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Interventional radiology meets immuno-oncology for hepatocellular carcinoma

  • Riad Salem
    Correspondence
    Corresponding author. Address: 676 N St Claire, Suite 800, Department of Radiology, Section of Interventional Radiology, Chicago, IL 60611 USA.
    Affiliations
    Department of Radiology, Northwestern Feinberg School of Medicine, Chicago, IL, USA
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  • Tim F. Greten
    Affiliations
    Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, Bethesda MD, USA

    NCI CCR Liver Cancer Program, Center for Cancer Research, NCI, Bethesda MD, USA
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Published:August 18, 2022DOI:https://doi.org/10.1016/j.jhep.2022.08.003

      Summary

      Locoregional and systemic therapies are the most used treatment options for patients with hepatocellular carcinoma (HCC). Interventional radiologists have improved and developed novel protocols and devices for both intratumoural ablative approaches with curative intent and various transarterial intrahepatic treatment options, which have continuously improved patient outcomes. Two large phase III randomised clinical trials have demonstrated the efficacy of different immune checkpoint inhibitors either as single agents or in combination in the first-line setting and immunotherapy has become the standard first-line treatment option for patients with advanced HCC. Herein, we discuss advances and perspectives in the area of interventional radiology (IR) and immune-oncology (IO). We summarise results from recent studies and provide an overview of ongoing studies in IR and IO. Based on the significant advances in both areas, we propose that IR and IO need to cover the emerging “discipline” of IR-IO, in which we develop and test novel approaches to combine locoregional therapies with immunotherapy, in order to develop sufficient evidence for them to be considered standard of care for patients with HCC in the near future.

      Keywords

      Introduction

      Results from two large, randomised phase III trials demonstrate that immune checkpoint inhibitor treatment leads to better survival than sorafenib treatment,
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.Y.
      • et al.
      Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
      ,
      • Abou-Alfa G.K.
      • Chan S.L.
      • Kudo M.
      • Lau G.
      • Kelley R.K.
      • Furuse J.
      • et al.
      Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA.
      which has been the best systemic treatment option for patients with advanced hepatocellular carcinoma (HCC) for many years.
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      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      These results have not only changed how patients with advanced HCC are being treated,
      • Greten T.F.
      • Abou-Alfa G.K.
      • Cheng A.L.
      • Duffy A.G.
      • El-Khoueiry A.B.
      • Finn R.S.
      • et al.
      Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma.
      but they have also encouraged interventional radiologists and physicians to collaborate and ask how interventional radiology (IR) and immunotherapy should be combined to achieve the best possible outcome in patients with HCC of all clinical stages.
      • Greten T.F.
      • Mauda-Havakuk M.
      • Heinrich B.
      • Korangy F.
      • Wood B.J.
      Combined locoregional-immunotherapy for liver cancer.
      In this article we summarise recent developments in IR and immune-oncology (IO), describe ongoing efforts to develop combined IR and immunotherapy-based approaches and discuss how we see the possible future of this rapidly developing field of combined IR and IO, which we propose to call “IR-IO”. We first provide a perspective from individual contributors (IR vs. immunotherapy) in the form of a dialogue and follow-up with a summary of how we use our complimentary expertise to develop novel treatment regimens.
      • Locoregional (transplantation, ablation, resection, embolisation, and radiotherapy) and systemic therapies represent the mainstay approaches for the treatment of HCC.
      • Immunotherapies have recently been demonstrated to significantly improve progression-free and overall survival in advanced HCC.
      • Ablation and embolisation improve survival in early and intermediate-stage disease, respectively.
      • Adding locoregional therapies such as ablation and embolisation may prime the immune system and augment the systemic effect of immunotherapies.
      • There is strong rationale for combining the cytotoxic effects of locoregional therapies with immunotherapies in HCC.

      What is the standard of care?

