in >80% of patients is unique and deserves to be

considered for its potential safety impact on the delivery of immunotherapy.

In terms of efficacy, the presence of a predominantly immunosuppressive microenvironment within the

liver might affect long-term disease control in patients with HCC. Attempts to personalise development of

ICPIs through multi-technology profiling of tumour samples poses a conflict with routine clinical practice,

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in which histological confirmation of the diagnosis has been largely abandoned in favour of radiologic

criteria2.

In the context of a rapid expansion of immuno-oncology, this review aims to outline the challenges and

opportunities that accompany the clinical development of immunotherapy in HCC. Here, we review the

basic immunobiologic foundations justifying the disease-modulating role of immunotherapy in HCC and

attempt to define how ICPI might be positioned alongside the evolving landscape of radical, loco-regional

and systemic treatments for HCC.

Rationale for development of ICPI in HCC

The liver as an immunologic gatekeeper

The liver sits at the junction between the host and a continuous influx of gut nutrients, toxins and

metabolites from its evolving microbiome. The plethora of immunologic interactions within the gut-liver

axis plays a significant role in health and disease and participates in the pathogenesis and progression of

HCC. Among the physiologic functions of the liver in governing host defense, the process of immune

distinction between gut pathogens and self requires polarisation of intrahepatic immune cells towards

immunosuppression. However, in chronic liver inflammation induced by various hepatotropic noxae,

enhancement of gut permeability (“leaky gut”) is thought to further polarise the liver microenvironment

towards immunosuppression3. Dissection of this complex interplay has highlighted a predominant role of

intestinal dysbiosis in facilitating fibrogenesis through hepatic stellate cell (HSC) activation4. The

resulting immunosuppressive milieu typical of progressive chronic liver diseases profoundly modulates

HCC growth by facilitating immune evasion5.

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The immune landscape of HCC

Impaired antigen presentation via alterations in major histocompatibility (MHC) class I and aberrant

expression of tumour neo-antigens6 are key mechanisms facilitating immune escape in HCC. Effector T-

cell function impairment occurs both via reduced recruitment of CD4+ and cytotoxic CD8+ (CTL) tumour-

infiltrating lymphocytes (TIL) as well as activation and expansion of tolerogenic dendritic cells (DC) and

regulatory T-cells (T-regs)7. Other cell types involved in immune evasion include myeloid-derived

suppressor cells (MDSCs)7, HSC and tumour-associated macrophages (TAMs). MDSCs are functionally

heterogeneous cells possessing T-cell suppressive activity in cirrhosis and HCC. Immunosuppressive M2-

polarised TAMs promote HCC growth and invasion predominantly via CCL22 chemokine secretion8.

Concurrently, HSC activation drives an inflamed, pro-fibrogenic microenvironment, with enrichment of

HSC-specific transcripts predicting for outcome after HCC resection9. Acknowledging the functional

heterogeneity of the tumour microenvironment (TME) of HCC is a point of greater consequence in the

development of strategies to overcome immunotherapy resistance.

Harnessing the immunogenicity of HCC

Despite the predominantly immunosuppressive microenvironment, certain patients can mount protective

immunity to HCC with anecdotal evidence of spontaneous remission10. Altered neo-epitope expression is

common in HCC6, in which chronically-inflamed hepatocytes express a repertoire of tumour-associated

antigens (TAAs) including alpha-fetoprotein (AFP), glypican-3 and many other cancer/testis antigens11.

Dense TIL infiltration and high prevalence of TAA-specific T-cell peripheral responses are commonly

found12, however, T-cell responses against immune-dominant epitopes exist in a suppressed state in HCC

patients13.

The presence of an immune-reactive microenvironment in HCC, rich in potentially actionable drivers of

the immune response, has been evident since the earliest genomic studies of HCC. In a study of 956 HCC

patients, 25% clustered within a coordinated pro-inflammatory gene expression profile, with increased

PD-1/PD-L1 expression, fewer chromosomal aberrations and dampened cytolytic activity14. Interestingly,

pro-inflammatory gene-expression signatures clustered with dysregulation of TGF-β signalling, in

keeping with enrichment of an exhausted immune response, suggesting this molecular subclass to be

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potentially sensitive to ICPI. Figure 1 summarises some of the key therapeutically relevant interactions

within the HCC TME.

