Increased Circulating Levels of CRP and IL-6 and Decreased Frequencies of T and B Lymphocyte Subsets Are Associated With Immune-Related Adverse Events During Combination Therapy With PD-1 Inhibitors for Liver Cancer

Abstract

BackgroundProgrammed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune-related adverse events (irAEs) are inevitable in patients with liver cancer. Although the incidence of severe irAEs is low, but can result in fatal consequences. To date, only a few commonly used clinical biomarkers have been reported.AimTo assess commonly used clinical biomarkers associated with the occurrence of irAEs to enable better management of irAEs by clinicians.MethodsWe retrospectively reviewed patients with liver cancer treated with at least one cycle of PD-1 immune checkpoint inhibitors (ICIs) combined with tyrosine kinase inhibitors (TKIs). IrAEs were documented according to the common terminology criteria for adverse events version 5. Clinical and laboratory parameters were also evaluated.ResultsA total of 67 patients were included, 36 with irAEs and 31 without irAEs. A total of 104 adverse events occurred; 83 of these events were grade 1/2 (G1/G2), 21 were grade 3/4 (G3/G4), and one died of G4 hepatitis. Patients with irAEs had higher levels of C-reactive protein (CRP) and interleukin-6 (IL-6) and lower levels of lymphocyte subsets, except natural killer (NK) cell counts, than those without irAEs (P <0.05). Patients who experienced G3/G4 irAEs had higher levels of CRP and IL-6 and lower levels of CD4+ T lymphocytes and B lymphocytes than those who experienced G1/G2 irAEs (P <0.05). Of note, impairments in liver function and routine blood tests were also observed (P <0.05). The results of univariate and multivariate analyses for any grade of irAEs revealed that the combination of sintilimab and lenvatinib (P= 0.004, odds ratio [OR]: 7.414, 95% confidence interval [95% CI]: 1.925–28.560) and CRP ≥8.2 mg/L (P= 0.024, OR: 3.727, CI: 1.185–11.726) were independent risk factors. Univariate and multivariate analyses of the risk factors of G3/G4 irAEs suggested that the combination of sintilimab and lenvatinib was a potential risk factor (P = 0.049, OR: 8.242, CI: 1.006–67.532).ConclusionChanges in patient CRP, IL-6, and lymphocyte subsets were associated with irAE onset and may act as potential biomarkers of irAEs. Impairments in liver function and routine blood tests owing to the occurrence of irAEs may become new concerns for clinicians.

Checkpoint inhibitor immune-related adverse events: A focused review on autoantibodies and B cells as biomarkers, advancements and future possibilities

“…A similar increase in CD21 lo B cells after the first cycle of combination therapy, was reported in 23 renal cell carcinoma patients who experienced irAEs ( 117 ). Liver cancer patients treated with anti-PD-1 and tyrosine kinase inhibitors also showed decrease B cells in severe irAE patients ( 118 ).…”

Abdominal pain accompanied by elevated serum inflammatory markers and biliary enzymes for diagnosing immune checkpoint inhibitor-induced sclerosing cholangitis

“…[22] [23] Regarding HCC treatment with anti-PD-1 Ab, the severity of irAEs is positively correlated with CRP and IL-6 and negatively correlated with the frequency of T and B lymphocyte subsets. [24] Our study found that CRP and NLR levels at the onset of liver-irAEs were higher in the irSC group. IL-6, which triggers the synthesis of is an in ammatory cytokine that plays an important role in immune processes and is involved in a variety of diseases including cancer.…”

Role of B cells in immune‐related adverse events following checkpoint blockade

“…Importantly, the changes in B cells preceded the development of clinical complications suggesting that they may be useful biomarkers for the initiation of preventive intervention or closer monitoring. Other studies in patients with liver cancer, renal cell cancer, or lung cancer patients have also described correlations between irAEs and similar changes in B cells including increase in CD21 lo B cells and plasmablasts in patients undergoing PD1 blockade or combination CTLA4 and PD1 checkpoint blockade 55–58 . Together, these studies support a possible role for B cells and particularly the CD21 lo Tbet + subset of human B cells in the pathogenesis of irAEs.…”

“…Several studies have now reported a correlation between therapy‐induced changes in B cells or plasmablasts and increased risk for the development of irAEs 54–58 . One of the earliest studies in this regard was by Das et al, who studied patients with melanoma undergoing combination checkpoint blockade 54 .…”