      Interventional radiology

      IR represents the discipline within radiology involved in the use of device and image-guidance for the diagnosis, staging and treatment of HCC. Consequently, interventional radiologists are trained to perform diagnostic procedures and deliver locoregional therapies (LRTs) at all stages of HCC.
      It has become evident over the last decade that obtaining tissue is critical before, during and after treatment with immunotherapies. The prediction of response, development of resistance, and prediction of side effects are integral components of IO clinical trials. In this context, multiple biopsies at scheduled timepoints are now routinely obtained, providing crucial insights on immune cell dynamics.
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      • Ouyang F.
      • Alshawa A.
      • et al.
      Decrease in tumor content assessed in biopsies is associated with improved treatment outcome response to pembrolizumab in patients with rare tumors.
      IR plays an essential role in this setting, as accurate targeting of the lesion for biopsy, as well as proper documentation of the lesion size, shape and location are necessary for the time-dependent and location-critical components of sequential biopsies in IO. Proper review of all anatomic and functional imaging by IR also assists the managing clinician with the identification of the optimal lesion that will permit overall staging at baseline and provide consistent access for repeat targeting during therapy. In summary, the critical role of IR in biopsy relates to obtaining sufficient tissue and cellularity for all types of sequencing, microscopic and metabolic analysis, and potentially functional in vitro studies.
      From a therapeutic standpoint, interventional radiologists perform procedures that can result in immune augmentation, enhancing the role of immunotherapies, including those that are ablative (radiofrequency and microwave ablation), or embolic in nature (chemoembolisation and radioembolisation).
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      Percutaneous ablation-induced immunomodulation in hepatocellular carcinoma.
      The innate immunological features of HCC, including chronic inflammation, the immunosuppressive environment and exhaustion of the T cell (known to promote disease progression), make this an ideal cancer type in which to investigate LRT combined with immunotherapy.
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      Oncolytic virus-based immunotherapies for hepatocellular carcinoma.
      LRTs can increase the immunogenicity of tumours by releasing tumour-associated antigens, resulting in increased systemic antitumor and tumour-infiltrating cytotoxic CD8+ T cells.
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      • Melero I.
      • Sangro B.
      Immunotherapy of hepatocellular carcinoma: facts and hopes.
      Inflammatory cytokines released following ablation result in the additional release of cytokines and chemokines, including interleukins, heat shock proteins, and tumour necrosis factor-α. This is believed to have an important prognostic effect, with investigators finding a correlation between survival and immunocyte infiltration in ablated HCC.
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      • Yu X.L.
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      • et al.
      Sequential pathological and immunologic analysis of percutaneous microwave coagulation therapy of hepatocellular carcinoma.
      Another mechanism where IR can help in the IO setting is based on direct tumoural injection. This concept was first introduced by Coley, who injected inflammatory bacterial extracts directly into sarcomas.
      • Coley W.B.
      The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases.
      Contemporarily, there has been a renewed interest in this approach. Intratumoural injections cause a release of antigens, optimise presentation to antigen-presenting cells, prime and activate the immune system, and subsequently result in the redistribution of effector immune cells yielding abscopal effects on distant metastases.
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      • Castanon E.
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      • Champiat S.
      • Marabelle A.
      Intratumoural administration and tumour tissue targeting of cancer immunotherapies.
      A prime example of this is T-VEC.
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      • Senzer N.
      • Chesney J.
      • et al.
      Talimogene laherparepvec improves durable response rate in patients with advanced melanoma.

      Immunotherapy for HCC

      Different immunotherapeutic approaches have been evaluated in patients with HCC since the early 1990s,
      • Greten T.F.
      • Manns M.P.
      • Korangy F.
      Immunotherapy of hepatocellular carcinoma.
      however, the field has dramatically changed with the introduction of IO.
      • Mellman I.
      • Coukos G.
      • Dranoff G.
      Cancer immunotherapy comes of age.
      Early trials in HCC evaluated the use of anti-CTLA4 (cytotoxic T-lymphocyte associated protein 4) in HCC either as a single agent
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      • de la Mata M.
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      • Garralda E.
      • Barrera P.
      • et al.
      A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C.
      or in combination with LRTs.
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      • Ulahannan S.V.
      • Makorova-Rusher O.
      • Rahma O.
      • Wedemeyer H.
      • Pratt D.
      • et al.
      Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma.
      Fig. 1 provides an overview of results from pivotal phase III studies conducted in HCC and important results are discussed in the following paragraphs.
      Figure thumbnail gr1
      Fig. 1Clinical outcome from pivotal phase III clinical trials in the first-line setting in HCC.
      Shown are OS (A), PFS (B), occurrence of treatment-related AEs ≥Grade 3 (C) and response rates (D). AB, atezolizumab + bevacizumab; AEs, adverse events; CA, cabozantinib + atezolizumab; CR, complete response; D, durvalumab; HCC, hepatocellular carcinoma; N, nivolumab; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; SI, sintilimab; Sor, sorafenib; T, tremelimumab.

      First-line

      Larger trials evaluating the use of anti-PD1 (programmed cell death 1) or anti-PD-L1 (programmed cell death ligand 1) followed and led to large, randomised phase III trials in patients with HCC.
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      • Abou-Alfa G.K.
      • Cheng A.L.
      • Duffy A.G.
      • El-Khoueiry A.B.
      • Finn R.S.
      • et al.
      Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma.
      While the CheckMate 459 trial testing single agent nivolumab did not meet its predefined primary endpoint of improved median overall survival with a median survival of 16.4 months for nivolumab vs. 14.7 months for sorafenib,
      • Yau T.
      • Park J.W.
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      • et al.
      Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial.
      Finn and colleagues reported in 2020 and 2021 the results from the IMbrave 150 study. In this clinical trial a total of 501 systemic treatment naïve patients from 17 countries with unresectable HCC were randomly assigned in a 2:1 ratio to receive either atezolizumab plus bevacizumab or sorafenib until unacceptable toxicity or a loss of clinical benefit. The authors initially reported the hazard ratio (HR) for death with atezolizumab–bevacizumab compared with sorafenib, which was 0.58 (95% CI 0.42 to 0.79; p <0.001) at the time of the primary analysis in August 2019.
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.Y.
      • et al.
      Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
      Longer follow-up analysis demonstrated an overall survival of 19.2 months (95% CI 17.0–23.7) with atezolizumab plus bevacizumab vs. 13.4 months (95% CI 11.4–16.9) with sorafenib (HR 0.66; 95% CI 0.52-0.85; descriptive p <0.001).
      • Cheng A.L.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.Y.
      • et al.
      Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma.
      In general, atezolizumab plus bevacizumab were well tolerated. Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least 1 dose of atezolizumab–bevacizumab and in 55.1% of 156 patients who received at least 1 dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab–bevacizumab group; however, other high-grade toxic effects were infrequent. Similarly, sintilimab plus a bevacizumab biosimilar (IBI305) provided a significant survival benefit for patients with unresectable, mainly HBV-associated HCC in the ORIENT-32 trial in China.
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      • Xu J.
      • Bai Y.
      • Xu A.
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      • Du C.
      • et al.
      Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study.
      Abou-Alfa and colleagues recently presented results from the second positive large multicentre phase III trial testing the combination of a single priming dose of tremelimumab (anti-CTLA4) and durvalumab (anti-PD-L1) in patients with unresectable HCC. In this trial, a total of 1,171 systemic treatment naïve patients were randomised to be treated with tremelimumab plus durvalumab (n = 393), durvalumab (n = 389), or sorafenib therapy (n = 389). Median overall survival improved for tremelimumab plus durvalumab to 16.4 months vs. 13.8 months in the sorafenib-treated group of patients (HR 0.78; 96% CI 0.65–0.92; p = 0.0035). In addition, the single agent durvalumab-treated group met the primary endpoint of non-inferiority vs. sorafenib, with a median survival of 16.6 months. Grade 3/4 treatment-related adverse events occurred in 25.8% of the patients treated with tremelimumab and durvalumab.
      • Abou-Alfa G.K.
      • Chan S.L.
      • Kudo M.
      • Lau G.
      • Kelley R.K.
      • Furuse J.
      • et al.
      Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA.
      In COSMIC-312, the combination of cabozantinib plus atezolizumab was tested as first-line treatment for advanced HCC in a randomised phase III trial. While the combination improved progression-free survival (PFS) from 4.2 to 6.8 months (HR 0.63; 99% CI 0.44-0.91; p = 0.0012), the dual primary endpoint of improved overall survival was not met (HR 0.90, 96% CI 0.69-1.18; p = 0.438).
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      Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial.
      More studies testing different combinations of tyrosine kinase inhibitors with immune checkpoint inhibitors are under way.

