High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma

Yang, Hannah; Kang, Beodeul; Ha, Yeonjung; Lee, Sung Hwan; Kim, Ilhwan; Kim, Hye-Yeong; Lee, Won Suk; Kim, Gwangil; Jung, Sanghoon; Rha, Sun Young; Gaillard, Vincent E.; Cheon, Jaekyung; Kim, Chan; Chon, Hong Jae

doi:10.1016/j.jhepr.2023.100672

Cited by 38 publications

(30 citation statements)

References 41 publications

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“…We were able to identify that patients with thyrotoxicosis had a lower level of baseline IL-6. This is consistent with our previous finding that high baseline IL-6 levels can be associated with reduced clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment [25].…”

Section: Discussionsupporting

confidence: 93%

“…We were able to identify that patients with thyrotoxicosis had a lower level of baseline IL-6. This is Song/Yang/Kang/Cheon/Kim/Kim/Lee/ Sang/Jung/Lim/Gaillard/Kim/Chon consistent with our previous finding that high baseline IL-6 levels can be associated with reduced clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment [25]. We found a favorable survival outcome in patients with thyroid AEs through univariate and multivariate analyses in a large multicenter cohort and IMbrave150 validation cohort.…”

Section: Discussionsupporting

confidence: 89%

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Thyroid Dysfunction after Atezolizumab and Bevacizumab Is Associated with Favorable Outcomes in Hepatocellular Carcinoma

Song¹,

Yang²,

Kang³

et al. 2023

Liver Cancer

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Introduction: Atezolizumab and bevacizumab (Ate/Bev) combination has become the new first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). Although several studies reported thyroid dysfunction after treatment with immune checkpoint inhibitors, the clinical and immunological significance of thyroid dysfunction in patients treated with Ate/Bev has not been comprehensively addressed. We aimed to comprehensively evaluate the clinical and immunological implications of thyroid dysfunction in unresectable HCC patients treated with Ate/Bev. Methods: We enrolled 208 patients with unresectable HCC treated with Ate/Bev from three Korean cancer centers. Thyroid adverse events (AEs) were reviewed, and cytokines and T cells in the blood samples were analyzed at baseline. For external validation, we analyzed clinical outcomes according to thyroid AEs in patients treated with Ate/Bev in the IMbrave150 study. Results: Forty-one (19.7%) out of 208 patients experienced thyroid dysfunction (hypothyroidism [17.3%] and thyrotoxicosis [5.8%]) after Ate/Bev treatment. Median time to onset of hypothyroidism and thyrotoxicosis after Ate/Bev treatment was 3.5 and 1.3 months, respectively. Patients with thyroid AEs demonstrated significantly better progression-free survival, overall survival, and objective response rate than those without thyroid AEs. These findings were still consistent even after adjusting for confounding factors. Furthermore, favorable survival outcomes in patients with thyroid AEs were also validated in a cohort of IMbrave150 patients. While patients with thyrotoxicosis showed a significantly lower level of baseline IL-6, those with hypothyroidism did not show significant differences in circulating cytokine levels and CD8+ T-cell fractions. Conclusions: A fraction of patients with HCC treated with Ate/Bev experienced thyroid dysfunction, and the development of thyroid AEs was associated with favorable clinical outcomes.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 89%

Thyroid Dysfunction after Atezolizumab and Bevacizumab Is Associated with Favorable Outcomes in Hepatocellular Carcinoma

Song¹,

Yang²,

Kang³

et al. 2023

Liver Cancer

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“…Serum IL-10 concentration was measured according to the manual provided by the CBA human Th1/Th2/Th17 Cytokine kit (BD bioscience), as described previously 31 . Briefly, the capture beads and detection reagents were incubated with the patient's serum at room temperature for approximately 2 h and 30 min and then washed.…”

Section: Methodsmentioning

confidence: 99%

“…For intracellular staining, cells were permeabilized using a FoxP3 Fixation and Permeabilization Kit (eBioscience). T cell activation and proliferation assays followed the previous protocols 31 , 40 . Cells were stained with interferon (IFN)- (clone B27, BD Biosciences), tumor necrosis factor (TNF)- (clone MAB11, BD Biosciences), and Ki-67 (clone Ki-67, BioLegend).…”

