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      Advances in immunotherapy for hepatocellular carcinoma


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          Hepatocellular carcinoma (HCC) is a prevalent disease with a progression that is modulated by the immune system. Systemic therapy is used in the advanced stage and until 2017 consisted only of antiangiogenic tyrosine kinase inhibitors (TKIs). Immunotherapy with checkpoint inhibitors has shown strong anti-tumour activity in a subset of patients and the combination of the anti-PDL1 antibody atezolizumab and the VEGF-neutralizing antibody bevacizumab has or will soon become the standard of care as a first-line therapy for HCC, whereas the anti-PD1 agents nivolumab and pembrolizumab are used after TKIs in several regions. Other immune strategies such as adoptive T-cell transfer, vaccination or virotherapy have not yet demonstrated consistent clinical activity. Major unmet challenges in HCC checkpoint immunotherapy are the discovery and validation of predictive biomarkers, advancing treatment to earlier stages of the disease, applying the treatment to patients with liver dysfunction and the discovery of more effective combinatorial or sequential approaches. Combinations with other systemic or local treatments are perceived as the most promising opportunities in HCC and some are already under evaluation in large-scale clinical trials. This Review provides up-to-date information on the best use of currently available immunotherapies in HCC and the therapeutic strategies under development.


          Immunotherapeutic interventions might be effective tools for the treatment of hepatocellular carcinoma. This Review provides up-to-date information on the clinical use of currently available immunotherapies in hepatocellular carcinoma, the mechanisms of response and resistance, and the therapeutic strategies under development.

          Key points

          • Multiple immune mechanisms are important in the development and progression of hepatocellular carcinoma (HCC) and correlate with prognosis.

          • Checkpoint inhibitors targeting PD1 and PDL1 and CTLA4 are active, tolerable and clinically beneficial against advanced HCC.

          • At present, the best available first-line treatment for advanced HCC is a combination of PDL1 blockade with atezolizumab and VEGF blockade with bevacizumab.

          • There is as yet an almost complete lack of suitable biomarkers to guide the development of checkpoint inhibitors and their combinations in HCC.

          • Immunotherapy is likely to synergize with local and locoregional interventions in earlier stages of HCC.

          • Other promising forms of immunotherapy for HCC such as additional checkpoint inhibitors, adoptive cell transfer, vaccination and virotherapy are being actively pursued.

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          Most cited references210

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          EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma

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            Signatures of mutational processes in human cancer

            All cancers are caused by somatic mutations. However, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here, we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, kataegis, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer with potential implications for understanding of cancer etiology, prevention and therapy.
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              Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma

              The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma.

                Author and article information

                Nat Rev Gastroenterol Hepatol
                Nat Rev Gastroenterol Hepatol
                Nature Reviews. Gastroenterology & Hepatology
                Nature Publishing Group UK (London )
                13 April 2021
                : 1-19
                [1 ]GRID grid.411730.0, ISNI 0000 0001 2191 685X, Liver Unit and HPB Oncology Area, , Clinica Universidad de Navarra-IDISNA and CIBEREHD, ; Pamplona, Spain
                [2 ]GRID grid.5924.a, ISNI 0000000419370271, Program of Immunology and Immunotherapy, , CIMA de la Universidad de Navarra, IDISNA and CIBEREHD, ; Pamplona, Spain
                [3 ]GRID grid.411730.0, ISNI 0000 0001 2191 685X, Department of Immunology and Immunotherapy, , Clinica Universidad de Navarra-IDISNA and CIBERONC, ; Pamplona, Spain
                Author information
                © Springer Nature Limited 2021

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                : 5 March 2021
                Review Article

                cancer therapy,liver cancer
                cancer therapy, liver cancer


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