TKIs in combination with immunotherapy for hepatocellular carcinoma

Stefanini, Bernardo; Ielasi, Luca; Chen, Rusi; Abbati, Chiara; Tonnini, Matteo; Tovoli, Francesco; Granito, Alessandro

doi:10.1080/14737140.2023.2181162

Cited by 52 publications

(42 citation statements)

References 94 publications

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“…Recently, combination therapies of immune checkpoint inhibitors (ICIs) with multikinase inhibitors have shown superior clinical efficacy. 29 The most studied ICIs currently target programmed cell death-1 (PD-1), its ligand PD-L1, and cytotoxic T lymphocyte-associated protein 4, with proven efficacy in advanced HCC. 30 Indoleamine 2,3-dioxygenase (IDO) is overexpressed in HCC; it is a kynurenine pathway enzyme responsible for degrading tryptophan, an AhR agonist.…”

Section: Discussionmentioning

confidence: 99%

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The aryl hydrocarbon receptor maintains antitumor activity of liver resident natural killer cells after partial hepatectomy in C57BL/6J mice

Sato,

Ohira,

Imaoka

et al. 2023

Cancer Medicine

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BackgroundLiver‐resident natural killer (lr‐NK) cells are distinct from conventional NK cells and exhibit higher cytotoxicity against hepatoma via tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL). However, the mechanism by which partial hepatectomy (PH) significantly suppresses TRAIL expression in lr‐NK cells remains unclear.MethodsThis study aimed to investigate the PH influence on the function and characteristics of liver‐resident NK (lr‐NK) cells using a PH mouse model.ResultsHere, we report that PH alters the differentiation pattern of NK cells in the liver, and an aryl hydrocarbon receptor (AhR) molecule is involved in these changes. Treatment with the AhR agonist 6‐formylindolo[3,2‐b]carbazole (FICZ) inhibited the maturation of NK cells. FICZ increased the immature subtype proportion of NK cells with high TRAIL activity and decreased the mature subtype of NK cells with low TRAIL activity. Consequently, FICZ increased the expression of TRAIL and cytotoxic activity of NK cells in the liver, and this effect was confirmed even after hepatectomy. The participation of AhR promoted FoxO1 expression in the mTOR signaling pathway involved in the maturation of NK cells, resulting in TRAIL expression.ConclusionOur findings provide direct in‐vivo evidence that partial hepatectomy affects lrNK cell activity through NK cell differentiation in the liver. Perioperative therapies using an AhR agonist to improve NK cell function may reduce the recurrence of hepatocellular carcinoma after hepatectomy.

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Section: Discussionmentioning

confidence: 99%

“…Recently, combination therapies of immune checkpoint inhibitors (ICIs) with multikinase inhibitors have shown superior clinical efficacy 29 . The most studied ICIs currently target programmed cell death‐1 (PD‐1), its ligand PD‐L1, and cytotoxic T lymphocyte‐associated protein 4, with proven efficacy in advanced HCC 30 .…”

Section: Discussionmentioning

confidence: 99%

The aryl hydrocarbon receptor maintains antitumor activity of liver resident natural killer cells after partial hepatectomy in C57BL/6J mice

Sato,

Ohira,

Imaoka

et al. 2023

Cancer Medicine

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“…Efforts have also been made to identify the most effective combination. More recently, PD-1 inhibitor plus TKI therapy have been con rmed as an effective and safe therapeutic approach for HCC patient with PVTT 35 ; for these HCC patients with PVTT, the combination therapy of bevacizumab plus atezolizumab has been approved as a rst-line therapy based on the results of the IMbrave150 trial 36 . atezolizumabbevacizumab therapy signi cantly extended OS and ORR in the IMbrave150 study.…”

Section: Discussionmentioning

confidence: 99%

Transarterial chemoembolization combined with lenvatinib, programmed death-1 inhibitor, and iodine-125 seed brachytherapy for hepatocellular carcinoma with portal vein tumor thrombosis