      Second-line

      Although not approved by the European Medicines Agency, there are various immune checkpoint inhibitor therapies approved by the Food and Drug Administration (FDA) in the second-line setting. Based on results from KEYNOTE-224, in patients with advanced HCC who had previously been treated with sorafenib, pembrolizumab monotherapy led to an objective response rate (ORR) of 17% (1 complete response and 17 partial responses) among 104 eligible patients, resulting in a median PFS of 4.9 months (95% CI 3.4–7.2)
      • Zhu A.X.
      • Finn R.S.
      • Edeline J.
      • Cattan S.
      • Ogasawara S.
      • Palmer D.
      • et al.
      Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.
      and approval by the FDA in 2018. Despite KEYNOTE-240, which was the confirmatory phase III study, not reaching statistical significance per specified criteria,
      • Finn R.S.
      • Ryoo B.Y.
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      • Kudo M.
      • Bouattour M.
      • Lim H.Y.
      • et al.
      Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial.
      the FDA approval remains in place after an FDA oncological drugs advisory committee review in April 2021. A second confirmatory trial conducted in 453 patients in Asia evaluating the efficacy and safety of pembrolizumab vs. placebo as second-line therapy met its primary endpoint of overall survival benefit (14.6 months for pembrolizumab vs. 13.0 months for placebo).
      • Qin S.
      • Chen Z.
      • Fang W.
      • Ren Z.
      • Xu R.
      • Ryoo B.-Y.
      • et al.
      Pembrolizumab plus best supportive care versus placebo plus best supportive care as second-line therapy in patients in Asia with advanced hepatocellular carcinoma (HCC): phase 3 KEYNOTE-394 study.
      The combination of nivolumab with ipilimumab was tested in a multicentre, open-label, multicohort, phase I/II trial (CheckMate 040). Patients with HCC were treated with 4 doses of nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks followed by 240 mg nivolumab every 2 weeks, which led to an ORR of 32% (95% CI 20%-47%) and hence to accelerated approval in the US.
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      Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial.

      Patient subgroups

      More than 80% of all patients with HCC develop their cancer in the setting of an underlying liver disease, of which the most common risk factors include HBV, HCV, alcohol consumption and non-alcoholic fatty liver disease (NAFLD). This, along with data from preclinical murine studies,
      • Ma C.
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      • Eggert T.
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      • Kleiner D.E.
      • Jin P.
      • et al.
      NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis.
      ,
      • Heinrich B.
      • Brown Z.J.
      • Diggs L.P.
      • Vormehr M.
      • Ma C.
      • Subramanyam V.
      • et al.
      Steatohepatitis impairs T-cell-directed immunotherapies against liver tumors in mice.
      was one of the reasons for comparing the effectiveness of immune checkpoint blockade in patients with different types of underlying liver disease.
      • Kelley R.K.
      • Greten T.F.
      Hepatocellular carcinoma - origins and outcomes.
      While underlying disease did not appear to matter in terms of efficacy in initial studies, Pfister and colleagues provided some preliminary data suggesting that patients with NAFLD may respond less well to immune checkpoint blockade.
      • Pfister D.
      • Nunez N.G.
      • Pinyol R.
      • Govaere O.
      • Pinter M.
      • Szydlowska M.
      • et al.
      NASH limits anti-tumour surveillance in immunotherapy-treated HCC.
      However, more recent data from other trials and more recently data from the HIMALAYA trial appeared not to support the notion that patients with NAFLD-related HCC benefit less from checkpoint blockade
      • Abou-Alfa G.K.
      • Chan S.L.
      • Kudo M.
      • Lau G.
      • Kelley R.K.
      • Furuse J.
      • et al.
      Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA.
      (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Efficacy of immunotherapy in HCC depending on underlying liver disease.
      Shown are HR for survival derived from different phase III trials. HCC, hepatocellular carcinoma; HR, hazard ratio.