Classes of the forerunner checkpoint molecules and their inhibitors

Cytotoxic T-lymphocyte-associated protein (CTLA-4).

Whilst CTLA-4 expression is not prognostic in HCC15, its ubiquity on T-regs and activated CTLs suggests

its clinical value as a therapeutic target. Disruption of the CTLA-4/CD80-CD86 interaction results in

tumour rejection via enhancement of T-cell effector responses and is associated with selective T-reg

depletion16. Ipilimumab and tremelimumab are monoclonal antibodies (mAbs) against CTLA-4 and have

both been studied in HCC (Table 1). In a small phase II trial of 21 patients with Hepatitis C-virus (HCV)-

virus-associated HCC, tremelimumab demonstrated anti-tumour and anti-viral activity defined by an

overall response rate (ORR) of 17.6%, a median time to progression (TTP) of 6.5 months and reduction in

HCV viraemia in a subgroup of patients17. Interestingly, tremelimumab enhances CTL density in HCC,

providing justification for its combination with loco-regional therapies (LRT)18. Whilst concern exists

over the greater toxicity of CTLA-4 inhibitors compared to anti-programmed cell death protein-1 (PD-1)

therapies, an increasingly relevant role for these molecules stems from their use in combination. In HCC,

ipilimumab and tremelimumab are being tested in combination with nivolumab (NCT01658878) and

durvalumab (NCT02519348), respectively.

Programmed cell death protein-1 (PD-1) and its ligands (PD-L1/PD-L2)

Binding of either PD-L1 or PD-L2 to PD-1 on T-cells inhibits their activation. PD-L1 is highly expressed in

HCC and surrounding antigen-presenting cells with prevalence ranging from 45% to 100%19. PD-L1

expression appears stage-independent and influences overall survival (OS), disease-free survival (DFS),

grade and vascular invasion in early-stage HCC19.

Pembrolizumab and nivolumab are potent and highly selective PD-1-targeting mAbs, whereas

atezolizumab, avelumab, and durvalumab target PD-L1. Nivolumab was licensed by the Food and Drug

Administration (FDA) for advanced HCC on the basis of Checkmate-040, a phase I study of sorafenib-

intolerant or refractory patients, stratified by Hepatitis B/C aetiology20. Eligibility was restricted to

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patients with good performance status (0-1), Child-Pugh score <7 for dose-escalation and <6 for dose-

expansion and evidence of adequate HBV control on antivirals. At 3 mg/kg every 2 weeks, nivolumab

resulted in 25% of patients developing treatment-related Grade 3 or 4 toxicities, of which 6% were

reported as serious adverse effects (AEs) affecting skin, adrenal and liver. Encouragingly, an ORR of 20%

and a promising 1-year OS rate of 62% were demonstrated. Similarly, preliminary results of second-line

treatment with pembrolizumab following sorafenib failure, has demonstrated an ORR of 16.3% and 6-

month OS rate of 77.9%21.

The positioning of immunotherapy in the treatment landscape of HCC.

As early signals of efficacy encourage the development of ICPI across the various stages of HCC, there is an

acute need for rational development of immunotherapy across its heterogeneous treatment landscape.

Whilst codified prognostic algorithms such as the Barcelona Clinic Liver Cancer (BCLC) staging system

have guided treatment allocation in routine care since the early 2000s, the rapid clinical development of

ICPI is expected to significantly change this framework.

Early-stage disease: can ICPI improve cure rates in HCC?

