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  • Review Article
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Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma

Nature Reviews Clinical Oncology volume 21, pages 294–311 (2024)Cite this article

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Abstract

Liver cancer, specifically hepatocellular carcinoma (HCC), is the sixth most common cancer and the third leading cause of cancer mortality worldwide. The development of effective systemic therapies, particularly those involving immune-checkpoint inhibitors (ICIs), has substantially improved the outcomes of patients with advanced-stage HCC. Approximately 30% of patients are diagnosed with early stage disease and currently receive potentially curative therapies, such as resection, liver transplantation or local ablation, which result in median overall survival durations beyond 60 months. Nonetheless, up to 70% of these patients will have disease recurrence within 5 years of resection or local ablation. To date, the results of randomized clinical trials testing adjuvant therapy in patients with HCC have been negative. This major unmet need has been addressed with the IMbrave 050 trial, demonstrating a recurrence-free survival benefit in patients with a high risk of relapse after resection or local ablation who received adjuvant atezolizumab plus bevacizumab. In parallel, studies testing neoadjuvant ICIs alone or in combination in patients with early stage disease have also reported efficacy. In this Review, we provide a comprehensive overview of the current approaches to manage patients with early stage HCC. We also describe the tumour immune microenvironment and the mechanisms of action of ICIs and cancer vaccines in this setting. Finally, we summarize the available evidence from phase II/III trials of neoadjuvant and adjuvant approaches and discuss emerging clinical trials, identification of biomarkers and clinical trial design considerations for future studies.

Key points

  • Approximately 30% of patients with hepatocellular carcinoma (HCC) undergo resection or local ablation as primary treatment. However, the probability of recurrence at 3 years is 30–50% and is associated with the size of the main tumour, microvascular invasion and poor differentiation degree.

  • In the phase III IMbrave 050 trial, patients with HCC at high risk of recurrence after resection or local ablation who received adjuvant atezolizumab plus bevacizumab had significantly improved recurrence-free survival compared with those who had active surveillance.

  • Neoadjuvant exposure to immunotherapies enables more-efficient interactions among T cells, antigen-presenting cells and cancer cells owing to a larger tumour burden compared with the adjuvant approach.

  • Neoadjuvant and adjuvant administration of immunotherapies results in significantly improved outcomes compared with adjuvant administration alone in patients with melanoma or non-small-cell lung cancer.

  • Phase II trials of cancer vaccines in combination with immune-checkpoint inhibitors in patients with melanoma or pancreatic adenocarcinoma have shown signals of efficacy; these approaches are currently being explored in HCC.

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Fig. 1: Immune cells in the hepatocellular carcinoma tumour microenvironment.
Fig. 2: Role of the hepatocellular carcinoma immune microenvironment in response to treatment.
Fig. 3: Mechanism of action of immunotherapies and vaccines in the neoadjuvant and adjuvant setting in hepatocellular carcinoma.
Fig. 4: Overview of updated management of hepatocellular carcinoma and proposed treatment approach after disease recurrence following adjuvant therapies.

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References

  1. Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 7, 7 (2021).

    Article  Google Scholar 

  2. Llovet, J. M. et al. Molecular pathogenesis and systemic therapies for hepatocellular carcinoma. Nat. Cancer 3, 386–401 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).

    Article  CAS  PubMed  Google Scholar 

  5. Llovet, J. M. et al. Immunotherapies for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 19, 151–172 (2022).

    Article  CAS  PubMed  Google Scholar 

  6. Cappuyns, S., Virginia, C., Yarchoan, M., Finn, R. S. & Llovet, J. M. Critical appraisal of guideline recommendations on systemic therapies for advanced hepatocellular carcinoma. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2023.2677 (2023).

  7. Singal, A. G. et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 78, 1922–1965 (2023).

    Article  PubMed  Google Scholar 

  8. Schmid, P. et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N. Engl. J. Med. 386, 556–567 (2022).

    Article  CAS  PubMed  Google Scholar 

  9. Patel, S. P. et al. Neoadjuvant–adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N. Engl. J. Med. 388, 813–823 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Spaander, M. C. W. et al. Young-onset colorectal cancer. Nat. Rev. Dis. Prim. 9, 22 (2023).

