Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC

Dong, Yucheng; Wong, Jeffrey Sum Lung; Sugimura, Ryohichi; Lam, Ka‐On; Li, Bryan; Kwok, Gerry Gin Wai; Leung, Roland; Chiu, Joanne Wing Yan; Cheung, Tan To; Yau, Thomas

doi:10.3390/cancers13081949

Cited by 33 publications

(18 citation statements)

References 108 publications

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“…Thirdly, dual ICI could raise inflammatory cytokine production, such as TNF-α and IFN-γ, while lowering T cell anergy. Finally, dual ICI could lead to the growth of memory T cells, which facilitates longer-term anti-tumor immunity ( 94 ). But the brain was an immune-specialized environment, in which immune responses against tumors were restricted.…”

Section: Discussionmentioning

confidence: 99%

The Long-Term and Short-Term Efficacy of Immunotherapy in Non-Small Cell Lung Cancer Patients With Brain Metastases: A Systematic Review and Meta-Analysis

et al. 2022

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BackgroundAlthough immunotherapy has been widely used, there is currently no research comparing immunotherapy for non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). This meta-analysis addresses a gap in the comparison of immunotherapy efficacy, including immune checkpoint inhibitors (ICIs), chemotherapy (CT), radiotherapy (RT), and ICI combined CT or RT.MethodsA search of Pubmed, Cochrane, EMBASE, and ClinicalTrial.gov was conducted to identify studies which enrolled NSCLC patients with BM treated with ICIs. The outcomes consisted of intracerebral overall response rate (iORR), intracerebral disease control rate (iDCR), extracranial overall response rate (EORR), distant brain failure (DBF), local control (LC), progression-free survival (PFS), and overall survival (OS).ResultsA total of 3160 participants from 46 trials were included in the final analysis. Patients treated with immunotherapy were associated with a longer PFS (0.48, 95%CI: 0.41-0.56), and a longer OS (0.64, 95%CI: 0.60-0.69) compared with immunotherapy-naive patients. In prospective studies, dual ICI combined CT and ICI combined CT achieved a better OS. The hazard ratio (HR) of dual ICI combined CT versus dual ICI was 0.61, and the HR of ICI combined CT versus ICI monotherapy was 0.58. Moreover, no statistical difference in PFS, OS, EORR, iORR, iDCR, and EDCR was found between patients with ICI monotherapy and ICI combined cranial radiotherapy. Concurrent ICI combined RT was shown to decrease the rate of DBF (OR = 0.15, 95% CI: 0.03-0.73) compared with RT after ICI. Patients treated with WBRT might have an inferior efficacy than those with SRS because the iORR of SRS was 0.75 (0.70, 0.80) and WBRT was 0. Furthermore, no obvious difference in PFS and OS was observed among the three different types of ICI, which targets PD-1, PD-L1, and CTLA-4, respectively.ConclusionsPatients treated with ICI got superior efficacy to those without ICI. Furthermore, dual ICI combined CT and ICI combined CT seemed to be optimal for NSCLC patients with BM. In terms of response and survival, concurrent administration of SRS and ICI led to better outcomes for patients with BMs than non-concurrent or non-SRS.Importance of the StudyIn the new era of immunotherapy, our meta-analysis validated the importance of immunotherapy for non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). By comparing the long-term and short-term impacts of various regimens, all immunotherapy treatments had superior efficacy to immunotherapy-naive. At the same time, through pairwise comparison in immunotherapy, our findings can help clinicians to make treatment decisions for NSCLC patients with BMs.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=269621, identifier CRD42021269621.

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Section: Discussionmentioning

confidence: 99%

The Long-Term and Short-Term Efficacy of Immunotherapy in Non-Small Cell Lung Cancer Patients With Brain Metastases: A Systematic Review and Meta-Analysis

et al. 2022

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“…In addition, in the dose-expansion phase, a total of 214 advanced HCC patients were enrolled into 4 cohorts, including uninfected sorafenib refractory (n = 57), uninfected sorafenib intolerance (n = 56), HCV infected (n = 50), and HBV infected (n = 51). The ORR was 20% (95% CI [15][16][17][18][19][20][21][22][23][24][25][26], the DCR was reported as 64% (95% CI, 50-71), and the median PFS was 4.0 months (95% CI, 2.9-5.4). The OS was not reached.…”

Section: Icis In Hccmentioning

confidence: 99%

“…However, not all patients (especially in the era of pre-liver transplantation) with HCC respond to immunotherapy, and more importantly, the ORR is low, and OS does not significantly improve with single-agent immunotherapy (22,23). Given these data, more effective combination therapies for the treatment of HCC are explored, including ICIs combined with other ICIs, TKIs, anti-VEGFs, and other agents (24). In recent years, the emergence of combination therapies using multi-ICIs or ICIs with antiangiogenics represents the main avenue for the treatment of advanced HCC (5,25).…”

Section: Introductionmentioning

confidence: 99%

Advances in Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma

Chen

Yuan

et al. 2022

Front. Immunol.