Whilst curative of both cancer and cirrhosis, orthotopic liver transplantation (OLT) is restricted to

patients who satisfy stringent criteria22. Despite high cure rates, the issue of post-transplant recurrence,

common in 10% of patients fulfilling Milan criteria23 and in many more patients outside these24, suggests

OLT is inadequate as a single therapeutic modality in guaranteeing life-time disease control in a

proportion of patients. Tumour recurrence is even greater following liver resection, with relapse rates up

to 70% with 5-year OS figures ranging between 17 to 53%25. Anti-tumour immunity is mechanistically

involved in modulating the risk of HCC relapse26, highlighting the rationale for the development of ICPI

alongside curative treatments for HCC.

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Perspectives for neoadjuvant use of ICPI

Neoadjuvant ICPI therapy offers the advantage of assessing sensitivity to treatment in the individual

patient: achievement of a pathologic complete response (pCR) is one of the strongest predictors of long-

term survival, with paradigmatic examples across a number of malignancies. Such a prognostic role holds

true in HCC, in which response to bridging therapy in OLT candidates predicts for improved prognosis27.

Neoadjuvant therapy has traditionally been a challenge in HCC, particularly because of the lack of

systemic agents capable of inducing significant down-staging of the disease. Whilst transarterial

chemoembolisation (TACE) and Yttrium-90 radioembolisation have been attempted in the pre-OLT

setting to reduce drop-out rates and maximise transplant eligibility, evidence of a survival benefit is

exclusively based on retrospective data28. Considering the treatment landscape of HCC, patients who are

candidates for liver resection and not eligible for OLT represent the most suitable population to

preliminarily investigate the neoadjuvant use of ICPI, aiming to positively impact on surgical outcomes

and control relapse risk.

Combination ICPI therapy with ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) is being tested in the

two-arm phase Ib OpACIN trial in melanoma as an adjuvant (4 courses post-surgery, n=10) or

neoadjuvant therapy (split into 2 courses pre- and 2 post-surgery, n=10). Whilst no additive

perioperative morbidity has been observed, discontinuation rates due to toxicity appear to be particularly

high in this study (90%), in which only 2 patients were able to complete the pre-defined treatment

schedule. Despite high toxicity, a radiological CR was observed in 80% of patients treated neoadjuvantly

with an encouraging 30% pCR rate29. In the setting of liver resection for HCC, the selected delivery of ICPI

to patients who have adequate liver functional and physical reserve to cope with anticipated

immunotoxicity mitigates the potential safety concerns linked with the delivery of systemic therapy.

However, a number of issues in the delivery of the neoadjuvant treatment schedule remain unanswered

including patient selection, optimal duration of treatment and choice of single-agent versus combined

ICPI approach. The appealing ORR and median OS (mOS) achieved by combined CTLA-4/PD-1 inhibition

in other indications, in excess of 30-40%, are appealing but discouraged by the high proportion of G3-4

AEs, which can exceed 50%30. As safety and efficacy data from dual checkpoint inhibition will

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prospectively emerge in advanced HCC, appropriate dose-adapted schedules should be evaluated, with a

focus on immune-mediated hepatotoxicity, which, although common in 5-10% of patients treated with

single-agent anti-PD-1 inhibitors, tends to be significantly higher with combined therapy30.

Despite the optimistic prospects, the complexity of HCC requires caution in the development of ICPI in

transplant candidates. Based on historical data, ideal candidates for neoadjuvant ICPI are patients at

higher risk of post-OLT relapse, i.e. those with multifocal tumours, with higher AFP levels, higher tumour

volume and poorer differentiation31. However, the need for lifetime immunosuppression in patients with

OLT might represent a barrier to the safe delivery of ICPI therapy, due to its documented potential of

precipitating graft rejection32. Most trials of ICPI exclude patients on long-term immunosuppression such

as transplants recipients, therefore evidence to support its safe use is limited in this population. In a pilot

study ICPI-mediated allograft rejection was documented in 1 of 6 treated patients33, underscoring the

need for larger studies to inform safe integration of ICPI therapy in transplant recipients.