  11. Haber, P. K. et al. Evidence-based management of hepatocellular carcinoma: systematic review and meta-analysis of randomized controlled trials (2002–2020). Gastroenterology 161, 879–898 (2021).

    Article  CAS  PubMed  Google Scholar 

  12. Qin, S. et al. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave 050): a randomised, open-label, multicentre, phase 3 trial. Lancet 402, 1835–1847 (2023).

    Article  CAS  PubMed  Google Scholar 

  13. Marron, T. U. et al. Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7, 219–229 (2022).

    Google Scholar 

  14. Ho, W. J. et al. Neoadjuvant cabozantinib and nivolumab converts locally advanced HCC into resectable disease with enhanced antitumor immunity. Nat. Cancer 2, 891–903 (2021).

    CAS  Google Scholar 

  15. Kaseb, A. O. et al. Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7, 208–218 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  16. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Melanoma: Cutaneous V.2.2023 (2023).

  17. Cercek, A. et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N. Engl. J. Med. 386, 2363–2376 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chalabi, M. et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat. Med. 26, 566–576 (2020).

    Article  CAS  PubMed  Google Scholar 

  19. Yang, X. et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N. Engl. J. Med. 379, e14 (2018).

    Article  PubMed  Google Scholar 

  20. Forde, P. M. et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N. Engl. J. Med. 386, 1973–1985 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Akinboro, O. et al. US Food and Drug Administration approval summary: nivolumab plus platinum-doublet chemotherapy for the neoadjuvant treatment of patients with resectable non-small-cell lung cancer. J. Clin. Oncol. 41, 3249–3259 (2023).

    Article  CAS  PubMed  Google Scholar 

  22. Galle, P. R. et al. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J. Hepatol. 69, 182–236 (2018).

    Article  Google Scholar 

  23. Kudo, M. et al. Management of hepatocellular carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update. Liver Cancer 10, 181–223 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Xie, D., Shi, J., Zhou, J., Fan, J. & Gao, Q. Clinical practice guidelines and real-life practice in hepatocellular carcinoma: a Chinese perspective. Clin. Mol. Hepatol. 29, 206–216 (2023).

    Article  PubMed  Google Scholar 

  25. Goh, M. J. et al. Clinical practice guideline and real-life practice in hepatocellular carcinoma: a Korean perspective. Clin. Mol. Hepatol. 29, 197–205 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Roayaie, S. et al. The role of hepatic resection in the treatment of hepatocellular cancer. Hepatology 62, 440–451 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. Llovet, J. M., Schwartz, M. & Mazzaferro, V. Resection and liver transplantation for hepatocellular carcinoma. Semin. Liver Dis. 25, 181–200 (2005).

    Article  PubMed  Google Scholar 

  28. Reveron-Thornton, R. F. et al. Global and regional long-term survival following resection for HCC in the recent decade: a meta-analysis of 110 studies. Hepatol. Commun. 6, 1813–1826 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Rumgay, H. et al. Global, regional and national burden of primary liver cancer by subtype. Eur. J. Cancer 161, 108–118 (2022).

    Article  PubMed  Google Scholar 

  30. Wolf, E., Rich, N. E., Marrero, J. A., Parikh, N. D. & Singal, A. G. Use of hepatocellular carcinoma surveillance in patients with cirrhosis: a systematic review and meta-analysis. Hepatology 73, 713–725 (2021).

    Article  PubMed  Google Scholar 

  31. Omata, M. et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol. Int. 11, 317–370 (2017).

    Article  PubMed  Google Scholar 

  32. Tsoulfas, G. Surgical Challenges in the Management of Liver Disease. https://doi.org/10.5772/intechopen.76553 (IntechOpen, 2019).

  33. Franssen, B. et al. Differences in surgical outcomes between hepatitis B- and hepatitis C-related hepatocellular carcinoma: a retrospective analysis of a single North American center. Ann. Surg. 260, 650–658 (2014).

    Article  PubMed  Google Scholar 

  34. Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 2, 16018 (2016).

    Article  PubMed  Google Scholar 

  35. Llovet, J. M. et al. Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment. Nat. Rev. Gastroenterol. Hepatol. 20, 487–503 (2023).