Lin

Yan

et al. 2023

Preprint

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Background: Therapy for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) is still controversial. This study was performed to evaluate the efficacy and safety of combination therapy comprising transarterial chemoembolization (TACE), lenvatinib, programmed death-1 inhibitor, and iodine-125 seed brachytherapy relative to TACE in combination with lenvatinib plus programmed death-1 inhibitor therapy and TACE plus lenvatinib therapy. Methods: The data of HCC patients with PVTT from July 2017 to August 2022 were assessed in this single-center retrospective study. Primary study outcomes were progression-free survival (PFS) and overall survival (OS), while the secondary outcomes were disease control rate (DCR) and objective response rate (ORR), and treatment-related adverse events. Results: We enrolled 150 patients finally, including 50 patients treated with TACE plus lenvatinib therapy (TACE+L group), 45 patients treated with TACE in combination with lenvatinib plus programmed death-1 inhibitor therapy (TACE+L+P group), and 55 patients treated with the combination therapy of transarterial chemoembolization along with iodine-125 seed brachytherapy, lenvatinib, and programmed death-1 inhibitor therapy (TACE+L+P+I125 group). The median OS in the TACE+L+P+I125 group (21.0; 95% confidence interval [CI]: 18.4~23.5 months) was significantly higher compared to the TACE+L group (10; 95% CI: 7.8~12.1months) (P = 0.006), while it was insignificantly higher compared to the TACE+L+P group (14.0; 95% CI: 10.7~17.2months) (P = 0.058). The median PFS in the TACE+L+P+I125 group (13.0; 95% CI: 10.2~15.7 months) was significantly higher compared to the TACE+L group (5.0; 95% CI: 4.2~5.7 months) (P = 0.014) and the TACE+L+P group (9.0; 95% CI: 6.7~11.2 months) (P = 0.048). Significant between-group differences in DCR (P = 0.015) were found. There were no significant between-group differences in treatment-related adverse events (P > 0.05). Conclusions: A combination therapy of TACE, lenvatinib, programmed death-1 inhibitor, and iodine-125 seed brachytherapy significantly improve OS, PFS, and DCR and show better survival prognosis for HCC patients accompanied by PVTT.

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“…While atezolizumab plus bevacizumab is the first-line standard of care for HCC, several combination therapies are being studied to determine the most efficacious subsequent treatment options. Recent studies have demonstrated synergistic effects of ICIs and TKIs, with both showing immunomodulatory effects on the tumor microenvironment [ 109 ]. The combination of pembrolizumab and lenvatinib in the KEYNOTE-524/Study 116 trial (NCT03006926) did not show any meaningful improvement over atezolizumab plus bevacizumab [ 67 , 90 ].…”

Section: Hcc Management In the Gulf: Staging And Treatment Modalities...mentioning

confidence: 99%

Current Status of Management of Hepatocellular Carcinoma in The Gulf Region: Challenges and Recommendations

Albarrak

Al-Shamsi

2023

Cancers

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The burden of hepatocellular carcinoma (HCC) is on the rise in the Gulf region, with most patients being diagnosed in the intermediate or advanced stages. Surgery is a treatment option for only a few, and the majority of patients receive either locoregional treatment (percutaneous ethanol injection, radiofrequency ablation, transarterial chemoembolization [TACE], radioembolization, radiotherapy, or transarterial radioembolization) or systemic therapy (for those ineligible for locoregional treatments or who do not benefit from TACE). The recent emergence of novel immunotherapies such as immune checkpoint inhibitors has begun to change the landscape of systemic HCC treatment in the Gulf. The combination of atezolizumab and bevacizumab is currently the preferred first-line therapy in patients not at risk of bleeding. Additionally, the HIMALAYA trial has demonstrated the superiority of the durvalumab plus tremelimumab combination (STRIDE regimen) therapy in efficacy and safety compared with sorafenib in patients with unresectable HCC. However, there is a lack of data on post-progression treatment after first-line therapy with either atezolizumab plus bevacizumab or durvalumab plus tremelimumab regimens, highlighting the need for better-designed studies for improved management of patients with unresectable HCC in the Gulf region.

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TKIs in combination with immunotherapy for hepatocellular carcinoma

Cited by 52 publications

References 94 publications

The aryl hydrocarbon receptor maintains antitumor activity of liver resident natural killer cells after partial hepatectomy in C57BL/6J mice

The aryl hydrocarbon receptor maintains antitumor activity of liver resident natural killer cells after partial hepatectomy in C57BL/6J mice

Transarterial chemoembolization combined with lenvatinib, programmed death-1 inhibitor, and iodine-125 seed brachytherapy for hepatocellular carcinoma with portal vein tumor thrombosis

Current Status of Management of Hepatocellular Carcinoma in The Gulf Region: Challenges and Recommendations

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