Editor’s Note:
Intrahepatic cholangiocarcinoma (ICC) refers to adenocarcinoma originating from the epithelium of secondary bile ducts and their branches, accounting for 10%-15% of primary malignant tumors in the liver. In recent years, the incidence of ICC has been rising significantly, garnering increasing clinical attention. While ICC and hepatocellular carcinoma (HCC) both belong to primary liver cancers, they have distinct biological characteristics. The complex disease characteristics and prognosis pose significant challenges for ICC’s clinical treatment. From September 7-9, 2023, the 17th annual meeting of the International Liver Cancer Association (ILCA) was grandly held in Amsterdam, Netherlands. At the conference, Dr. Qiang Gao from Zhongshan Hospital, Fudan University, China, shared recent advancements in the study of tumor-immune interactions in ICC. This article compiles an in-depth interview with Dr. Gao for our readers.
Hepatology Digest: Compared to the more familiar HCC, ICC has garnered less public attention. Can you introduce the epidemiology and current treatment status of this disease?
Dr. Gao: ICC is the second most common malignant liver tumor in humans. Despite both being primary liver cancers, ICC significantly differs from HCC in terms of genetic features, clinical treatments, and prognosis. Over the years, the widespread vaccination against hepatitis B in our country has halted the rise in HCC’s incidence. However, ICC’s incidence has been steadily increasing globally, especially in Asian countries like Thailand, Japan, South Korea, and China. Consequently, it has gained attention from oncologists, hepatobiliary surgeons, and researchers. Historically, radical surgical resection was the preferred curative treatment for ICC patients. However, due to ICC’s insidious onset and high invasiveness, many patients are diagnosed at stages where surgery is no longer viable. With the rapid development of targeted therapies and immune checkpoint inhibitors, there’s hope for more effective treatments for advanced ICC patients.
Hepatology Digest: Your team has made significant advancements in tumor-immune interaction research within ICC in recent years. Could you share some of these findings with us?
Dr. Gao: Currently, the first-line treatment for ICC combines immunotherapy with chemotherapy. Before the advent of immunotherapy, chemotherapy alone had limited effects on ICC patients. However, with immunotherapy, we see many new possibilities and survival benefits for many patients. For instance, some inoperable patients have shown significant tumor shrinkage after combined immunotherapy, allowing surgical removal and extending their lifespan. With this in mind, our team has been investigating the immune microenvironment, such as tumor antigen mutations, immune evasion, and new therapeutic strategies for ICC. We have proposed molecular subtypes based on the distinct immune and tumor features of different patients and suggested tailored immunotherapy strategies. Furthermore, our studies have explored the impact of various driver mutations on the immune microenvironment. For instance, common ICC tumor gene mutations, such as KRAS, show increased immune suppression and reduced sensitivity to PD-1 monoclonal therapy. In contrast, ICC driven by FGFR2 gene mutations exhibit lower antigen loads and immune cell infiltration, indicating a potential combined treatment with FGRF2 inhibitors and immune checkpoint inhibitors.
Hepatology Digest: What clinical insights do these research findings provide? What is their clinical significance?
Dr. Gao: As is well known, in HCC’s clinical treatment, all patients are given multi-target drugs, resulting in varying treatment outcomes. However, as our understanding of ICC deepens, we realize that precision treatment is attainable, guided by molecular subtyping and genomics. From a mutation perspective, we’ve identified several ICC mutation types and developed corresponding drugs. For instance, ICC driven by FGFR2 gene mutations can be treated with FGFR inhibitors; those with isocitrate dehydrogenase (IDH) mutations can opt for IDH inhibitors. Furthermore, there are dual-specificity antibodies for HER2-positive ICC patients and potential TCR-T cell therapies or vaccine strategies for those with KRAS mutations. Of course, these precision treatment strategies require further large-scale clinical research for validation. Many new drugs are also awaiting exploration.
Hepatology Digest: What challenges remain in ICC’s clinical treatment, and what research directions are worth exploring in the future?
Dr. Gao: Over the past two years, our in-depth understanding of ICC’s genomics and immune microenvironment has revolutionized its clinical treatment. In 2022, the American NCCN guidelines recommended a plethora of first-line treatments involving immunotherapies and targeted drugs, offering more options and clinical benefits to patients. Under the leadership of Dr. Jia Fan, China also released its guidelines on ICC treatment in 2022, discussing targeted treatments and combined immunotherapy in detail. For second-line treatments, we, led by Dr. Jia Fan and Dr. Jian Zhou, initiated a Phase II clinical trial combining targeted treatments, immunotherapies, and chemotherapy, increasing the treatment efficacy rate to 80%. However, the remaining 20% of non-responding or recurrent patients present a challenge for clinicians and researchers alike. We’re exploring various avenues, such as perioperative combinations of targeted treatments, immunotherapies, and chemotherapy. Preliminary data suggests a significant reduction in postoperative tumor recurrence. But these are initial steps, and further exploration is needed.
TAG: ILCA 2023, Interview, ICC