    Article  CAS  PubMed  Google Scholar 

  36. Kudo, M. Surveillance, diagnosis, and treatment outcome of hepatocellular carcinoma in Japan: 2023 update. Liver Cancer 12, 95–102 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Shan, T. et al. Disparities in stage at diagnosis for liver cancer in China. J. Natl Cancer Cent. 3, 7–13 (2023).

    Article  Google Scholar 

  38. Ishizawa, T. et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 134, 1908–1916 (2008).

    Article  PubMed  Google Scholar 

  39. Di Benedetto, F. et al. Safety and efficacy of robotic vs open liver resection for hepatocellular carcinoma. JAMA Surg. 158, 46–54 (2023).

    Article  PubMed  Google Scholar 

  40. Llovet, J. M. et al. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 18, 293–313 (2021).

    Article  CAS  PubMed  Google Scholar 

  41. Lin, S.-M., Lin, C.-J., Lin, C.-C., Hsu, C.-W. & Chen, Y.-C. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less. Gut 54, 1151–1156 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Doyle, A. et al. Outcomes of radiofrequency ablation as first-line therapy for hepatocellular carcinoma less than 3 cm in potentially transplantable patients. J. Hepatol. 70, 866–873 (2019).

    Article  PubMed  Google Scholar 

  43. Shiina, S. et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am. J. Gastroenterol. 107, 569–577 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Charalel, R. A. et al. Long-term survival after surgery versus ablation for early liver cancer in a large, nationally representative cohort. J. Am. Coll. Radiol. 19, 1213–1223 (2022).

    Article  PubMed  Google Scholar 

  45. Pompili, M. et al. Long-term effectiveness of resection and radiofrequency ablation for single hepatocellular carcinoma ≤ 3 cm. Results of a multicenter Italian survey. J. Hepatol. 59, 89–97 (2013).

    Article  PubMed  Google Scholar 

  46. Kudo, M. et al. Report of the 22nd nationwide follow-up Survey of Primary Liver Cancer in Japan (2012–2013). Hepatol. Res. 52, 5–66 (2022).

    Article  PubMed  Google Scholar 

  47. Yoon, J. S. et al. Hepatocellular carcinoma in Korea between 2008 and 2011: an analysis of Korean Nationwide Cancer Registry. J. Liver Cancer 20, 41–52 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Meloni, M. F. et al. Use of contrast‐enhanced ultrasound in ablation therapy of HCC. J. Ultrasound Med. 40, 879–894 (2021).

    Article  PubMed  Google Scholar 

  49. Jie, T., Guoying, F., Gang, T., Zhengrong, S. & Maoping, L. Efficacy and safety of fusion imaging in radiofrequency ablation of hepatocellular carcinoma compared to ultrasound: a meta-analysis. Front. Surg. 8, 728098 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Feng, Q., Chi, Y., Liu, Y., Zhang, L. & Liu, Q. Efficacy and safety of percutaneous radiofrequency ablation versus surgical resection for small hepatocellular carcinoma: a meta-analysis of 23 studies. J. Cancer Res. Clin. Oncol. 141, 1–9 (2015).

    Article  PubMed  Google Scholar 

  51. Takayama, T. et al. Surgery versus radiofrequency ablation for small hepatocellular carcinoma: a randomized controlled trial (SURF Trial). Liver Cancer 11, 209–218 (2022).

    Article  CAS  PubMed  Google Scholar 

  52. Sheta, E. et al. Comparison of single-session transarterial chemoembolization combined with microwave ablation or radiofrequency ablation in the treatment of hepatocellular carcinoma: a randomized-controlled study. Eur. J. Gastroenterol. Hepatol. 28, 1198–1203 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Peng, Z.-W. et al. Radiofrequency ablation with or without transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma: a prospective randomized trial. J. Clin. Oncol. 31, 426–432 (2013).

    Article  PubMed  Google Scholar 

  54. Tabrizian, P., Jibara, G., Shrager, B., Schwartz, M. & Roayaie, S. Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis. Ann. Surg. 261, 947–955 (2015).

