Editor’s Note:
Primary hepatocellular carcinoma is one of the most common malignant tumors in China, ranking second in the mortality rate of malignant tumors in the country. In recent years, significant progress has been made in HCC immunotherapy, bringing new hope to countless HCC patients. The evolution of HCC immunotherapy has gone through the era of PD-1/PD-L1 monotherapy 1.0, combined molecular targeted drug application 2.0, and further combined local treatment 3.0. With ongoing clinical research, the effectiveness of HCC immunotherapy has greatly improved. So, what will the era of HCC immunotherapy 4.0 look like? What challenges will we face next? At the recently concluded 17th International Liver Cancer Association (ILCA) Annual Meeting, Hepatology Digest had the honor of conducting an in-depth interview with Dr. Tim Greten from the National Institutes of Health and the National Cancer Institute’s Cancer Research Center.
Hepatology Digest: How does single-cell analysis reveal the mechanisms of cancer drug resistance and guide immunotherapy strategies?
Dr.Greten: As you know, single-cell sequencing analysis is a very powerful tool that can help us better study specimens from patients. We can investigate various T cell subgroups and other immune cells and can clarify the mechanisms of tumor resistance, understanding how tumors evade immune responses.
However, we’re not yet at the point where it can be said to genuinely impact cancer treatment. To achieve this, we need to conduct larger-scale studies, especially large-scale studies involving significant sequencing sample sizes, particularly in HCC patients, where we have yet to achieve this.
Hepatology Digest: What challenges remain in achieving the best immune response in HCC patients?
Dr. Greten: I believe the current challenges are mainly as follows: First, not all patients will respond to immunotherapy. Thus, developing effective biological markers to predict efficacy is an essential research direction so that we can genuinely achieve patient screening. Second, many patients still experience severe adverse events during immunotherapy, so we need to consider the safety of treatment. Third, although we have achieved considerable success in HCC immunotherapy, there’s still a possibility of disease progression in some patients. To achieve a complete cure, we have a long journey ahead.
Hepatology Digest: The combination of interventional treatment and immunotherapy for HCC treatment is widely recognized. How do these two fields work together?
Dr. Greten: That’s an interesting question. In fact, several years ago, we started research in this area, launching the world’s first clinical trial combining anti-CTLA-4 with local HCC treatment. Our scientific hypothesis was that local treatment would lead to tumor cell death, and we could use these dead tumor cells as a deactivated vaccine to induce an immune response. Then, combined with immune checkpoint inhibitors, this effect could be further amplified to achieve better anti-tumor effects. Clinically, most of our HCC patients miss the opportunity for surgery. An increasing number of clinical trials show that the strategy of combining immunotherapy with local treatment can effectively control disease progression and prolong patient survival.
Moreover, our current research indicates that early-stage HCC patients might have a better immunotherapy response than late-stage patients. The potential applications of immunotherapy are vast, but in-depth exploration is required. Currently, in intermediate-stage HCC patients, the combination of immunotherapy and local treatment has yielded positive results. Simultaneously, as an adjuvant treatment, immunotherapy in post-surgical HCC patients has also produced positive outcomes, effectively reducing tumor recurrence rates and improving long-term prognosis.
Hepatology Digest: Looking forward to the era of HCC immunotherapy 4.0, what unmet clinical needs do you see currently?
Dr. Greten: First and foremost, we need to actively conduct large-scale clinical research to prove its efficacy. Additionally, as mentioned earlier, we need to explore biological markers that can effectively predict patient outcomes and select those who can benefit. Another aspect I’m very interested in is determining the optimal timing for the use of immune checkpoint inhibitors: when is the best time for immunotherapy, and how should we manage patients who may progress after adjuvant treatment? These are critical issues that need addressing.
TAG: ILCA 2023, Interview, HCC, Immunotherapy