Section: Methodsmentioning

confidence: 99%

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High levels of baseline serum IL-10 are associated with reduced clinical benefit from first-line immune checkpoint inhibitor therapy in advanced renal cell carcinoma

Kim¹,

Yang²,

Lee³

et al. 2023

J. Cancer

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Immune checkpoint inhibitor (ICI) became a standard treatment for advanced renal cell carcinoma (RCC). However, clinically valid biomarkers of therapeutic outcome are lacking. We investigated the role of interleukin-10 (IL-10) as a predictive biomarker for first-line ICI therapy in patients with advanced RCC. Baseline serum samples were prospectively collected and analyzed using a cytometric bead assay. Patients were divided into two groups according to their serum IL-10 levels using maximally selected rank statistics. A fraction (13.0%) of patients had high levels of serum IL-10 at baseline. High serum IL-10 levels (> 4.3 ng/mL) were associated with a significantly shorter progression-free (median: 5.2 months vs. not reached, P = 0.007) and overall survival (median: 13.9 months vs. not reached, P < 0.001). Multivariate Cox regression analysis confirmed the independent association between high serum IL-10 levels and poor survival outcomes. Effector cytokine production and the proliferative response of CD8 + T cells were significantly lower in patients with high serum IL-10 levels, who also had a shorter duration of response to first-line ICI therapy (4.6 months vs. not reached, P < 0.001). In conclusion, elevated serum IL-10 levels at baseline were associated with reduced clinical benefit from first-line ICI therapy in patients with advanced RCC.

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Serum CXCL10 levels at the start of the second course of atezolizumab plus bevacizumab therapy predict therapeutic efficacy in patients with advanced BCLC stage C hepatocellular carcinoma: A multicenter analysis

Suzuki,

Matsuura,

Suzuki

et al. 2023

Cancer Medicine

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Background & AimsRelationships of serum C‐C motif chemokine ligand 5 (CCL5) and C‐X‐C motif chemokine ligand 10 (CXCL10) levels with hot immune features have been reported in patients with hepatocellular carcinoma (HCC). Therefore, we examined the utility of their levels for predicting the efficacy of atezolizumab plus bevacizumab (Atez/Bev) in patients with HCC.DesignIn total, 98 patients with HCC treated with Atez/Bev were enrolled, and their initial responses were evaluated at least once via dynamic computed tomography or magnetic resonance imaging. Serum CCL5 and CXCL10 levels were assessed by enzyme‐linked immunosorbent assay before treatment and at the start of the second course of Atez/Bev therapy, and their relationships with treatment efficacy were determined.ResultsNo analyzed factor was associated with the initial therapeutic response. Among the 56 patients with Barcelona Clinic Liver Cancer (BCLC) stage C, serum CXCL10 levels at the beginning of course two (CXCL10‐2c) tended to be higher in responders than in non‐responders in the initial evaluation, and its optimal cutoff level of 690 pg/mL could be used to stratify patients regarding overall survival (OS; high vs. low: not reached vs. 17.6 months, p = 0.034) and progression‐free survival (high vs. low: 13.6 vs. 5.1 months, p = 0.014). In multivariate analysis, high CXCL10 levels and neutrophil‐to‐lymphocyte ratios at the start of course two and Child–Pugh stage A at baseline were independent predictive factors of improved OS.ConclusionsSerum CXCL10‐2c levels were predictive of Atez/Bev efficacy in patients with BCLC stage C HCC.

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High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma

Cited by 38 publications

References 41 publications

Thyroid Dysfunction after Atezolizumab and Bevacizumab Is Associated with Favorable Outcomes in Hepatocellular Carcinoma

Thyroid Dysfunction after Atezolizumab and Bevacizumab Is Associated with Favorable Outcomes in Hepatocellular Carcinoma

High levels of baseline serum IL-10 are associated with reduced clinical benefit from first-line immune checkpoint inhibitor therapy in advanced renal cell carcinoma

Serum CXCL10 levels at the start of the second course of atezolizumab plus bevacizumab therapy predict therapeutic efficacy in patients with advanced BCLC stage C hepatocellular carcinoma: A multicenter analysis

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