    Article  PubMed  Google Scholar 

  55. Vibert, E., Schwartz, M. & Olthoff, K. M. Advances in resection and transplantation for hepatocellular carcinoma. J. Hepatol. 72, 262–276 (2020).

    Article  CAS  PubMed  Google Scholar 

  56. Chen, R. et al. Recurrence after percutaneous radiofrequency ablation of hepatocellular carcinoma: analysis of the pattern and risk factors. Front. Oncol. 13, 1–11 (2023).

    CAS  Google Scholar 

  57. Zhu, Y. et al. Factors influencing early recurrence of hepatocellular carcinoma after curative resection. J. Int. Med. Res. 48, 0300060520945552 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Xu, X.-F. et al. Risk factors, patterns, and outcomes of late recurrence after liver resection for hepatocellular carcinoma: a multicenter study from China. JAMA Surg. 154, 209–217 (2019).

    Article  PubMed  Google Scholar 

  59. Ringelhan, M., Pfister, D., O’Connor, T., Pikarsky, E. & Heikenwalder, M. The immunology of hepatocellular carcinoma. Nat. Immunol. 19, 222–232 (2018).

    Article  CAS  PubMed  Google Scholar 

  60. Zheng, C. et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 169, 1342–1356.e16 (2017).

    Article  CAS  PubMed  Google Scholar 

  61. Zhang, Q. et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell 179, 829–845.e20 (2019).

    Article  CAS  PubMed  Google Scholar 

  62. Geh, D. et al. Neutrophils as potential therapeutic targets in hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 19, 257–273 (2022).

    Article  CAS  PubMed  Google Scholar 

  63. Hoechst, B. et al. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 135, 234–243 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Han, Y. et al. Human CD14+ CTLA-4+ regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2,3-dioxygenase production in hepatocellular carcinoma. Hepatology 59, 567–579 (2014).

    Article  CAS  PubMed  Google Scholar 

  65. Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ramadori, P., Kam, S. & Heikenwalder, M. T cells: friends and foes in NASH pathogenesis and hepatocarcinogenesis. Hepatology 75, 1038–1049 (2022).

    Article  CAS  PubMed  Google Scholar 

  67. Jardim, D. L., Goodman, A., de Melo Gagliato, D. & Kurzrock, R. The challenges of tumor mutational burden as an immunotherapy biomarker. Cancer Cell 39, 154–173 (2021).

    Article  CAS  PubMed  Google Scholar 

  68. Samstein, R. M. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51, 202–206 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhu, A. X. et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat. Med. 28, 1599–1611 (2022).

    Article  CAS  PubMed  Google Scholar 

  70. Bassaganyas, L. et al. Copy-number alteration burden differentially impacts immune profiles and molecular features of hepatocellular carcinoma. Clin. Cancer Res. 26, 6350–6361 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sia, D. et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology 153, 812–826 (2017).

    Article  CAS  PubMed  Google Scholar 

  72. Haber, P. K. et al. Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma. Gastroenterology 164, 72–88.e18 (2023).

    Article  CAS  PubMed  Google Scholar 

  73. Ruiz de Galarreta, M. et al. β-Catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 9, 1124–1141 (2019).

    Article  CAS  PubMed  Google Scholar 

  74. Moeini, A. et al. An immune gene expression signature associated with development of human hepatocellular carcinoma identifies mice that respond to chemopreventive agents. Gastroenterology 157, 1383–1397.e11 (2019).

    Article  CAS  PubMed  Google Scholar 

  75. Xu, Y. et al. Translation control of the immune checkpoint in cancer and its therapeutic targeting. Nat. Med. 25, 301–311 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Li, J. et al. Epigenetic driver mutations in ARID1A shape cancer immune phenotype and immunotherapy. J. Clin. Invest. 130, 2712–2726 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Shen, J. et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat. Med. 24, 556–562 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Montironi, C. et al. Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification. Gut 72, 129–140 (2023).

    Article  CAS  PubMed  Google Scholar 

  79. Fehrenbacher, L. et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387, 1837–1846 (2016).

    Article  CAS  PubMed  Google Scholar 

  80. Sangro, B. et al. Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. J. Hepatol. 73, 1460–1469 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Ayers, M. et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest. 127, 1–11 (2017).

