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ABSTRACT
Introduction
Advanced hepatocellular carcinoma (HCC) represents a significant global health burden, whose treatment has been recently revolutionized by the advent of biologic treatments. Despite that, innovative therapeutic regimens and approaches, especially immune-based, remain to be explored aiming at extending the therapeutic benefits to a wider population of patients.
Areas covered
This review comprehensively discusses the evolving landscape of biological treatment modalities for advanced HCC, including immune checkpoint inhibitors, antiangiogenic monoclonal antibodies, tumor-targeting monoclonal antibodies either naked or drug-conjugated, therapeutic vaccines, oncolytic viruses, adoptive cell therapies, and cytokine-based therapies. Key clinical trials and preclinical studies are examined, highlighting the actual or potential impact of these interventions in reshaping treatment paradigms for HCC.
Expert opinion
Tailored and rational combination strategies, leveraging the synergistic effects of different modalities, represent a promising approach to maximize treatment efficacy in advanced HCC, which should aim at conversion endpoints to increase the fraction of patients eligible for curative approaches. The identification of predictive biomarkers holds the key to optimizing patient selection and improving therapeutic outcomes.
Article highlights
ICIs targeting PD-1/PD-L1 and CTLA-4/B7 axes have significantly transformed HCC treatment, but HCC’s immunosuppressive microenvironment hinders therapeutic efficacy of monotherapies.
Antiangiogenic agents like anti-VEGF mAbs and TKIs can disrupt tumor angiogenesis, one of HCC histological hallmarks, and synergize with ICIs.
The combination of two ICIs or of an ICI with antiangiogenic agents, such as in the STRIDE or atezolizumab plus bevacizumab regimens respectively, have shown remarkable efficacy, leading to their approval as first-line treatments.
Studies to establish best second-line treatments following progression on new SOC first-line regimens are particularly needed.
Emerging evidence of ICI clinical efficacy in earlier disease stages, such as in the adjuvant, neoadjuvant settings or in combination with locoregional approaches is going to broaden the use of ICIs for HCC treatment.
Tumor-targeting naked or drug-conjugated mAbs, therapeutic vaccines, OVs, adoptive cell therapies and cytokine-based therapies show promise in preclinical and early clinical trials, offering potential new therapeutic options pending further validation.
List of abbreviations
| ACT | = | Adoptive Cell Transfer |
| ADAs | = | Anti-Drug Antibodies |
| ADC | = | Antibody-Drug Conjugate |
| ADCC | = | Antibody-dependent cell cytotoxicity |
| AdV | = | Adenovirus |
| AEs | = | Adverse events |
| AFP | = | Alphafetoprotein |
| APC | = | Antigen-Presenting Cell |
| CAR | = | Chimeric Antigen Receptor |
| CLDN1 | = | Claudin-1 |
| CTLA-4 | = | Cytotoxic T-Lymphocyte Antigen 4 |
| DC | = | Dendritic cell |
| DCR | = | Disease Control Rate |
| GM-CSF | = | Granulocyte-Macrophage Colony-Stimulating Factor |
| GPC3 | = | Glypican 3 |
| HBV | = | Hepatitis B Virus |
| HCC | = | Hepatocellular carcinoma |
| HIF | = | Hypoxia Inducible Factor |
| HLA | = | Human Leucocyte Antigen |
| HSV | = | Herpes Simplex Virus |
| ICI | = | Immune Checkpoint Inhibitor |
| IFN | = | Interferon |
| IL | = | Interleukin |
| IPTW | = | Inverse Probability of Treatment Weighting |
| mAb | = | monoclonal Antibody |
| MHC | = | Major Histocompatibility Complex |
| mPFS/OS | = | median PFS/OS |
| mRNA | = | messenger RNA |
| NSCLC | = | Non-Small Cell Lung Cancer |
| ORR | = | Objective Response Rate |
| OS | = | Overall Survival |
| OVs | = | Oncolytic Viruses |
| PD-1 | = | Programmed death protein 1 |
| PD-L1 | = | Programmed death ligand 1 |
| PFS | = | Progression Free Survival |
| SOC | = | Standard of Care |
| STRIDE | = | Single Tremelimumab Regular Interval Durvalumab |
| TAA | = | Tumor-associated antigen |
| TCR | = | T-cell receptor |
| TGF | = | Transforming Growth Factor |
| TILs | = | Tumor-infiltrating Lymphocytes |
| TKI | = | Tyrosine Kinase Inhibitors |
| TME | = | Tumor Microenvironment |
| Treg | = | T regulatory cells |
| TTP | = | Time to Progression |
| VEGF | = | Vascular-Endothelial Growth Factor |
| VEGFR | = | Vascular-Endothelial Growth Factor Receptor |
| VV | = | Vaccinia Virus |
Declaration of interest
A Casadei-Gardini has received grants and personal fees from MSD, Eisai, Bayer, and is an advisor for MSD, Eisai, Bayer, Bristol-Myers Squibb, AstraZeneca and GSK. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Author contributions
F Rossari: conceptualization, visualization, writing – original draft, review & editing; S Foti, S Camera, M Persano: writing – review & editing; A Casadei-Gardini, M Rimini: conceptualization, supervision, writing – review & editing.