Adjuvant ICPI therapy

Whilst sorafenib after liver resection/RFA has failed to demonstrate a significant relapse-free survival/OS

benefit34, multiple studies have highlighted adequate control of aetiological factors such as HBV

suppression35 or HCV eradication36 as key determinants of long-term survival in early-stage HCC. These

studies emphasise the role of the TME in shaping the risk of relapse, a contribution that may potentially

confound the assessment of benefit from tumour-directed adjuvant interventions. Cytokine-induced killer

(CIK) cell therapy, defined by the infusion of autologous peripheral blood mononuclear cells after

treatment with Interleukin-2, may reduce relapses and increase survival according to randomised trials37.

However, the precise immunobiologic mechanisms underlying efficacy are poorly understood and the

need for specialist expertise to deliver CIK has limited the use of this approach.

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A key challenge in the optimal delivery of adjuvant ICPI therapy in HCC stems from the multifactorial

nature of HCC relapse. Early intrahepatic recurrence is traditionally attributed to true disease re-

occurrence after radical treatment as opposed to de novo tumour formation, with a 2-year cut-off period

suggested as an empirical threshold to differentiate the two entities38. Whilst adjuvant ICPI is expected to

reduce recurrence by facilitating systemic clearance of residual micro-metastatic disease and prolonging

progression-free survival, the potential for a “chemopreventative” role of immunotherapy in influencing

de novo tumourigenesis is based on much less solid evidence. Identification of histopathologic high-risk

features post resection including higher tumour burden, poorer differentiation, multifocality and most

importantly microvascular invasion may aid the identification of optimal candidates for adjuvant

treatment.

Perhaps more strongly than in the neoadjuvant setting, adjuvant ICPI therapy in HCC lacks clear guidance

in terms of duration of therapy and choice of agents. Toxicity, which was significant in the adjuvant

melanoma study, EORTC 1807139, might limit the selection of a CTLA-4 inhibitor in the adjuvant setting in

HCC.

Integrating ICPI with loco-regional therapies (LRT)

Despite active screening programmes, approximately 50-60% of HCC cases present with intermediate-

stage disease in which TACE is the recommended first-line therapy40. Wide clinical heterogeneity exists in

this patient population who will inevitably progress after TACE with mOS 24 months41. Migration of this

patient group to systemic treatment is possible, but survival outcomes are poor due to the limited efficacy

of sorafenib42. Combination of TACE with anti-angiogenic therapies has failed to improve outcomes43.

Adaptive T-cell responses against TAA are key mechanisms regulating tumour-rejection in HCC. These

can be enhanced in vivo using autologous DC vaccines or by tumour lysate stimulation44 and are

dynamically modulated in response to TACE13. Similarly, regulation of T-cell suppressive responses

relates to the efficacy of TACE and makes restoration of effective anti-tumour adaptive immunity an

appealing therapeutic strategy in HCC. A key question is whether the ischaemic damage imposed by TACE

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may facilitate priming to a broad range of previously inaccessible neo-epitopes and exert synergistic anti-

tumour effects with immunotherapy. TACE plays a role in activating a hypoxic response, promoting the

release of Vascular Endothelial Growth Factor (VEGF) and other pro-angiogenic cytokines45. Evidence

suggests PD-L1 expression is transcriptionally regulated by hypoxia-inducible factor (HIF-1α)46, which

strengthens the rationale of combining TACE with PD-1/PD-L1 inhibitors. Figure 2 summarises the key

immune-modulating effects of RFA and TACE.

In a pilot study of tremelimumab following subtotal chemoembolisation or RFA in 32 patients with HCC,

an ORR was observed in 5/19 evaluable patients (26%) with TTP of 7.4 months18. Post-treatment tumour

biopsies showed enhanced CTL infiltration, qualifying TACE as an immunogenic cell death (ICD) inducer.

Whilst encouraging, the small sample size and the lack of comparator arms in this trial does not allow

dissection of the individual role of tremelimumab as a synergistically acting agent in promoting ICD. A

number of studies are ongoing in this area including PETAL, the first trial to explore the safety,

tolerability and preliminary bioactivity of pembrolizumab in combination with TACE in intermediate-

stage HCC (NCT03397654) and a second study evaluating nivolumab in association with DEB-TACE

(NCT03143270). The results of these studies will be instrumental in planning proof-of-concept

multicentre phase II/III studies.