    Article  Google Scholar 

  82. Magen, A. et al. Intratumoral dendritic cell–CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma. Nat. Med. 29, 1389–1399 (2023).

    Article  CAS  PubMed  Google Scholar 

  83. Pinyol, R., Sia, D. & Llovet, J. M. Immune exclusion-Wnt/CTNNB1 class predicts resistance to immunotherapies in HCC. Clin. Cancer Res. 25, 2021–2023 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Llovet, J. M. & Bruix, J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 37, 429–442 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Okita, K. et al. Peretinoin after curative therapy of hepatitis C-related hepatocellular carcinoma: a randomized double-blind placebo-controlled study. J. Gastroenterol. 50, 191–202 (2015).

    Article  CAS  PubMed  Google Scholar 

  86. Yoshida, H. et al. Effect of vitamin K2 on the recurrence of hepatocellular carcinoma. Hepatology 54, 532–540 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Mazzaferro, V. et al. Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis. Hepatology 44, 1543–1554 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Chen, L.-T. et al. Long-term results of a randomized, observation-controlled, phase III trial of adjuvant interferon Alfa-2b in hepatocellular carcinoma after curative resection. Ann. Surg. 255, 8–17 (2012).

    Article  PubMed  Google Scholar 

  89. Raoul, J. et al. Prospective randomized trial of chemoembolization versus intra-arterial injection of 131I-labeled-iodized oil in the treatment of hepatocellular carcinoma. Hepatology 26, 1156–1161 (1997).

    CAS  PubMed  Google Scholar 

  90. Bruix, J. et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 16, 1344–1354 (2015).

    Article  CAS  PubMed  Google Scholar 

  91. Geissler, E. K. et al. Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label phase 3 trial. Transplantation 100, 116–125 (2016).

    Article  CAS  PubMed  Google Scholar 

  92. Li, S.-H. et al. Postoperative adjuvant hepatic arterial infusion chemotherapy with FOLFOX in hepatocellular carcinoma with microvascular invasion: a multicenter, phase III randomized study. J. Clin. Oncol. 41, 1898–1908 (2023).

    Article  CAS  PubMed  Google Scholar 

  93. Wang, Z. et al. Adjuvant transarterial chemoembolization for HBV-related hepatocellular carcinoma after resection: a randomized controlled study. Clin. Cancer Res. 24, 2074–2081 (2018).

    Article  CAS  PubMed  Google Scholar 

  94. Lee, J. H. et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 148, 1383–1391.e6 (2015).

    Article  CAS  PubMed  Google Scholar 

  95. Wu, C.-Y. et al. Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection. JAMA 308, 1906 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. Reig, M. et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J. Hepatol. 65, 719–726 (2016).

    Article  CAS  PubMed  Google Scholar 

  97. Singal, A. G. et al. Direct-acting antiviral therapy for hepatitis C virus infection is associated with increased survival in patients with a history of hepatocellular carcinoma. Gastroenterology 157, 1253–1263.e2 (2019).

    Article  CAS  PubMed  Google Scholar 

  98. Yin, J. et al. Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J. Clin. Oncol. 31, 3647–3655 (2013).

    Article  CAS  PubMed  Google Scholar 

  99. Jørgensen, J. T. The current landscape of the FDA approved companion diagnostics. Transl. Oncol. 14, 101063 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Litchfield, K. et al. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell 184, 596–614.e14 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Pfister, D. et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 592, 450–456 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Llovet, J. M. Exploring a new pathway for biomarker-based approval of immunotherapies. Nat. Rev. Clin. Oncol. 20, 279–280 (2023).

    Article  PubMed  Google Scholar 

  103. Topalian, S. L. et al. Neoadjuvant immune checkpoint blockade: a window of opportunity to advance cancer immunotherapy. Cancer Cell 41, 1551–1566 (2023).

    Article  CAS  PubMed  Google Scholar 

  104. Garg, M. et al. Tumour gene expression signature in primary melanoma predicts long-term outcomes. Nat. Commun. 12, 1137 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lucas, M. W., Versluis, J. M., Rozeman, E. A. & Blank, C. U. Personalizing neoadjuvant immune-checkpoint inhibition in patients with melanoma. Nat. Rev. Clin. Oncol. 20, 408–422 (2023).