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Hepatocellular carcinoma (HCC) is usually diagnosed in an advanced stage and has become the second deadliest type of cancer worldwide. The systemic treatment of advanced HCC has been a challenge, and for decades was limited to treatment with tyrosine kinase inhibitors (TKIs) until the application of immune checkpoint inhibitors (ICIs) became available. Due to drug resistance and unsatisfactory therapeutic effects of monotherapy with TKIs or ICIs, multi-ICIs, or the combination of ICIs with antiangiogenic drugs has become a novel strategy to treat advanced HCC. Antiangiogenic drugs mostly include TKIs (sorafenib, lenvatinib, regorafenib, cabozantinib and so on) and anti-vascular endothelial growth factor (VEGF), such as bevacizumab. Common ICIs include anti-programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1), including nivolumab, pembrolizumab, durvalumab, and atezolizumab, and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4), including tremelimumab and ipilimumab. Combination therapies involving antiangiogenic drugs and ICIs or two ICIs may have a synergistic action and have shown greater efficacy in advanced HCC. In this review, we present an overview of the current knowledge and recent clinical developments in ICI-based combination therapies for advanced HCC and we provide an outlook on future prospects.

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“…In addition, CCDC6 may be used as a molecular predictor for the prognosis of this kind of comprehensive therapy in patients with CCDC6 mutations. The benefits of this comprehensive therapy (also known as stereotactic therapy) have been apparent for a patient with HCC in our clinical practice (Supplementary Figure 7) [44,45]. Clinical trials of single or combination therapy with PARP inhibitors, immune checkpoint inhibitors and epigenetic drugs for ovarian, breast, pancreatic, and lung cancers are underway.…”

Section: Correlation Between Ccdc6 and Immune Infiltrating Cells And ...mentioning

confidence: 99%

High expression of CCDC6 in relation to unfavorable outcome and immune cells infiltration in hepatobiliary carcinoma

Wu¹,

Jiang²,

Xu³

et al. 2022

J. Cancer

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Background:The diagnosis of hepatobiliary carcinoma includes both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the first and the second most common hepatobiliary malignancies, respectively. CCDC6 (coiled-coil domain-containing protein 6) is a protein that interacts with apoptosis and DNA damage response elements and is commonly detected in cells. The prognostic and biological roles of CCDC6 in hepatobiliary carcinoma remain unknown. Methods: We used data from UALCAN, GEPIA, TIMER, GeneMANIA, STRING and HPA databases to determine the prognostic values and biological functions of CCDC6 in HCC and CCA. We downloaded the original online data from TCGA and GEO databases and analyzed them with R 3.2.2. We also gathered clinical records from patients with HCC (n = 94) and iCCA (n = 99) in our hospital to explore associations between CCDC6 expression and hepatobiliary carcinoma using immunohistochemistry detection. We used KEGG, GO and GESA analyses to explore relative pathways of CCDC6 in HCC and CCA. In addition, we assessed correlations between CCDC6 expression and tumor-infiltrating immune cells using data from the TIMER and GEPIA databases. Finally, we assessed associations between CCDC6 and marker genes of tumor-infiltrated immune cells in HCC to confirm some of our findings. Results: The mRNA and protein expressions of CCDC6 were noticeably upregulated in HCC and CCA tissues as compared with the expressions in healthy control tissues. The high CCDC6 expression levels were significantly correlated with advanced tumor grades as well as poor prognosis in patients with HCC, but not in patients with CCA. Our functional enrichment analysis revealed that CCDC6 is mainly involved in cell cycle processes, gene transcription, and immune cell-related pathways. Moreover, we found that the CCDC6 levels were positively correlated with the presence of tumor-infiltrating immune cells, including macrophages, CD4+T cells and dendritic cells. Conclusion: CCDC6 expression was increased in hepatobiliary carcinoma tissues. High expressions of CCDC6 were significantly associated with clinical severity variables (especially with advanced cancer stages and pathological tumor grades) and poor prognoses in patients with HCC. CCDC6 upregulation is associated with histone acetylation and immune infiltration in hepatobiliary carcinoma. In addition, CCDC6 has the potential to be used as a predictive biomarker during targeting therapy and immunotherapy.

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Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC

Cited by 33 publications

References 108 publications

The Long-Term and Short-Term Efficacy of Immunotherapy in Non-Small Cell Lung Cancer Patients With Brain Metastases: A Systematic Review and Meta-Analysis

The Long-Term and Short-Term Efficacy of Immunotherapy in Non-Small Cell Lung Cancer Patients With Brain Metastases: A Systematic Review and Meta-Analysis

Advances in Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma

High expression of CCDC6 in relation to unfavorable outcome and immune cells infiltration in hepatobiliary carcinoma

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