Immunotherapy in Hepatocellular Carcinoma - An Overview

Introduction

The third most common cause of cancer-related death globally is liver cancer, the seventh most frequently diagnosed cancer. The most prevalent type of liver cancer, hepatocellular carcinoma (HCC), has a high morbidity and mortality rate. Liver cirrhosis is the primary clinical risk factor for developing HCC. Cirrhosis is primarily brought on by long-term heavy alcohol consumption and chronic hepatitis B and C virus infections.

In the clinical management of early-stage HCC, surgical removal, a liver transplant, and radiation therapy (RFA) are frequently used. Transarterial chemoembolization is the first-line therapy for patients with intermediate HCC (BCLC stage B). Although numerous treatment modalities have increased clinical efficacy, patients with HCC experience tumor recurrence and have low survival rates. New therapeutic approaches are thus desperately needed. The survival of patients with a variety of tumors has increased due to the rapid development of cancer immunotherapy (CIT) in recent years. Only a small percentage of patients, particularly those with rare cancers like Hodgkin's lymphoma or melanoma, show life-changing improvements with CIT. Immunotherapies still have a poor prognosis for most patients with solid tumors.

What Are the Immunotherapeutic Approaches for Hepatocellular Carcinoma?

The primary approaches involved in immunotherapy for cancer are:

• Vaccines- They focus on specific antigens. For the treatment of HCC, a few vaccines are being studied. In a phase I trial, 15 patients with advanced HCC were investigated for the use of AFP (alpha-fetoprotein)-derived peptides as an anti-tumor vaccine. The outcomes showed that the vaccine was both secure and efficient. In one patient, the peptides produced peptide-specific T-cell receptors (TCRs), which led to a full recovery, and in eight other patients, tumor progression was slowed.

• Adoptive Cell Transfer (ACT)- They act on specific antigens using genetically modified T cells.

• Immune Checkpoint Inhibitors (ICI)- ICI blocks the suppressive T cell regulators and activates the already active antitumor immune responses that kill tumor cells.

What Are the Limitations of Current Immunotherapy Treatment Modalities?

Although immunotherapy has demonstrated promising clinical results in many tumor types, such as melanoma, non-small cell lung carcinoma, and urothelial carcinoma, its use in HCC remains limited due to many factors.

• Tumor Mutation Burden- Due to the low tumor mutational burden of HCC compared to that of melanoma or non-small cell lung carcinoma, immunotherapies are less effective for treating HCC. Neoantigens are recently expressed antigens that can be recognized and provided to T cells to activate the adaptive immune system. They are found on the surface of tumor cells. They are tumor-specific peptides that are produced when cancer cells undergo somatic mutations. A low tumor mutational burden in HCC results in limited neoantigen release. The antigen presentation pathway mutation also prevents the presentation of tumor-specific peptides. Due to their low immunogenicity, the majority of these neoantigens are unable to induce potent anti-tumor immunity. While tumors with a high load of subclonal neoantigens are resistant to immunotherapy, tumors with a high load of clonal neoantigens respond very well to ICI therapy.

• Tumor Microenvironment- The components of the tumor microenvironment (TME) include an extracellular-derived matrix made of collagen and proteoglycans, lymphocytes, blood vessels, fibroblastic cells, and bone marrow inflammatory cells. Three characteristics of the tumor's immune status influence the clinical effectiveness of ICI. First, the TME must contain antigen-specific CD8+ T cells. Second, an immune permissive state must be polarized in the resident immune cell populations in the TME. Third, the primary immune tolerance mechanism in tumor cells must be MHC class I-mediated antigen presentation and PD-1 signaling. These characteristics make a tumor susceptible to ICIs and are known as immune "hot" tumors. Tumors that lack these specifics have a poor clinical response to ICI (immune checkpoint inhibitors). There are few or no effector CD8+ T cells, many regulatory CD4+ T cells, and other immunosuppressive cells in the tumor microenvironment, which is immunosuppressive in status and is linked to a poor clinical response to immunotherapy.

What Are the Efforts Made to Enhance Immunotherapy Treatment Modality?

• Epigenetic Modulation- The progression of tumors is significantly influenced by epigenetic modification, which alters immune function and causes transcriptional aberrations in gene expression that may produce a favorable TME. Epigenetic therapy can also encourage the expression of immunogenic antigens, such as cancer-testis antigens, on the tumor surface. A variety of proteins known as cancer-testis antigens, which are only expressed in male germ cells and not in normal adult somatic tissues, can be used as target antigens for antitumor immunotherapy.

• Antiangiogenic Therapy- The microenvironment of hypoxia encourages the growth of HCC and tumor angiogenesis. Advanced HCC can be treated with medicines that target angiogenic pathways, such as vascular endothelial growth factor (VEGF). Anti-VEGF therapy is frequently used to treat HCC. Tyrosine kinase inhibitor (TKI) Sorafenib is authorized for the treatment of HCC and can disrupt the VEGF signaling pathway. Despite the observed survival benefits, Sorafenib's use in advanced HCC treatment is constrained by its high rate of acquired resistance.

• Activating Tertiary Lymphoid Structure Formation- Recent research has shown that the presence of intra-tumoral tertiary lymphoid structures (TLSs) enhances the effectiveness of ICI treatment for melanoma. TLSs are ectopic lymphoid aggregates that are defined by mature differential cells in a T-cell zone close to B-cell follicles with a germinal center as a result of lymphoid neogenesis occurring in non-lymphoid tissues in response to chronic inflammation. Most cancer types contain TLSs, and higher TLS densities are linked to better clinical outcomes. Intra-tumoral TLSs are associated with a lower risk of early HCC recurrence following surgical excision in HCC, which may indicate persistent, efficient antitumor immunity. Therapeutic methods to promote TLS formation may improve HCC antitumor immunotherapy.

• Locoregional Therapy- Although locoregional therapies like RFA (radiofrequency ablation) (heat is used to destroy the tissues) can be as effective as surgically removing HCC nodules, patients who receive this therapy frequently develop cancer again. Locoregional therapy induces tumor cell death through the release of tumor antigens and stimulation of antitumor immunity, known as immunogenic cell death (ICD), even though it is ineffective as a monotherapy.

• Cytokines- Although cytokines play many different roles in the development of the immune system, there are limitations to cytokine therapy alone as an immunotherapy for HCC. The first immunotherapy investigated in numerous clinical trials was IFN (interferon) alpha. Despite IFN alpha’s anti-proliferative, immunostimulatory, and anti-angiogenesis properties, the majority of studies did not demonstrate any clinical advantages.

• Chemotherapy- Oxaliplatin is one example of a chemotherapy drug that has had limited effects on the overall survival of patients with advanced HCC. These cytotoxic medications cause tumor cell death and also promote anti-tumor immunity through immunogenic cell death (ICD), which involves changes in the cell surface).

Conclusion

Immunotherapy has been used both alone and in conjunction with other therapeutic modalities. Most patients with advanced HCC do not benefit from these therapeutic strategies, though some do. The effectiveness of novel immunotherapy methods is being studied right now, and many new studies are being conducted to evaluate their further efficacy in patients with hepatocellular carcinoma.