    Article  PubMed  Google Scholar 

  106. Liu, J. et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov. 6, 1382–1399 (2016).

    Article  CAS  PubMed  Google Scholar 

  107. Oba, T., Kajihara, R., Yokoi, T., Repasky, E. A. & Ito, F. Neoadjuvant in situ immunomodulation enhances systemic antitumor immunity against highly metastatic tumors. Cancer Res. 81, 6183–6195 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hughes, E. et al. Primary breast tumours but not lung metastases induce protective anti-tumour immune responses after Treg-depletion. Cancer Immunol. Immunother. 69, 2063–2073 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Pai, C.-C. S. et al. Clonal deletion of tumor-specific T cells by interferon-γ confers therapeutic resistance to combination immune checkpoint blockade. Immunity 50, 477–492.e8 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Friedman, J. et al. Neoadjuvant PD-1 immune checkpoint blockade reverses functional immunodominance among tumor antigen-specific T cells. Clin. Cancer Res. 26, 679–689 (2020).

    Article  CAS  PubMed  Google Scholar 

  111. Cottrell, T. R. et al. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). Ann. Oncol. 29, 1853–1860 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Rozeman, E. A. et al. LBA75 — 18-months relapse-free survival (RFS) and biomarker analyses of OpACIN-neo: a study to identify the optimal dosing schedule of neoadjuvant (neoadj) ipilimumab (IPI) + nivolumab (NIVO) in stage III melanoma. Ann. Oncol. 30, v910 (2019).

    Article  Google Scholar 

  113. Amaria, R. N. et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat. Med. 24, 1649–1654 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Tetzlaff, M. T. et al. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma. Ann. Oncol. 29, 1861–1868 (2018).

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  115. Rozeman, E. A. et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 20, 948–960 (2019).

    Article  CAS  PubMed  Google Scholar 

  116. von Minckwitz, G. et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J. Clin. Oncol. 30, 1796–1804 (2012).

    Article  Google Scholar 

  117. Springfeld, C. et al. Neoadjuvant therapy for pancreatic cancer. Nat. Rev. Clin. Oncol. 20, 318–337 (2023).

    Article  PubMed  Google Scholar 

  118. Allard, M.-A. et al. Does pathological response after transarterial chemoembolization for hepatocellular carcinoma in cirrhotic patients with cirrhosis predict outcome after liver resection or transplantation? J. Hepatol. 63, 83–92 (2015).

    Article  PubMed  Google Scholar 

  119. Llovet, J. M. et al. Trial design and endpoints in hepatocellular carcinoma: AASLD consensus conference. Hepatology 73, 158–191 (2021).

    Article  PubMed  Google Scholar 

  120. Wakelee, H. et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N. Engl. J. Med. 389, 491–503 (2023).

    Article  CAS  PubMed  Google Scholar 

  121. Topalian, S. L. et al. Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab. JAMA Oncol. 5, 1411–1420 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Huang, A. C. et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545, 60–65 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Robert, C. et al. Durable complete response after discontinuation of pembrolizumab in patients with metastatic melanoma. J. Clin. Oncol. J. Am. Soc. Clin. Oncol. 36, 1668–1674 (2018).

    Article  CAS  Google Scholar 

  124. Spicer, J. et al. Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). J. Clin. Oncol. 39, 8503 (2021).

    Article  Google Scholar 

  125. Lissoni, P. et al. Effects of the conventional antitumor therapies surgery, chemotherapy, radiotherapy and immunotherapy on regulatory T lymphocytes in cancer patients. Anticancer Res. 29, 1847–1852 (2009).

