Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma

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.

Fig. 1 |. Immune cells in the hepatocellular carcinoma tumour microenvironment.

The hepatocellular carcinoma (HCC) immune microenvironment comprises different cell types that can have either a pro-tumoural role or an anti-tumoural role. Pro-tumoural role: Immune cells with pro-tumoural roles are largely immunosuppressive and thus hinder the development of effective innate and adaptive anti-tumour immunity. These cells include tissue-resident macrophages (Kupffer cells), regulatory T (T_reg) cells, monocyte-derived macrophages, type 2 neutrophils (N2 neutrophils) and myeloid-derived suppressor cells (MDSCs). Anti-tumoural role: Immune cells with effector anticancer activity counteract the immunosuppressive tumour microenvironment. These cells include CD8 T cells, liver-resident natural killer (NK) cells, type 1 macrophages (M1 macrophages) and type 1 neutrophils (N1 neutrophils). Furthermore, immune cells have immune checkpoints, which can either suppress (for example, PD-1, CTLA4, LAG3, TIGIT and TIM3) or enhance (for example, CD28, GITR and OX40) their effector function. Immunotherapeutic agents known as immune-checkpoint inhibitors (ICIs) block specific immune checkpoints, such as PD-1, CTLA4, LAG3, TIGIT or TIM3, rendering anti-tumoural activity. CAF, cancer-associated fibroblast; CCL, chemokine (C-C motif) ligand; CXCL, chemokine (C-X-C motif) ligand; DC, dendritic cell; FLT3L, Fms-related tyrosine kinase 3 ligand; GZMB, granzyme B; HLA, human leukocyte antigen; IDO, indoleamine-2,3-dioxygenase; IL, interleukin; LAG3, lymphocyte activation gene 3; M2 macrophage, macrophage type 2; MHC, major histocompatibility complex; NO, nitric oxide; PGE₂, prostaglandin E₂; ROS, reactive oxygen species; TCR, T cell receptor; TGFβ, transforming growth factor-β; TIGIT, T cell immunoglobulin and ITIM domain; TIM3, T cell immunoglobulin and mucin domain-containing protein 3; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor.

Fig. 2 |. Role of the hepatocellular carcinoma immune microenvironment in response to treatment.

Spatial organization of the immune infiltrate in patients with hepatocellular carcinoma (HCC). These tumours can be classified as inflamed and non-inflamed on the basis of infiltration patterns and molecular traits. The correlation of these patterns with response to immune-checkpoint inhibitors is shown schematically as well as with representative images of haematoxylin and eosin-stained resected lesions from patients who had previously received anti-PD-1 antibodies^,. Patients with a response (‘responders’) can have either complete or partial pathological responses, as determined through histopathological examinations of the resected tumour bed. Similar to many tumour types, tumours from patients with HCC who have received immune-checkpoint inhibitors can be classified as ‘hot’, with robust infiltration of lymphoid and myeloid cells; excluded, in which the lymphoid cell infiltrate is largely limited to the stroma; and ‘cold’, with a paucity of lymphoid infiltrate. Patients with tumours classified as hot can be responders, although a minority are non-responders. Postoperative samples from patients with excluded and cold tumours typically show little-to-no significant tumour necrosis. Images provided by T. Marron.

Fig. 3 |. Mechanism of action of immunotherapies and vaccines in the neoadjuvant and adjuvant setting in hepatocellular carcinoma.

a, Adjuvant approaches involve administration of immune-checkpoint inhibitors (ICIs) after surgery, leading to the activation of different subsets of T cells. b, In neoadjuvant approaches, ICIs are administered before surgery, fostering the development of a broader range of T cell responses compared with adjuvant approaches. c, When used, cancer vaccines are administered after resection. In the development of mRNA-based anti-tumoural vaccines, resected tumour tissues undergo targeted sequencing to identify specific tumour mutations. Peptides containing these mutations are then selected on the basis of their immunogenicity. Selected neoantigens are incorporated into plasmids as DNA fragments and subsequently transcribed into mRNA in vitro. Finally, these mRNAs are packed into nanoparticles. Vaccine-based approaches, such as mRNA-based or dendritic cell (DC)-based vaccines, can also be considered as neoadjuvant therapies. d, Mechanism of action of neoantigens-based vaccines. Nanoparticles containing mRNAs encoding selected neoantigens are endocytosed by DCs, where mRNAs are released and transcribed by ribosomes. Given that they are neoantigens, the resulting neoantigens are fragmented by the proteasome and presented on the cell surface through major histocompatibility complex (MHC) class I molecules. DC-mediated antigen presentation activates CD8⁺ T cells, subsequently leading to cancer cell apoptosis. Alternatively, neoantigens produced within DCs can be secreted and internalized by other antigen-presenting cells, where they are degraded into fragments subsequently presented through MHC class II molecules, activating CD4⁺ cells and inducing B cells to generate antibodies for cancer cell destruction. TCR, T cell receptor.

Fig. 4 |. Overview of updated management of hepatocellular carcinoma and proposed treatment approach after disease recurrence following adjuvant therapies.

a, Treatment algorithm incorporating new adjuvant agents for patients with early stage hepatocellular carcinoma who are at high risk of recurrence after resection or local ablation^a (ref. 7). The management of patients with hepatocellular carcinoma follows a treatment strategy guided by the Barcelona Clinic Liver Cancer staging system, which classifies disease into five stages. Asymptomatic patients with a low tumour burden and good liver function (Barcelona Clinic Liver Cancer stage (BCLC) 0) should undergo local curative treatments, such as resection or local ablation. For those with BCLC A disease (patients with single tumours or up to three nodules each <3 cm), transplantation or local curative treatments are considered on the basis of clinical factors, including presence of portal hypertension, number of nodules and liver function. In patients at high risk of recurrence, atezolizumab plus bevacizumab is recommended as adjuvant therapy after resection or ablation^a (ref. 7). Asymptomatic patients with multinodular disease and adequate liver function (BCLC B) should receive chemoembolization, whereas those with portal thrombosis or extrahepatic spread (BCLC C) should be treated with systemic therapies. Regimens approved on the basis of results from phase III trials are shown in red. Drug combinations that have shown positive results in phase III trials but have not yet been approved are shown in yellow. b, Proposed treatment approach after recurrence to adjuvant atezolizumab plus bevacizumab in patients with a high risk of recurrence after local curative treatment. ^aBased on guidance from the American Association for the Study of Liver Diseases (AASLD). ECOG, Eastern Cooperative Oncology Group performance status; LRT, locoregional therapy; M1, distant metastasis; N1, lymph node metastasis; q3mo, every three months; q6mo, every 6 months; SBRT, stereotactic body radiotherapy; TACE, transarterial chemoembolization; TARE, transarterial radioembolization.