Advanced disease: evolving rationale for immunotherapy combinations

In contrast to other cancer types, systemic treatments have traditionally played a comparatively modest

role in advanced HCC, in which mOS rarely extends beyond 1 year. Amongst a number of late-stage

failures in clinical development, the provision of systemic anti-cancer treatment in HCC is still

unsupported by predictive correlates of response47, a point of greater consequence now that treatment

options for HCC are expanding from sorafenib to alternative first-line options with lenvatinib and second-

line therapies with regorafenib and cabozantinib48. With immunotherapy displaying evidence of disease-

modulating effects in HCC as a single-agent, the rationale for combination strategies is becoming evident.

Table 2 provides a summary of openly recruiting combination trials in the advanced disease setting.

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Combination immuno-oncological approaches

Combination of PD-1 and CTLA-4 receptor blockade has proven synergistic in preclinical and clinical

studies in melanoma, in which ORR of 57% were demonstrated30. ORR of 38-47% and 42% have since

been respectively reported in the first line treatment of NSCLC and renal cell carcinoma49,50. The

expanding ICPI efficacy data across solid tumour indications are encouraging but toxicity concerns have

driven research towards defining the relative contribution of PD-1/PD-L1 versus CTLA-4 blockade in

determining depth and durability of responses. Preliminary data from the durvalumab/tremelimumab

phase I HCC study suggest this combination is well tolerated, with the most-frequent treatment-related

AE being asymptomatic AST rise (10%). Efficacy seems encouraging, with an ORR of 35% demonstrated

in patients who were not virally infected51.

Similarly to other indications, there is a rationale to block other immune checkpoints (Lag-3, TIM-3) and

to evaluate antibodies that agonistically bind co-stimulatory receptors on immune cells (OX40, GITR,

CD137) to enhance the efficacy of ICPI52. Therapeutic modulation of some of these targets is hypothesised

to synergise with PD-1 by their alternative mechanism of action with lower anticipated toxicity than

CTLA-4 inhibitors. The combination of nivolumab and the anti-CCR4 antibody mogamulizumab, which

has shown efficacy in T-cell lymphomas53, is being tested in an open phase I/II trial in HCC

(NCT02705105). Targeting the cytokine drive towards immunosuppression may be especially relevant in

view of the inflammatory nature of HCC, and the combination of the TGF-β inhibitor, galunisertib with

nivolumab in patients with refractory HCC (NCT02423343) is under investigation. Natural killer (NK)

cells mediate antitumour activity both by innate immune and antibody-dependent cell-mediated

cytotoxicity. Therapeutic modulation of NK function with the anti-killer inhibitor receptor (KIR) receptor

antibody, lirilumab is under investigation in combination with nivolumab (NCT01714739). An alternative

approach is targeting TME metabolism inhibition of the immunosuppressive enzyme indoleamine-2,3

dioxygenase (IDO); a strategy tested by combining epacadostat, an IDO-inhibitor, with pembrolizumab in

solid tumours including in HCC (NCT02178722). Other combination approaches include epigenetic

enhancement of anti-tumour immunity through histone deacetylation inhibition, is supported by

preclinical evidence suggesting increased HCC cell line apoptosis with vorinostat54.

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Anti-angiogenics and other tyrosine kinase inhibitors (TKI)

Emerging evidence suggests that anti-angiogenic therapies may also have immunomodulatory effects.

TKIs can exert “off-target” effects on the TME including vascular stabilisation, changes in tumour

perfusion and may exert a conditioning role on TILs that suggests potential for synergy with ICPI55.

Sorafenib has been shown to modulate infiltration of inflammatory cells including CTLs56 and NK cells57.

Combination treatment with sorafenib and inhibitors of stromal-derived-factor-1a receptor have shown

incremental anti-tumour efficacy maximised by the concomitant inhibition of PD-L158.