    CAS  PubMed  Google Scholar 

  126. Tang, F., Tie, Y., Tu, C. & Wei, X. Surgical trauma-induced immunosuppression in cancer: recent advances and the potential therapies. Clin. Transl. Med. 10, 199–223 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Bakos, O., Lawson, C., Rouleau, S. & Tai, L.-H. Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity. J. Immunother. Cancer 6, 86 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Marron, T. U. et al. Neoadjuvant clinical trials provide a window of opportunity for cancer drug discovery. Nat. Med. 28, 626–629 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Marron, T. U. et al. Considerations for treatment duration in responders to immune checkpoint inhibitors. J. Immunother. Cancer 9, e001901 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Schiller, J. T. & Lowy, D. R. Vaccines to prevent infections by oncoviruses. Annu. Rev. Microbiol. 64, 23–41 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Yarchoan, M., Johnson, B. A., Lutz, E. R., Laheru, D. A. & Jaffee, E. M. Targeting neoantigens to augment antitumour immunity. Nat. Rev. Cancer 17, 209–222 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Blass, E. & Ott, P. A. Advances in the development of personalized neoantigen-based therapeutic cancer vaccines. Nat. Rev. Clin. Oncol. 18, 215–229 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Dolgin, E. The tangled history of mRNA vaccines. Nature 597, 318–324 (2021).

    Article  CAS  PubMed  Google Scholar 

  135. Szebeni, J. et al. Applying lessons learned from nanomedicines to understand rare hypersensitivity reactions to mRNA-based SARS-CoV-2 vaccines. Nat. Nanotechnol. 17, 337–346 (2022).

    Article  CAS  PubMed  Google Scholar 

  136. Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Precision medicine meets cancer vaccines. Nat. Med. 29, 1287 (2023).

  138. Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. mRNA vaccine slows melanoma recurrence. Cancer Discov. 13, 1278 (2023).

  140. Weber et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet 403, 632–644 (2024).

    Article  CAS  PubMed  Google Scholar 

  141. Yarchoan, M. et al. Personalized DNA neoantigen vaccine in combination with plasmid IL-12 and pembrolizumab for the treatment of patients with advanced hepatocellular carcinoma. J. Clin. Oncol. 39, TPS2680 (2021).

    Article  Google Scholar 

  142. Liu, C. et al. mRNA-based cancer therapeutics. Nat. Rev. Cancer 23, 526–543 (2023).

    Article  PubMed  Google Scholar 

  143. Llovet, J. M., Brú, C. & Bruix, J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin. Liver Dis. 19, 329–338 (1999).

    Article  CAS  PubMed  Google Scholar 

  144. de Haas, R. J. et al. Curative salvage liver transplantation in patients with cirrhosis and hepatocellular carcinoma: an intention-to-treat analysis. Hepatology 67, 204–215 (2018).

    Article  PubMed  Google Scholar 

  145. Mehta, N. et al. Downstaging outcomes for hepatocellular carcinoma: results from the multicenter evaluation of reduction in tumor size before liver transplantation (MERITS-LT) consortium. Gastroenterology 161, 1502–1512 (2021).

    Article  CAS  PubMed  Google Scholar 

  146. Mazzaferro, V. et al. Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial. Lancet Oncol. 21, 947–956 (2020).

    Article  CAS  PubMed  Google Scholar 

  147. Kudo, M. et al. Lenvatinib as an initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria and Child–Pugh a liver function: a proof-of-concept study. Cancers 11, 1084 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Abou-Alfa, G. K. 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. J. Clin. Oncol. 40, 379 (2022).

    Article  Google Scholar 

  149. Kudo, M. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 391, 1163–1173 (2018).

    Article  CAS  PubMed  Google Scholar 

  150. Wong, J. S. L. et al. Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors. J. Immunother. Cancer 9, e001945 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  151. von Felden, J., Garcia-Lezana, T., Schulze, K., Losic, B. & Villanueva, A. Liquid biopsy in the clinical management of hepatocellular carcinoma. Gut 69, 2025–2034 (2020).

    Article  Google Scholar 

  152. Roayaie, S. et al. Resection of hepatocellular cancer ≤2 cm: results from two Western centers. Hepatology 57, 1426–1435 (2013).

    Article  PubMed  Google Scholar 

  153. Zhu, Q. et al. Hepatocellular carcinoma in a large medical center of China over a 10-year period: evolving therapeutic option and improving survival. Oncotarget 6, 4440–4450 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Aroldi, F. & Lord, S. R. Window of opportunity clinical trial designs to study cancer metabolism. Br. J. Cancer 122, 45–51 (2020).

