Association between circulating cytokines expression patterns and outcomes to immune-checkpoint (ICI)–based regimens in metastatic renal cell carcinoma (mRCC).
Authors: Linville Laura Meili , Feinaj Ardit , Nathani Kaizen , Singla Nirmish , Yarchoan Mark , Markowski Mark Christopher , Carducci Michael Anthony , Munjal Kabeer , Thoburn Christopher , Gizzi Jennifer , Kao Chester , Elias Roy , Ged Yasser 
Published: July 2024

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Background: ICI combinations (combos) in the form of dual ICI or ICI plus tyrosine kinase inhibitors (TKI) combos currently represent the most effective therapies in mRCC patients (pts). However, there is an unmet need to discover biomarkers predictive of clinical benefit to ICI combos. Circulating cytokines are important regulators of the immune system and may contribute to cancer immunotherapy outcomes. In mRCC, prior studies showed that baseline cytokines expression may influences outcomes to ICI monotherapy, but this association is unknown in ICI combos. Herein, we examined the association between circulating cytokines and ICI combos in mRCC. Methods: We prospectively collected baseline blood samples from mRCC pts receiving ICI combos at our institution. Circulating cytokine profile was assessed using a 32-plex cytokine assay. Baseline demographic, clinical characteristics, and treatment outcomes were collected from electronic health record review. IMDC risk categories were determined at ICI combo initiation. Clinical benefit was defined as radiologic partial response, complete response, or stable disease ≥ 12 months. Median cytokine concentration was used to stratify cytokine expression levels (high vs. low). Univariate and multivariate logistic regression was used to evaluate cytokines expression with time to next treatment (TNT). Results: A total of 29 mRCC pts who received ICI combos were included. 76% were men with a median age of 66 years (IQR 37-80) and 69% had clear cell tumors. ICI combos included ICI+ICI in 15 pts (52%) and ICI+TKI in 14 pts (42%). Poor-risk according to IMDC classification was positively associated with IL-6 (p= 0.03) and IL-8 (p=0.01) baseline expression, while intermediate-risk was positively associated with IL-22 expression (p=0.028). 38% of pts had clinical benefit from ICI combos in our cohort. Clinical benefit was negatively associated with IL-8 (p=0.04), IL-10 (p=0.03) and VEGF-alpha (p=0.03) baseline expression. Pts with high IL-6, IL-8, IL-10, and VEGF-Alpha baseline expression had a median TNT of 5.09 vs. 17.32 months (p= 0.07), 5.32 vs. 17.32 months (p =0.09), 5.32 vs. 25.59 months (p=0.04), and 3.77 vs. not reached (NR) (p=0.00), respectively. Among pts with intermediate risk mRCC, those with high VEGF-alpha and IL-6 expression had a median TNT of 5.07 months vs. NR (p=0.00), and 5.32 vs.17.32 month (p=0.002) respectively. In multivariate COX regression analysis VEGF-alpha expression was found to be an independent risk factor for TNT (HR, 2.56, 95% CI, 1.27-5.18; P = 0.009). Conclusions: Baseline expressions of IL-6, IL-8, IL-10 VEGF-alpha, may represent an important prognostic biomarker that can further risk stratify intermediate risk mRCC and predict clinical outcomes to ICI combos. Analysis of the association between ICI combo outcomes and post-treatment cytokine profiles is in progress.