Clinically, potential synergistic combinations between anti-angiogenics and ICPI are being explored in

advanced HCC. The first line combination of sorafenib with nivolumab is being tested in a Phase II trial

(NCT03439891), while the expansion of the Checkmate 040 study now has alternative VEGFR inhibitor

arms, including in combination with sorafenib and cabozantanib (NCT01658878). Other combination

trials of axitinib with avelumab (NCT03289533) and of the MET-inhibitor, capmatanib with the anti-PD-1

inhibitor, PDR-001 are recruiting (NCT02795429).

Cellular immunotherapy

Although the use of vaccines with59 or without DC infusions60 has thus far been disappointing in the clinic,

evidence of anti-tumour effects including on circulating cytokine and AFP levels within these trials,

warrants further research on cellular immunotherapy perhaps in combination with ICPI. Intratumoural

injections of oncolytic and immunotherapeutic vaccinia virus JX-594 (pexa-vec) showed early signal of

antitumour efficacy61 and has provided the rationale for an ongoing first line phase III study comparing

the combination of JX-594 with sorafenib versus sorafenib alone (NCT02562755) and in combination

with nivolumab (NCT03071094).

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Predicting efficacy to ICPI: the challenge of patient selection

Whilst ICPI represent a novel and effective therapeutic class in the oncology clinic, response rates to

single-agent immunotherapy is limited to 20% of patients across indications. As newer therapies expand

in the treatment of advanced HCC, identification of predictive correlates of response is becoming critical

to spare patients from potentially life-threatening toxicity in the absence of clinical benefit.

PD-L1 expression by immunohistochemistry (IHC) has been suggested to underscore responsiveness to

ICPI in selected tumour types. However, such a role has not been replicated in HCC. Heterogeneity in PD-

L1 IHC assays exists and might have clinical implications in disease stratification. The efficacy of ICPI

relies on the breadth and depth of effector T-cell responses. Enrichment of Interferon-γ-related

signatures identified through transcriptomic profiling is a common trait of ICPI-responsive

malignancies62. Microsatellite instability (MSI) occurs due to defective mismatch repair (MMR) and leads

to a somatic hypermutated phenotype with higher neoantigen burden. The exquisite immunogenicity of

microsatellite-unstable malignancies was demonstrated by the high response rates to anti-PD-1 therapies

across histotypes63 leading to the first tumour agnostic FDA-approval of pembrolizumab in MMR-

deficient solid tumours irrespective of histology. Higher tumour mutational burden (TMB) induces a

polyclonal, efficacious T-cell effector response by promoting a broadened recognition of tumour neo-

antigens. HCC typically demonstrates a moderate TMB, amounting to 2 mutations/megabase further

underscoring the overall antigenic potential of HCC64. The link between higher TMB and responsiveness

to PD-1/PD-L1 blockade65 is established in melanoma and NSCLC, suggesting a better predictive role than

PD-L1 expression across tumour types66. Whilst linked to worse prognosis67, the predictive role of this

biomarker TMB for ICPI efficacy in HCC should be prospectively tested. A number of other factors have

been postulated to modulate responsiveness to immunotherapy including aetiology of underlying liver

disease, and TIL density and composition68. Interestingly, despite the wide heterogeneity characterising

the composition and functionality of the liver-resident immune infiltrate across the various aetiologies of

HCC, patients with non-HCV/non-HBV-mediated HCC had similar responses to virally induced HCC in

both Keynote-22421 and Checkmate-04020 suggesting independence between anti-tumour activity and

viral aetiology of HCC. A number of other host determinants are known to reduce effector T-cell activity.

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Given the strong pathogenic link between gut dysbiosis and the molecular pathogenesis of HCC in

cirrhosis, studies evaluating the role of bacterial phylogeny with the characteristics of the anti-tumour

immune response should be prioritised. Other host factors include the presence of a systemic

inflammatory response69, circulating cytokine levels, and changes in immune effector composition, which

deserve evaluation for a predictive role in HCC68.