    Article  PubMed  Google Scholar 

  155. Hu, C. & Dignam, J. J. Biomarker-driven oncology clinical trials: key design elements, types, features, and practical considerations. JCO Precis. Oncol. https://doi.org/10.1200/PO.19.00086 (2019).

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Acknowledgements

The authors thank M. Zeitlhoefler (Icahn School of Medicine at Mount Sinai and IDIBAPS) for his help in preparing the tables for this manuscript. J.M.L. is supported by grants from Asociación Española Contra el Cáncer (Proyectos Generales: PRYGN223117LLOV), the European Commission (Horizon Europe-Mission Cancer, THRIVE, Ref. 101136622), by an Accelarator Award from Cancer Research UK, Fondazione per la Ricerca sul Cancro (AIRC) and Fundación Científica de la Asociación Española Contra el Cáncer (FAECC) (HUNTER, Ref. C9380/A26813), Generalitat de Catalunya (AGAUR, 2021-SGR 01347), Acadèmia de Ciències Mèdiques i de la Salut de Catalunya i Balears; NIH (R01-CA273932-01, RO1DK56621 and RO1DK128289), the Samuel Waxman Cancer Research Foundation and the Spanish National Health Institute (MICINN, PID2022-139365OB-I00).

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Authors and Affiliations

  1. Liver Cancer Translational Research Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain

    Josep M. Llovet & Roser Pinyol

  2. Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Josep M. Llovet & Thomas U. Marron

  3. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain

    Josep M. Llovet

  4. Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA

    Mark Yarchoan

  5. Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Mark Yarchoan

  6. Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Amit G. Singal

  7. Department of Liver Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Myron Schwartz

  8. The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel-Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem, Israel

    Eli Pikarsky

  9. Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan

    Masatoshi Kudo

  10. Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Richard S. Finn

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Competing interests

J.M.L. receives research support from Bayer HealthCare Pharmaceuticals, Eisai Inc. and Sagimet; has received consulting fees from AstraZeneca, Bayer HealthCare Pharmaceuticals, Bristol–Myers Squibb, Eisai Inc., Exelixis, Genentech, Glycotest, Merck, Moderna and Roche. M.Y. has received institutional research support from Bristol–Myers Squibb, Genentech and Incyte; honoraria from Astrazeneca, Eisai, Exelixis, Genentech, Hepion and Replimune; and is a co-founder of and holds equity in Adventris Pharmaceuticals. A.G.S. has served as a consultant or on advisory boards for AstraZeneca, Bayer, Boston Scientific, Eisai, Exact Sciences, Exelixis, Freenome, FujiFilm Medical Sciences, GRAIL, Genentech, Glycotest, Roche and Universal Dx. T.U.M. has served on advisory and/or data safety monitoring boards for AbbVie, Arcus, Astellas, AstraZeneca, Atara, Boehringer Ingelheim, Bristol–Meyers Squibb, Celldex, Chimeric, DBV Technologies, DrenBio, G1 Therapeutics, Genentech, Glenmark, Merck, NGMbio, Regeneron, Rockefeller University, Simcere and Surface; and received research grants from Boehringer Ingelheim, Bristol–Myers Squibb, Merck and Regeneron. M.K. has received research support from Bayer Pharmaceutical, Chugai, Eisai, Ono Pharmaceutical and Takeda; consultancy or lecture fees from AbbVie, AstraZeneca, Bayer, Chugai, EA Pharma, Eisai, Eli Lilly, GE Healthcare, Gilead Sciences, Merck, Otsuka, Roche, Sumitomo Dainippon Pharma and Takeda. R.P., M.S., E.P. and R.S.F. declare no competing interests.

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Nature Reviews Clinical Oncology thanks S.-Q. Cheng; A. Kaseb, who co-reviewed with M. LaPelusa; T. Pawlik; and S. Qin for their contribution to the peer review of this work.

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Llovet, J.M., Pinyol, R., Yarchoan, M. et al. Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma. Nat Rev Clin Oncol 21, 294–311 (2024). https://doi.org/10.1038/s41571-024-00868-0

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