      Biomarkers

      Although the introduction of immune checkpoint blockade has greatly improved treatment options and outcomes for patients with HCC, only a minority of all patients with HCC appear to benefit from this type of treatment. The identification of potential biomarkers predicting response to therapy could potentially greatly improve patient selection, however, most attempts to identify biomarkers have failed so far. Analysis of the mutational tumour burden and PD-L1 staining has been widely used in other tumours, but the results have been disappointing in HCC.
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      Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma.
      ,
      • Rizzo A.
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      Predictive biomarkers for checkpoint inhibitor-based immunotherapy in hepatocellular carcinoma: where do we stand?.
      Fig. 3 provides an overview of what type of potential biomarkers are currently being investigated, how they may be used in the future and how IR can be integrated into this type of research.
      Figure thumbnail gr3
      Fig. 3Biomarker use for IR-immunotherapy combinations.
      Biologic (tumour, blood, stool, urine), clinical and imaging biomarkers can be used to identify novel biomarkers through bioinformatic analysis. These markers can be used as prognostic markers, to determine the best treatment option (predictive biomarker) and potentially used in future biomarker driven trials designs. IHC, immunohistochemistry; IR, interventional radiology; RNA-seq, RNA sequencing; WES, whole-exome sequencing.

      Future treatments

      It is expected that anti-PD1/PD-L1 and anti-CTLA4 are only the start when it comes to immune-based treatment options for patients with HCC. One can expect that other immune checkpoint inhibitors, such as anti-LAG3 (lymphocyte activating 3), which very recently received approval for the treatment of patients with melanoma in combination with anti-PD1 based on the results from the RELATIVITY-047 trial, will be used for HCC. The study showed an increase in the median PFS from 4.6 months (95% CI 3.4 to 5.6) with nivolumab to 10.1 months (95% CI 6.4 to 15.7) with relatlimab-nivolumab (hazard ratio for progression or death 0.75; 95% CI 0.62 to 0.92; p = 0.006 by the log-rank test).
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      Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma.
      A number of other immune checkpoint inhibitors are either already under clinical investigation in HCC, such as anti-LAG3 (NCT04567615, NCT04658147), anti-TIM3 (NCT03680508), anti-4-1BB (NCT02315066), anti-OX40 (NCT02315066), anti-IL27 (NCT04374877), galunisertib (LY2157299 monohydrate) an oral transforming growth factor (TGF)-β receptor-1 inhibitor (NCT02240433),
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      A phase 2 study of galunisertib (TGF-beta1 receptor type I inhibitor) and sorafenib in patients with advanced hepatocellular carcinoma.
      anti-TGF-β (NCT02947165), bi-specific anti-LAG3/anti-CTLA-4 (NCT03849469), bi-specific anti-PD-1 and anti-LAG3 (NCT04212221), or are expected to be tested in the near future (anti-CD47, anti-TIGIT). ERY974 is a bi-specific anti-glypican-3/CD3 antibody
      • Ishiguro T.
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      that is currently being studied in combination with atezolizumab + bevazicumab (NCT02748837/NCT05022927). Morpheus-Liver (NCT04524871) is an open-label multicentre, randomised, umbrella study comparing the addition of different combinations to atezolizumab plus bevacizumab in patients with HCC. Combination partners in this trial consist of anti-TIGIT (tiragolumab), anti-IL6 (tocilizumab) and anti-TGF-β (SAR439459).

      Rationale for IR-immunotherapy

      The rationale for combination therapies, irrespective of their drug/device class and mechanisms of action, rests on the assumption that each agent (as monotherapy) of a combination provides a certain clinical benefit. Given that all therapies have a limited ability to provide benefit, and progression invariably ensues, combining them is the next rationale step. Presumably, each component becomes complementary and ultimately, provides augmented clinical benefit in terms of response, duration of response, delay in progression and prolonging overall survival.
      Unfortunately, the last decade has demonstrated that despite this rationale, results are disappointing. As prime examples, in SPACE, TACE-2, ORIENTAL, BRISK-TA and POST-TACE trials, overall survival benefit was not demonstrated when adding molecular targeted therapies to embolotherapy.
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      The only exception is in the recently published TACTICS trial, where the novel endpoint time-to-untreatable-progression was used, and the combination prolonged time-to-untreatable progression compared to TACE alone.
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      Furthermore, the addition of an anti-VEGF also did not appear to prolong survival.
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      When combining LRTs and immunotherapies, one could postulate the effect to be purely immunologic, or one where the tumour microenvironment is primed, resulting in synergy between the two modalities, or one where tumour debulking via LRT enhances the effect of immunotherapy. It has been shown that IL-6 is the primary cytokine that is elevated following embolisation, with low baseline IL-6 prior to transarterial chemoembolisation (TACE) being associated with improved survival.
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      Antigen-specific CD8+ T cells are also predictive of longer recurrence-free survival after TACE or ablation.
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      Strong CD8(+) T-cell responses against tumor-associated antigens prolong the recurrence-free interval after tumor treatment in patients with hepatocellular carcinoma.
      Embolotherapy also increases alpha-fetoprotein-specific CD4+ T-cell responses as well as circulating T helper 17 cells, both of which correlate with improved clinical responses.
      • Ayaru L.
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      Unmasking of alpha-fetoprotein-specific CD4(+) T cell responses in hepatocellular carcinoma patients undergoing embolization.
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      • et al.
      Increased circulating Th17 cells after transarterial chemoembolization correlate with improved survival in stage III hepatocellular carcinoma: a prospective study.
      This rationale, combined with the practice-changing clinical trials that demonstrated the benefit of immune checkpoint inhibition (alone) on survival in patients with advanced HCC, set the stage for more strategically designed trials capitalising on the strengths of each modality.
      • Abou-Alfa G.K.
      • Chan S.L.
      • Kudo M.
      • Lau G.
      • Kelley R.K.
      • Furuse J.
      • et al.
      Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA.
      Two retrospective investigations have been published describing no increased adverse events when combining LRT with immune checkpoint inhibition in HCC.
      • Zhan C.
      • Ruohoniemi D.
      • Shanbhogue K.P.
      • Wei J.
      • Welling T.H.
      • Gu P.
      • et al.
      Safety of combined yttrium-90 radioembolization and immune checkpoint inhibitor immunotherapy for hepatocellular carcinoma.
      ,
      • Marinelli B.
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      • et al.
      Safety and efficacy of locoregional treatment during immunotherapy with nivolumab for hepatocellular carcinoma: a retrospective study of 41 interventions in 29 patients.