Conclusion.

After a decade of stagnation in drug development, therapeutic reversal of immune-exhaustion with PD-1-

targeting ICPI has been shown to improve survival outcomes. Rampant clinical development of novel

ICPIs, either as monotherapy or in combination, has rapidly followed in an attempt to improve on the

20% ORR seen in early-phase trials of PD-1-targeted therapies. Despite widespread optimism, the

development programme of ICPI in HCC needs to be interpreted with a word of caution. In HCC alone, as

of the end of March 2018, there are at least 57 openly recruiting trials of immunotherapeutic agents

registered on clinicaltrials.gov70. Whilst seamless clinical development of immunotherapies has certainly

helped patients to obtain expedited access to novel therapies, the parallel testing of multiple therapeutic

combinations in small proof-of-concept studies has been questioned for its efficiency.

As highlighted in this review, the specific context of HCC is accompanied by various factors that further

complicate the drug-development process. Concerns over safety and tolerability of ICPI, patient selection

based on clinical characteristics and stage rather than biomarkers as well as the documented influence of

treatment-related and geographical heterogeneity in patients’ survival are amongst the key disease-

specific issues ascribing HCC patients as a challenging population. Anecdotal evidence showing complete

responses from anti-PD-1 therapy in BCLC-D disease are highly provocative, but in line with concurrent

evidence questioning poor performance status and organ dysfunction as absolute contraindications for

systemic anticancer treatment71. To overcome these numerous challenges, the successful development of

ICPI in HCC is likely to require the concerted efforts of various stakeholders across industry, academic,

and regulatory bodies.

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Table 1. Clinical trials of ICPI in HCC.

Phase,

inclusion

Patient

Population

Drug Efficacy Highest grade

toxicities (%)

NCT

(reference)

Phase II (n=21) hepatitis C–

related HCC,

Child-Pugh A

or B

tremelimumab ORR 17.6%;

statistically

significant

decrease in

hepatitis C

viral load in 11

patients at day

105 and in six

patients at day

210 (p = .017)

Grade 3

elevation in BR

(10%), Grade

3-4

transaminitis:

(45%), rash,

diarrhoea, and

neutropenia

(5%),

NCT01008358

17

CheckMate 040

CA209-040,

checkmate 040

Phase I/II

(n=48)

uninfected,

HBV infected,

HCV infected

nivolumab ORR 19%; 12

mo OS rate

62%

Grade 3/4

lipase

elevation

(13%), Grade 3

transaminitis

(10%)

NCT02828124 20

CheckMate 040 cohort 2 expansion (n=214)

57 uninfected

sorafenib

refractory, 56

uninfected

sorafenib

naive/intolera

nt, 50 HCV, 51

HBV

nivolumab ORR

uninfected

sorafenib

refractory 19

%, sorafenib

naive or

intolerant 20

%, HCV 14%,

HBV 12%; 9

mo OS rate

70%

Grade 3-4

transaminitis

(10%)

NCT02828124 20

Phase III

CHECKMATE

459 (n = 726)

1st line nivolumab vs

sorafenib

pending pending NCT02576509

KEYNOTE 224 after sorafenib

failure/intoler

pembrolizuma ORR 16.3%; 6

mo OS rate

Any Grade 3

(including

NCT02702401

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Phase II ance b single arm 77.9% transaminitis,

fatigue,

pruritis) 25%

21

KEYNOTE 240

Phase III

(n=408)

after sorafenib

failure/intoler

ance

pembrolizuma

b vs placebo

pending pending NCT02702401

Phase I/II

(n=440)

1st line tremelimumab

+ durvalumab

vs

tremelimumab

35% ORR

(uninfected),

20% ITT

grade 3

pneumonitis,

grade 3

colitis/diarrhe

a,

asymptomatic

grade 4

elevated AST

and ALT (2%)

NCT02519348 51

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Table 2. Selected trials of combinations of ICPI with targeted therapies and novel immunotherapies in

advanced HCC

Ph

ase

Sample

size (n)

