Treatment options for hepatocellular carcinoma using immunotherapy: present and future

Hepatocellular carcinoma (HCC) is a primary liver cancer predominantly arising from chronic liver diseases such as hepatitis B and C infections, alcohol abuse, and metabolic disorders. It's one of the most common cancers worldwide and is increasingly prevalent in Western countries. Effective treatment options for HCC vary depending on tumor load, location, and comorbidities, including liver transplantation, surgical resection, percutaneous ablation, trans-arterial chemoembolization (TACE), and radio-embolization.

The progression of HCC is significantly influenced by the tumor microenvironment (TME), which plays a crucial role in immune suppression and maintenance of self-tolerance. Key players in this process include regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), inhibitory B cells, and M2-polarized tumor-associated macrophages (TAMs). These cells contribute to the evasion of immune surveillance by increasing co-inhibitory lymphocyte signals and producing tolerogenic enzymes. Understanding these interactions is vital for developing effective immunotherapies.

Immune checkpoint inhibitors have revolutionized the treatment of various cancers, including HCC. These monoclonal antibodies target proteins such as programmed cell death protein 1 (PD-1), its ligand (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). By blocking these checkpoints, ICIs enhance the immune system's ability to recognize and destroy cancer cells. Clinical trials have shown that ICIs can be used alone or in combination with other therapies, offering new hope for patients with advanced HCC.

Combining ICIs with targeted therapies, such as kinase inhibitors or angiogenesis inhibitors, has shown promising results in treating HCC. These combinations aim to enhance the efficacy of ICIs by disrupting tumor growth pathways and improving immune cell infiltration into the tumor microenvironment. Studies have demonstrated that these combinations can improve overall survival rates and progression-free survival in patients with HCC.

Advanced cellular immunotherapies, including T cell receptor (TCR) T cell therapy and chimeric antigen receptor (CAR) T cell therapy, are being explored for HCC treatment. TCR T cell therapy involves engineering T cells to express specific TCRs that target tumor antigens. CAR T cell therapy modifies T cells to express CARs that can recognize and attack cancer cells. These therapies offer a personalized approach to cancer treatment and have shown potential in early-phase clinical trials.

Oncolytic virotherapy uses genetically modified viruses to selectively infect and kill cancer cells while stimulating an anti-tumor immune response. Cancer vaccines aim to elicit a strong and specific immune response against tumor-associated antigens. Both approaches are in various stages of research and clinical development for HCC. They represent innovative strategies that could complement existing treatments and improve patient outcomes.

Despite the advancements in immunotherapy for HCC, several challenges remain. These include identifying reliable biomarkers for predicting treatment response, managing immune-related adverse events, and overcoming primary or acquired resistance to immunotherapy. Future research should focus on optimizing combination therapies, developing novel immune-modulating agents, and understanding the mechanisms of immune evasion by HCC cells.

Immunotherapy has transformed the landscape of HCC treatment, offering new hope to patients with this challenging disease. By targeting the tumor microenvironment and harnessing the power of the immune system, various immunotherapeutic approaches have shown significant potential. Ongoing research and clinical trials will be crucial in addressing current challenges and improving the efficacy and safety of these treatments. The future of HCC therapy lies in the continued integration of innovative immunotherapies into clinical practice.

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https://www.xiahepublishing.com/2310-8819/JCTH-2023-00462

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

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