      Ablation

      Currently, the routine use of ablative technology in combination with immunotherapy is not considered standard of care. Rather, their combination is scientifically rational, but still in the investigational phases. In an early report from over 15 years ago, tumour-specific T-cell activation by ablation was demonstrated in a VX2 rabbit model.
      • Wissniowski T.T.
      • Hänsler J.
      • Neureiter D.
      • Frieser M.
      • Schaber S.
      • Esslinger B.
      • et al.
      Activation of tumor-specific T lymphocytes by radio-frequency ablation of the VX2 hepatoma in rabbits.
      While there has not been an analysis comparing the magnitude of each effect, radiofrequency and microwave ablation have both been shown to induce an immune response. In fact, one study further postulated that recurrence-free survival following ablation correlated with the number of antigen-specific T cells, an observation potentially related to ablation time or degree of necrosis induced.
      • Mizukoshi E.
      • Yamashita T.
      • Arai K.
      • Sunagozaka H.
      • Ueda T.
      • Arihara F.
      • et al.
      Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma.
      Finally, it has been proposed that heat-based ablation, as opposed to cryoablation, is able to modify the T-cell balance favouring the cytotoxic over regulatory lymphocyte.
      • Takaki H.
      • Imai N.
      • Thomas C.T.
      • Yamakado K.
      • Yarmohammadi H.
      • Ziv E.
      • et al.
      Changes in peripheral blood T-cell balance after percutaneous tumor ablation.
      In one of the few prospective studies on the LRT-immunotherapy combination, tremelimumab, a human monoclonal antibody that binds CTLA-4 on the activated T lymphocyte, was used to enhance the effects of ablation or embolisation. In a pilot safety study in 32 patients, predominantly with advanced disease, the combination demonstrated no dose-limiting toxicities, with a 26% partial response rate in the 19 evaluable patients. Interestingly, a 6-week tumour biopsy confirmed increased CD8+ T cells. Median time-to-progression and overall survival were 7.4 (95% CI 4.7-19.4) and 12.3 (95% CI 9.3-15.4) months, respectively. The authors concluded that an LRT-immunotherapy combination could indeed lead to the accumulation of intratumoural CD8+ T cells.
      • Duffy A.G.
      • Ulahannan S.V.
      • Makorova-Rusher O.
      • Rahma O.
      • Wedemeyer H.
      • Pratt D.
      • et al.
      Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma.