ICPI Combination Mechanism of action NCT Estimat

ed

Comple

tion

II 40 nivolumab sorafenib Multiple tyrosine kinase

inhibitor including

VEGFR, PDGFR

NCT03439891 Dec

2020

II 620 nivolumab

(and

ipilimumab)

sorafenib/

cabozantanib

Multiple tyrosine kinase

inhibitor including

VEGFR, PDGFR;

cabozantanib in addition

is c-MET, AXL inhibitor

NCT01658878 July

2019

I 20 avelumab axitinib VEGFR NCT03289533 Jan

2020

I/II 108 PDR-001 capmatanib c-MET inhibitor NCT02795429 Dec

2018

I/II 114 nivolumab mogamulizuma

b

CCR4 binding and

initiation of ADCC

NCT02705105 Oct

2018

II 650 nivolumab lirilumab KIR inhibitor NCT01714739 Feb

2021

I/II 75 nivolumab galunisertib TGF-B inhibitor NCT02423343 Oct

2019

I/II 30 nivolumab pexa-vec anti-tumour multipeptide

vaccine

NCT03071094 Oct

2019

VEGFR, vascular endothelial growth factor receptor, PDGFR, platelet derived growth factor receptor; c-

MET, hepatocyte growth factor receptor; CCR4, C-C chemokine receptor type 4; ADCC, antibody

dependent cell mediated cytotoxicity; KIR, natural killer cell inhibitor receptor; TGF-B, transforming

growth factor beta.

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Figure Legends.

Figure 1. The hepatic tumour microenvironment: targets for therapy. The complex maturation of

naive Th (T helper) 0 cells is driven by different cytokines and growth factors; to the predominantly

immunostimulatory Th1 or Th17 or the immunosuppressive Th2 or T-reg. This complex interplay

between cell types is bi-directional. Tumour cells present CTLA-4, CCR4 and PD-L1, each of which can be

targeted by antibodies anti-CTLA4, anti-CCR4 and anti-PD-L1 antibodies, respectively. Oncolytic viruses

are preferentially replicate within tumour cells and induce tumour lysis. Damaged tumour cells drive

activation of hepatic stellate cells (HSC) and further release of activating cytokines including

immunostimulatory IL-12 and IL-15. PD-L1 also binds to PD-1 on activated CD8 T cells which suppresses

tumour inflammation. Antigen presenting cells (APCs) drive their activation which in part is suppressed

further by PD-L1/PD-1 interactions. Anti-PD-1 antibodies intercept this inhibition and promote anti-

tumour immunity. Vaccines which drive preferential expression of antigens expressed on tumour cells on

these cells, stimulate CD8+ T cell activation.

Figure 2. Immune modulating effects of loco-regional therapies for HCC. Radiofrequency ablation

(RFA) induces vascular disruption and vasoconstriction, causing necrosis of tumour cells and release of

both damage associated molecular patterns (DAMPs) and pathogen associated molecular patterns

(PAMPs). These induce changes in the immunologic milieu including an increase in CD4+ and cytotoxic

CD8+ T cell, but reduce T-reg cell infiltration. Transarterial chemoembolisation (TACE) is delivered via

vessel catheterisation inducing ischaemia which drives both necrosis and apoptosis of tumour cells.

Similarly the release of DAMPs and PAMPs, drives changes in the tumour microenvironment, which

include the increased infiltration of CD4+ and cytotoxic CD8+ T cells, as well as the increased release of

growth factors, hypoxia inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF).

CD4+ T cells present released antigens to APC (antigen presenting cells) which, stimulated by cytokines

including, IL-12, IL-14 and Type 1 interferon-gamma (IFN-γ),activate natural killer (NK) cells and CD8+ T

cells.

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Conflicts of Interest.

None to disclose.

Acknowledgements.

DJP is supported by the National Institute of Healthcare Research (NIHR) as well as project

grant funding from Cancer Research UK for the immune phenotyping of HCC (Postdoctoral

Bursary Grant Ref. C57701/A26137).

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