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 77 publications

(56 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%

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%

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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“…In addition to the liver function and nutritional indices noted above, etiology, AFP reduction rate, macrovascular invasion, extrahepatic spread, AEs (skin reaction, liver damage, hypertension, proteinuria), serum interleukin-6, granulocytes expressing PD-1, vascular endothelial growth factor, angiopoietin-2, insulin-like growth factor-1, and circulating tumor DNA have been shown to be related to the outcome of Atez/Bev treatment. 44 Biomarkers of immune checkpoint inhibitor therapy reported include PD-L1, ratio of tissue-resident memory T cells to depleted CD8+ T cells in the tumor microenvironment, regulatory T cells, 11-gene signature, high expression of CD274, T-effector signature, and intertumoral CD8+ T cell density. 45 The present study aimed to construct a prognostic score that is easy to use in clinical practice and does not require examination of blood or tissue-based biomarkers.…”

Section: Clinical Features Of Present Cohortmentioning

confidence: 99%

Clinical usefulness of newly developed prognostic predictive score for atezolizumab plus bevacizumab for hepatocellular carcinoma

Ohama,

Hiraoka,

Tada

et al. 2024

Cancer Reports

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AimsThe aim of the present study was to elucidate detailed parameters for prediction of prognosis for patients with unresectable hepatocellular carcinoma (uHCC) receiving atezolizumab plus bevacizumab (Atez/Bev) treatment.MethodsA total of 719 patients (males 577, median age 74 years) treated with Atez/Bev between September 2020 and January 2023 were enrolled. Factors related to overall survival (OS) were extracted and a prognostic scoring system based on hazard ratio (HR) was created. OS and progression‐free survival (PFS) were retrospectively examined, and the prognostic ability of the newly developed system was compared to CRAFITY score using concordance index (c‐index) and Akaike information criterion (AIC) results.ResultsCox‐hazards multivariate analysis showed BCLC classification C/D (HR 1.4; 1 point), AFP ≥100 ng/mL (HR 1.4; 1 point), mALBI 2a (HR 1.7; 1 point), mALBI 2b/3 (HR 2.8; 2 points), and DCP ≥100 mAU/mL (HR 1.6; 1 point) as significant factors. The assigned points were added and used to develop the IMmunotherapy with AFP, BCLC staging, mALBI, and DCP evaluation (IMABALI‐De) scoring system. For IMABALI‐De scores of 0, 1, 2, 3, 4, and 5, OS was not applicable (NA), NA, 26.11, 18.79, 14.07, and 8.32 months, respectively (p < .001; AIC 2788.67, c‐index 0.699), while for CRAFITY scores of 0, 1, and 2, OS was 26.11, 20.29, and 11.32 months, respectively (p < .001; AIC 2864.54, c‐index 0.606). PFS periods for those IMABALI‐De scores were 21.75, 12.89, 9.18, 8.0, 5.0, and 3.75 months, respectively (p < .001; AIC 5203.32, c‐index 0.623) and for the CRAFITY scores were 10.32, 7.68, and 3.57 months, respectively (p < .001; AIC 5246.61, c‐index 0.574). As compared with CRAFITY score, IMABALI‐De score had better AIC and c‐index results for both OS and PFS.ConclusionThe present results indicated that the proposed IMABALI‐De score may be favorable for predicting prognosis of uHCC patients receiving Atez/Bev therapy.

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TKIs in combination with immunotherapy for hepatocellular carcinoma

Cited by 77 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

Clinical usefulness of newly developed prognostic predictive score for atezolizumab plus bevacizumab for hepatocellular carcinoma

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