      Embolisation

      Just as with ablation, the combination of an embolic approach with immunotherapy is in the experimental stages.
      Conventional/drug-eluting TACE: In 2002, TACE was shown to improve survival over best supportive care.
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      • Real M.I.
      • Montaña X.
      • Planas R.
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      • Aponte J.
      • et al.
      Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial.
      Since then, it has become the standard of care for BCLC B disease, with contemporary median survival reaching 25 months.
      • Llovet J.M.
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      • et al.
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      Unfortunately, most patients eventually succumb to disease progression.
      • Llovet J.M.
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      • Kulik L.
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      • Meyer T.
      • et al.
      Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma.
      Combining this embolic approach with immunotherapy represents a rational next step. Recently, the impact of the chemotherapeutic regimen on immune cell recruitment and immune checkpoint marker expression in a VX2 rabbit model was reported.
      • Berz A.M.
      • Santana J.G.
      • Iseke S.
      • Gross M.
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      • et al.
      Impact of chemo-embolic regimen on immune cell recruitment and immune checkpoint marker expression following transcatheter arterial chemoembolization in a VX2 rabbit liver tumor model.
      Drug-eluting bead TACE induced significantly more intratumoural T-cell and antigen-presenting cell infiltration than conventional TACE, and also resulted in significantly higher intratumoural immune checkpoint marker levels in the treated tumours.
      Transarterial radioembolisation: Radioembolisation involves the injection of millions of beta-emitting particles into the tumour bed, where the radiation is deposited as low dose-rate brachytherapy over 2 weeks. The therapy is effectively delivered using techniques such as radiation segmentectomy or lobectomy.
      • Vouche M.
      • Habib A.
      • Ward T.J.
      • Kim E.
      • Kulik L.
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      • et al.
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      ,
      • Vouche M.
      • Lewandowski R.J.
      • Atassi R.
      • Memon K.
      • Gates V.L.
      • Ryu R.K.
      • et al.
      Radiation lobectomy: time-dependent analysis of future liver remnant volume in unresectable liver cancer as a bridge to resection.
      In surgically resected specimens, the tumour microenvironment showed alterations in the immune cell composition following TARE, with an increased expression of tumour necrosis factor-α on CD4 and CD8 T cells.
      • Chew V.
      • Lee Y.H.
      • Pan L.
      • Nasir N.J.M.
      • Lim C.J.
      • Chua C.
      • et al.
      Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma.
      It has also been suggested that TARE might induce inflammatory cytokines, such as IL-6, resulting in reduced overall survival. In the only prospective investigation combining radioembolisation with immunotherapy, 36 patients received TARE followed by nivolumab. ORR was 31%, with adverse events including pruritus (50%) and maculopapular rash (36%). Two (6%) patients experienced grade 3–4 treatment-related adverse events (elevated alanine aminotransferase, bilirubin, aspartate aminotransferase, maculopapular rash). Five (14%) patients exhibited treatment-related serious adverse events (Steven-Johnson syndrome, hepatitis E infection, fever, liver abscesses, and ascites). The authors concluded that TARE combined with immunotherapy was a promising option despite seeing lower than expected response rates.
      • Tai D.
      • Loke K.
      • Gogna A.
      • Kaya N.A.
      • Tan S.H.
      • Hennedige T.
      • et al.
      Radioembolisation with Y90-resin microspheres followed by nivolumab for advanced hepatocellular carcinoma (CA 209-678): a single arm, single centre, phase 2 trial.
      This is consistent with a retrospective series of 22 patients treated with checkpoint inhibition, albeit in hepatic metastases from mainly uveal melanoma and sarcoma.
      • Ruohoniemi D.M.
      • Zhan C.
      • Wei J.
      • Kulkarni K.
      • Aaltonen E.T.
      • Horn J.C.
      • et al.
      Safety and effectiveness of yttrium-90 radioembolization around the time of immune checkpoint inhibitors for unresectable hepatic metastases.

      The clinical landscape of ongoing clinical trials in IR-IO

      The concept of combining LRT with immunotherapy is scientifically sound and clinically rational; hence, there is significant clinical trial activity in this field. A recent search on clinicaltrials.gov dated March 11, 2022 using search terms “hepatocellular carcinoma AND open studies” demonstrated that of 860 active clinical trials on HCC, 75 related to IR-immunotherapy. Broadly, these can be categorised as trials in the (neo)adjuvant setting, or, where the LRT is either combined with or compared to immunotherapy in the palliative setting. We highlight select trials from each category (Table S1). The most common trial type was LRT combined with immunotherapy, with 55 of the 75 trials categorised as such.

      (Neo)adjuvant setting

      1-neoadjuvant: NCT05250843 is investigating the role of TACE or hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and sintilimab as neoadjuvant therapy before liver resection (to prevent recurrence) in high-risk HCC. NCT05171335 is assessing the combination of lenvatinib with TACE in patients outside Milan criteria prior to liver transplantation, with percentage of tumour necrosis as the endpoint. NCT05042336 is exploring camrelizumab/lenvatinib combined with TACE in patients with borderline resectable HCC. In a similar design, NCT04814043 is exploring sintilimab with lenvatinib and HAIC in a borderline resectable HCC group to assess ultimate resection rates.
      2-adjuvant: NCT05162898 is a multicentre, prospective, single-arm, open-design phase II study exploring radiofrequency ablation combined with the anti-PD-1 antibody toripalimab and lenvatinib in patients with early HCC recurrence. NCT04981665 is an open-label, multicentre, phase II study evaluating tislelizumab as adjuvant therapy in HCC at high-risk of recurrence after curative resection. Recurrence-free survival is the primary endpoint (PEP) in both studies.

