Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Opportunities and Challenges

Liu, Xiufeng; Qin, Shukui

doi:10.1634/theoncologist.2019-io-s1-s01

Cited by 118 publications

(98 citation statements)

References 83 publications

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“…Currently, the tyrosine kinase inhibitors (TKI) sorafenib and lenvatinib are the first-line treatments in advanced HCC [5][6][7][8]. Regorafenib, nivolumab, cabozantinib, and ramucirumab were approved as second line therapies following their recent successes in several clinical trials [9][10][11][12][13][14][15]. Despite these breakthroughs, many patients still do not survive advanced HCC.…”

Section: Introductionmentioning

confidence: 99%

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A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy

Park

Lee³

et al. 2020

Cancers

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The chemotherapeutics sorafenib and regorafenib inhibit shedding of MHC class I-related chain A (MICA) from hepatocellular carcinoma (HCC) cells by suppressing a disintegrin and metalloprotease 9 (ADAM9). MICA is a ligand for natural killer (NK) group 2 member D (NKG2D) and is expressed on tumor cells to elicit attack by NK cells. This study measured ADAM9 mRNA levels in blood samples of advanced HCC patients (n = 10). In newly diagnosed patients (n = 5), the plasma ADAM9 mRNA level was significantly higher than that in healthy controls (3.001 versus 1.00, p < 0.05). Among four patients treated with nivolumab therapy, two patients with clinical response to nivolumab showed significant decreases in fold changes of serum ADAM9 mRNA level from 573.98 to 262.58 and from 323.88 to 85.52 (p < 0.05); however, two patients with no response to nivolumab did not. Using the Cancer Genome Atlas database, we found that higher expression of ADAM9 in tumor tissues was associated with poorer survival of HCC patients (log-rank p = 0.00039), while ADAM10 and ADAM17 exhibited no such association. In addition, ADAM9 expression showed a positive correlation with the expression of inhibitory checkpoint molecules. This study, though small in sample size, clearly suggested that ADAM9 mRNA might serve as biomarker predicting clinical response and that the ADAM9-MICA-NKG2D system can be a good therapeutic target for HCC immunotherapy. Future studies are warranted to validate these findings.

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Section: Introductionmentioning

confidence: 99%

“…These immunological features enable HCC to benefit from immunotherapy. Thus, harnessing these immune characters through combination immunotherapy is proposed as the next important step in treatment of advanced HCC [4,[13][14][15]21,22].…”

Section: Introductionmentioning

confidence: 99%

A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy

Park

Lee³

et al. 2020

Cancers

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“…Immune checkpoint inhibitors such as antibodies against PD-L1 and PD-1 have been introduced into clinical practice for a number of cancers [117,118]. In HCC, double-blind randomized clinical trials studies have shown that immune checkpoint inhibitor therapy can provide favorable responses in patients with advanced HCC [119]. However, recent results from phase III CheckMate 459 and KEYNOTE-240 studies of PD-1-targeted antibodies for advanced HCC did not achieve statistical significance or superiority in the overall survival in comparison to sorafenib [120,121].…”

Section: Exosomal Mirnas' Future Implications For Immunotherapy In Hccmentioning

confidence: 99%

The Crosstalk between Tumor Cells and the Microenvironment in Hepatocellular Carcinoma: The Role of Exosomal microRNAs and Their Clinical Implications

Pascut

Pratama

Võ

et al. 2020

Cancers

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The communication between hepatocellular carcinoma (HCC) cells and their microenvironment is an essential mechanism supporting or preventing tumor development and progression. Recent evidence has identified extracellular vesicles (EVs) as one of the mechanisms mediating paracrine signaling between cells. Exosomes, the most described class of EVs, deliver proteins, mRNAs, noncoding RNAs, DNA, and lipids to recipient cells, also at remote distances. MicroRNAs (miRNAs), as part of the non-coding RNA exosomal cargo, have an important role in regulating cellular pathways in targeted cells, regulating several processes related to tumor progression invasion and metastasis, such as angiogenesis, immune-escape, epithelial-to-mesenchymal transition, invasion, and multi-drug resistance. Accumulating evidence suggests exosomal miRNAs as relevant players in the dynamic crosstalk among cancerous, immune, and stromal cells in establishing the tumorigenic microenvironment. In addition, they sustain the metastasic niche formation at distant sites. In this review, we summarized the recent findings on the role of the exosome-derived miRNAs in the cross-communication between tumor cells and different hepatic resident cells, with a focus on the molecular mechanisms responsible for the cell re-programming. In addition, we describe the clinical implication derived from the exosomal miRNA-driven immunomodulation to the current immunotherapy strategies and the molecular aspects influencing the resistance to therapeutic agents.

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“…A small retrospective analysis noted that treatment with TKIs then immunotherapy then TKIs appears to be safe, and some patients did derive added benefits, but the data are too preliminary to draw any conclusions [49]. An excellent review article published in 2019 listed all the current ongoing trials involving checkpoint inhibitors; many are utilizing a combination approach [50]. We are eagerly awaiting these trial results to determine if any particular combination proves to be more effective than others.…”

Section: Immune-check Point Inhibitorsmentioning

confidence: 99%

Medical oncology management of advanced hepatocellular carcinoma 2019: a reality check

Lee

2019

Front. Med.

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In terms of global cancer-related deaths, hepatocellular carcinoma (HCC) has the fourth highest mortality rate. Up until 2017, treatment of advanced HCC was largely limited to sorafenib, an oral tyrosine kinase inhibitor, with little to no success in the development of alternative treatment options. However, in the past two years, there has been an unprecedented increase in both the number and type of treatment options available for HCC. As of 2019, the US FDA has approved four oral tyrosine kinase inhibitors, two immune checkpoint inhibitors, and one anti-angiogenesis antibody for the treatment of HCC. Even with this new variety, systemic treatment of advanced HCC remains largely unsatisfactory, and the median survival rate stands at approximately one year. The expected breakthrough of using immune checkpoint inhibitors in advanced HCC did not materialize in 2019. The use of immune checkpoint inhibitors in conjunction with oral tyrosine kinase inhibitors or antiangiogenesis medications is the current clinical research trend, the results of which are eagerly anticipated. Despite limited progress in survival, HCC research is currently experiencing a period of growth and innovation, and there is hope for significant advances in the treatment of advanced HCC as the field continues to develop.

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Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Opportunities and Challenges

Abstract: This review focuses on the opportunities and challenges of immune checkpoint inhibitor therapies for hepatocellular carcinoma, especially hepatitis B virus‐related hepatocellular carcinoma.

Cited by 118 publications

References 83 publications

A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy

A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy

The Crosstalk between Tumor Cells and the Microenvironment in Hepatocellular Carcinoma: The Role of Exosomal microRNAs and Their Clinical Implications

Medical oncology management of advanced hepatocellular carcinoma 2019: a reality check

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