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Heterogeneous responses in hepatocellular carcinoma: the achilles heel of immune checkpoint inhibitors.

ABSTRACT: Treatment of patients with hepatocellular carcinoma (HCC) remains a serious challenge due to high heterogeneity and limited treatment options. In the past few decades, immune therapy, especially immune checkpoint therapy, has become an alternative option for the treatment of malignancies including HCC. Immune checkpoint inhibitors (ICIs) have raised attention because of their significant antitumor effect and low toxicity. However, such immunotherapy fails to be responsive in a major proportion of patients with HCC. Recent studies suggest that failures in antigen presentation, an impaired immune microenvironment, alterations in immune checkpoint molecules and immune-suppressive cells are responsible for the heterogeneous responses and resistance. Based on the specific characteristics above, we proposed a model stratifying patients with HCC into two subtypes that could predict response or resistance to ICI. Furthermore, supplementing ICIs with agents targeting the microenvironment could achieve an increased response rate, which is a step forward in precision treatment for HCC. In addition, emerging studies have revealed that liver transplantation, epigenetic drugs and other novel strategies also provide synergistic effects with ICIs in the treatment of HCC.

SUBMITTER: Lin Z

PROVIDER: S-EPMC7191099 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Heterogeneous responses in hepatocellular carcinoma: the achilles heel of immune checkpoint inhibitors.

Lin Zuyuan Z Lu Di D Wei Xuyong X Wang Jianguo J Xu Xiao X

American journal of cancer research 20200401 4

Treatment of patients with hepatocellular carcinoma (HCC) remains a serious challenge due to high heterogeneity and limited treatment options. In the past few decades, immune therapy, especially immune checkpoint therapy, has become an alternative option for the treatment of malignancies including HCC. Immune checkpoint inhibitors (ICIs) have raised attention because of their significant antitumor effect and low toxicity. However, such immunotherapy fails to be responsive in a major proportion o ...[more]

PMID: 32368387

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Project description:Hepatocellular carcinoma (HCC) is the most common malignancy worldwide, and is especially common in China. A total of 70%-80% of patients are diagnosed at an advanced stage and can receive only palliative care. Sorafenib has been the standard of care for a decade, and promising results for regorafenib as a second-line and lenvatinib as a first-line treatment were reported only 1 or 2 years ago. FOLFOX4 was recently recommended as a clinical practice guideline by the China Food and Drug Administration. All approved systemic therapies remain unsatisfactory, with limited objective response rates and poor overall survival. Immune checkpoint inhibitors (CPIs) offer great promise in the treatment of a rapidly expanding spectrum of solid tumors. Immune checkpoint molecules are involved in almost the whole process of viral-related hepatitis with cirrhosis and HCC and in the most important resistance mechanism of sorafenib. The approval of nivolumab by the U.S. Food and Drug Administration on September 23, 2017, for the treatment of patients with HCC, based only on a phase I/II clinical trial, is a strong hint that immunotherapy will introduce a new era of HCC therapy. CPI-based strategies will soon be a main approach in anticancer treatment for HCC, and we will observe the rapid advances in the therapeutic use of CPIs, even in an adjuvant setting, with great interest. How shall we face the opportunities and challenges? Can we dramatically improve the prognosis of patients with HCC? This review may provide some informed guidance. IMPLICATIONS FOR PRACTICE: Immune checkpoint molecules are involved in almost the whole process of viral-related hepatitis with cirrhosis and hepatocellular carcinoma (HCC) and in the most important resistance mechanism of sorafenib. As all approved systemic therapies in HCC remain unsatisfactory, checkpoint inhibitor (CPI)-based strategies will soon be a main approach in anticancer treatment for advanced stage of HCC, even in an adjuvant setting. In virus-related HCC, especially hepatitis B virus-related HCC, whether CPIs can control virus relapse should be further investigated. Combination strategies involving conventional therapies and immunotherapies are needed to increase clinical benefit and minimize adverse toxicities with regard to the underlying liver disease.

Project description:Introduction: Several immune checkpoint inhibitors (CPIs) are under clinical development in hepatocellular carcinoma (HCC) and the field is advancing rapidly. In this comprehensive review, we discuss published results and report on ongoing clinical trials. Methods: A literature search was carried out using PubMed and EMBASE; data reported at international meetings and clinicaltrials.gov were included as well. The search was updated 5 March 2021. We evaluated studies with monotherapy CPI's, combinations of CPI's and combinations of CPI's with other treatment modalities separately. Only studies with at least 10 included patients were considered. Results: We identified 2649 records published in the English language literature. After review, 29 studies remained, including 12 studies with preliminary data only. The obtained overall response rate of PD-1/PDL-1 monotherapy in phase II studies in the second-line setting was 15-20% with disease control in approximately 60% of patients. The responses were of long duration in a subset of patients. Furthermore, the safety profiles were manageable. However, a phase III study comparing nivolumab with sorafenib in the first-line setting and a phase III study evaluating pembrolizumab versus best supportive care in the second-line setting did not meet their prespecified endpoints. More recently, a phase I/II study of nivolumab and ipilimumab has resulted in a response rate of approximately 30% with a median OS of 22 months in the second-line setting. Multiple trials have been initiated to evaluate CPIs in combination with molecularly targeted drugs, especially anti-angiogenic drugs or local therapy. A phase III study investigating atezolizumab plus bevacizumab versus sorafenib in the first-line setting showed significantly increased survival in the combination arm. Conclusions: The combination of atezolizumab and bevacizumab represents a new standard of care in the first-line setting for fit patients with preserved liver function. CPIs can produce durable tumor remission and induce long-standing anti-tumor immunity in a subgroup of patients with advanced HCC. Although phase III trials of CPI monotherapy have been negative, the combination of PD-1/PD-L1 inhibitors with other anti-angiogenic drugs, CTLA-4 inhibitors or other modalities may result in new treatment options for patients with HCC. Research on predictive biomarkers is crucial for further development of CPIs in HCC.

Dataset Information

Heterogeneous responses in hepatocellular carcinoma: the achilles heel of immune checkpoint inhibitors.

Publications

Heterogeneous responses in hepatocellular carcinoma: the achilles heel of immune checkpoint inhibitors.

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