      Palliative setting

      1-LRT vs. immunotherapy: The ABC-HCC trial (NCT04803994) is a randomised, multicentre, open-label study designed to evaluate the safety and efficacy of atezolizumab plus bevacizumab vs. TACE in patients with intermediate-stage HCC, with the primary endpoint being time to failure of treatment strategy. RENO-TACE (NCT04777851) is a randomised, open-label trial evaluating regorafenib and nivolumab vs. TACE as first-line treatment in patients with BCLC B intermediate stage HCC beyond the up-to-seven criteria.
      2-LRT combined with immunotherapy: This was by far the most common category. Studies with samples size >100 or of special interest given their design are described herein. LEAP-012 (NCT04246177) is a 950-patient study evaluating the efficacy and safety of lenvatinib and pembrolizumab in combination with TACE vs. TACE alone in participants with incurable, non-metastatic HCC; PEPs are PFS and overall survival. Preliminary results announced in August 2022 demonstrated that the study failed to meet the dual primary endpoints. CHECKMATE 74W (NCT04340193) is a randomised 765-patient trial comparing nivolumab with and without ipilimumab in combination with TACE to TACE alone in patients with BCLC B HCC; PEPs are overall survival and time to TACE progression. EMERALD-1 (NCT03778957), with PFS as the PEP, is a randomised, double-blind, placebo-controlled, multicentre, global phase III study looking at TACE in combination with durvalumab monotherapy vs. TACE with durvalumab/bevacizumab vs. TACE alone in 724 patients with unresectable HCC not amenable to curative therapy. CHANCE-001 (NCT04975932) is a real-world study of 542 patients with HCC undergoing TACE in combination with immune checkpoint inhibitors (atezolizumab, pembrolizumab, nivolumab, camrelizumab, tislelizumab, sintilimab), with PFS as the PEP. TACE-3 (NCT04268888) evaluates the addition of nivolumab to TACE/TAE in the treatment 522 patients with BCLC B HCC; PEPs are overall survival and time to TACE progression. NCT04712643 is evaluating atezolizumab plus bevacizumab combined with on-demand TACE compared to on-demand TACE alone in 342 patients with HCC that is not amenable to curative therapy; PEPs are overall survival and time-to-untreatable-progression/death. NCT04523467 is a 320-patient study randomising TACE with the anti-angiogenic targeted drugs and ginsenoside Rg3 vs. TACE alone in patients with BCLC B/C HCC; PFS is the PEP. NCT04559607 is randomising 188 patients with BCLC B/C to TACE combined with camrelizumab and apatinib vs. TACE alone, with PFS as the PEP. NCT05233358 is a 176-patient randomised study comparing HAIC with regorafenib and immune checkpoint inhibitors vs. TACE with regorafenib and immune checkpoint inhibitors; PFS is the PEP. NCT05171166 is a 156-patient study evaluating HAIC-TACE and donafenib compared to TACE plus donafenib in patients with BCLC B stage HCC beyond the up-to-seven criteria; PFS is the PEP. ROWAN (NCT05063565) is a 150-patient randomised trial evaluating TARE with or without durvalumab with tremelimumab in patients with BCLC A/B HCC who are not eligible for or who have declined curative treatment; PEPs included ORR and duration of response. NCT03864211 is a 147-patient study randomising patients to ablation with or without toripalimab (anti-PD-1 monoclonal antibody), with PFS as the PEP. NCT04541173 is a 128-patient multicentre, randomised phase II study comparing TARE followed by bevacizumab and atezolizumab to Y90 TARE alone in unresectable intermediate-stage HCC; PFS is the PEP. NCT04663035 is a randomised, controlled, 120-patient phase II study assessing ablation followed by tislelizumab vs. ablation alone in patients with early recurrent HCC; recurrence-free survival is the PEP. NCT04150744 is a 120-patient study looking at RFA + anti-PD-1 antibody (carrizumab) compared with carrizumab alone in advanced HCC; the PEP is PFS. The DEMAND trial (NCT04246177) is a 106-patient randomised, 2-arm non-comparative phase II study of atezolizumab plus bevacizumab followed by on-demand TACE at progression or initial synchronous treatment with TACE and atezolizumab plus bevacizumab; 24-month survival rate is the PEP. NCT04947826 is a 100-patient randomised trial comparing HAIC with HLX10 (anti-PD-1 antibody) and HLX04 (VEGF antibody) to HAIC and placebo in patients with HCC and major portal vein tumour thrombosis. IMMUWIN (NCT04522544) is a randomised 84-patient trial testing durvalumab and tremelimumab with either TACE or TARE, which will use ORR to determine which combination performs better. IMMUTACE (NCT03572582) combines TACE with nivolumab in a 49-patient single-arm study assessing ORR in patients with BCLC B HCC.
      Two trials not categorised above deserve special mention. NCT04823403 is a novel 27-patient pilot trial trying to determine the maximum tolerated dose and recommended phase II dose of intra-arterial infusion of ipilimumab in combination with intravenous nivolumab. NCT03755739 is a 200-patient non-randomised trial investigating and comparing the safety, response rates and survival outcomes of patients with advanced solid tumours receiving intra-arterial or intratumoural infusions of pembrolizumab and/or ipilimumab; PEPs are overall survival and complete response rate at 6 months.

