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Review

Treatment options for advanced hepatocellular carcinoma: the potential of biologics

, , , , &
Pages 455-470 | Received 08 Apr 2024, Accepted 30 May 2024, Published online: 24 Jun 2024
 

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.

Additional information

Funding

This paper was not funded.

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