Peripheral blood cytokines and outcomes with immune checkpoint blockade: a systematic review and meta-analysis

Background: Tumor-promoting inflammation and inflammatory cytokines are linked to immune checkpoint blockade (ICB) resistance. Methods: We assessed the associations between pre-treatment Interleukin-6 (IL-6), Interleukin-8 (IL-8) levels and on-treatment changes in IL-6, IL-8 and C-reactive protein (CRP) with ICB trial end points. Results: 27 studies representing 6,719 patients were included. Low pre-treatment IL-6 levels were associated with improved objective response rate (ORR) (odds ratio (OR) = 0.31 [0.18–0.55]) and better progression-free survival (PFS) (hazard ratio (HR) = 0.59 [0.48–0.72]) and overall survival (OS) [95% confidence interval (CI)] (HR = 0.42 [0.35–0.50]). Low pre-treatment IL-8 levels were associated with improved ORR (OR = 0.47 [0.36–0.61]) and better PFS (HR = 0.65 [0.58–0.74]) and OS (HR = 0.44 [0.39–0.51]). On-treatment decline in CRP was associated with improved ORR (OR = 0.18 [0.11–0.20]), PFS (HR = 0.40 [0.31–0.91]) and OS (HR = 0.48 [0.40–0.58]). Conclusion: Peripheral blood cytokines warrant further evaluation as enrichment and pharmacodynamic biomarkers for strategies targeting tumor-promoting inflammation.