      Imaging and response assessment in immunotherapy

      The standard approach for assessing response in oncology has been RECIST 1.1, where sequential measurements of target lesions are obtained. Once a threshold for size reduction has been achieved, an ORR is declared. Conversely, if a threshold in size augmentation has been noted, progressive disease is noted. Superseding the size of target lesions is the presence of new lesions, which constitute progressive disease if observed.
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • Schwartz L.H.
      • Sargent D.
      • Ford R.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      More recently, the modified RECIST was developed to address specific normal baseline imaging features, the pattern of response such as loss of vascularity, and the pattern of progression unique to HCC.
      • Lencioni R.
      • Llovet J.M.
      Modified RECIST (mRECIST) assessment for hepatocellular carcinoma.
      Embedded in response assessment are other variables believed to be measures of clinical benefit, such as time-to-progression and PFS.
      There are two novel imaging concepts that have emerged as a result of immunotherapy. The first is the duration of response, where, in an unpredictable subset of patients, the response is robust and maintained for a long period of time. This observation was first reported in a melanoma study.
      • Hodi F.S.
      • O'Day S.J.
      • McDermott D.F.
      • Weber R.W.
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      • Haanen J.B.
      • et al.
      Improved survival with ipilimumab in patients with metastatic melanoma.
      Since then, duration of response has become one of the most highlighted benefits of immunotherapy. The second interesting observation relates to progression. In some cases, a pseudoprogression pattern may be observed, where lesions enlarge after treatment, which would be declared progression under standard imaging criteria, before subsequently regressing. As such, specific for IO, immune-related response criteria (irRC) and the immune-modified RECIST have been developed.
      • Chiou V.L.
      • Burotto M.
      Pseudoprogression and immune-related response in solid tumors.
      ,
      • Wolchok J.D.
      • Hoos A.
      • O'Day S.
      • Weber J.S.
      • Hamid O.
      • Lebbe C.
      • et al.
      Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.
      Molecular imaging represents the next generation methodology for assessing response in IO. Molecular imaging modalities include optical imaging, MRI, ultrasound, PET, SPECT (single-photon emission CT) and CT.
      • Willmann J.K.
      • van Bruggen N.
      • Dinkelborg L.M.
      • Gambhir S.S.
      Molecular imaging in drug development.
      Abnormal cells with pathological phenotypes, representing the “molecular expression”, may be used for diagnosis, identification of optimal target drugs, therapy planning, and assessing response. This approach can also provide real-time information about target/receptor expression levels. This would allow clinicians to predict which patients may benefit from immunotherapy and account for differing responses in individual patients.
      Ultimately, it appears response assessment after immunotherapy will require further investigation and refining. The specificity of techniques such as irRC may provide valuable insights into the change of tumour size, morphology and behaviour in a time-dependent manner, and may help investigators capture the true anti-tumoural effect of immunotherapy. The development of imaging response criteria tailored specifically to certain treatments, while superficially beneficial, may inadvertently increase the complexity of tumour outcome assessment when LRTs and immunotherapies are combined. Studies combining agents that require irRC with others requiring mRECIST add a complexity that will require further investigation.

      The future of IR-IO

      While we have discussed the immediate future of IR-IO, we believe that the future is probably even more exciting. Fig. 4 provides points to consider during the planning of new trials. Ongoing and future clinical trials will test novel clinical endpoints such as “time-to-treatment failure”, the concept of “on-demand TACE” will require further considerations in clinical trials. It will be important to identify the best patient population and combination for a combined IR-IO approach in HCC. It is a well-known fact that LRTs can cause various immune effects.
      • Greten T.F.
      • Duffy A.G.
      • Korangy F.
      Hepatocellular carcinoma from an immunologic perspective.
      Currently only very few studies attempt to study the concept of locoregional delivery of immunotherapy. However, such treatment approaches may not only cause significant synergy, leading to much better efficacy than systemic treatment, but may also be associated with less adverse events especially in the context of cirrhosis. Adoptive cell therapy approaches are still in their infancy in HCC. The ability to deliver cytotoxic cells directly into the tumour environment certainly provides a great advantage over systemic delivery. Given the fact that adoptive cell transfer does not require multiple applications, it appears to be a very promising approach once we can overcome potential technical obstacles associated with a high-pressure delivery into the arterial system. Also of interest is the role of LRTs in the advanced setting, with recent randomised level I data demonstrating survival improvement when added to systemic therapy.
      • Peng Z.
      • Fan W.
      • Zhu B.
      • Li J.
      • Kuang M.
      Lenvatinib combined with transarterial chemoembolization as first-line treatment of advanced hepatocellular carcinoma: a phase 3, multicenter, randomized controlled trial.
      Finally, there is one important consideration to keep in mind with any of these new developments, which will ultimately improve patient’s outcome: they will only happen if we improve our basic understanding of how LRTs may affect tumour-specific immune responses; this will require interventional radiologists and physicians (hepatologists, oncologists, surgeons, pathologists, translational scientists) to continue collaboration in order to advance the field.
      Figure thumbnail gr4
      Fig. 4Future TACE + immunotherapy combination trials will need to take specific inclusion criteria, treatment options and endpoints into consideration.
      TACE, transarterial chemoembolisation; TARE, transarterial radioembolisation;

      Abbreviations

      CTLA4, cytotoxic T-lymphocyte associated protein 4; FDA, Food and Drug Administration; HAIC, hepatic arterial infusion chemotherapy; HCC, hepatocellular carcinoma; HR, hazard ratio; IO, immune-oncology; IR, interventional radiology; irRC, immune-related response criteria; LAG3, lymphocyte activating 3; LRT, locoregional therapy; NAFLD, non-alcoholic fatty liver disease; ORR, objective response rate; PD1, programmed cell death 1; PD-L1, programmed cell death ligand 1; PEP, primary endpoint; PFS, progression-free survival; TACE, transarterial chemoembolisation; TGF, transforming growth factor.

      Financial support

      T.F.G is supported by the NIH intramural program (ZIA BC 011343 and ZIA BC 011870). No other funding was provided for this manuscript.

      Authors’ contributions

      Riad Salem and Tim Greten contributed equally in the form of conception the work, acquisition, analysis, and interpretation of researched data, drafting and critically revising the manuscript for important intellectual content, and final approval of the version to be published.

      Conflict of interest

      Riad Salem is a consultant for Boston Scientific, Cook, Eisai, Astrazeneca, Genentech, Autem, Sirtex, Siemens and Bard. Tim Greten is funded by NIH intramural program ZIA BC 011343and ZIA BC 011870.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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