Circulating cytokines associated with clinical response to systemic therapy in metastatic renal cell carcinoma

Abstract

Background: Circulating cytokines and angiogenic factors have been associated with clinical outcomes in patients with metastatic renal cell carcinoma (RCC) receiving systemic therapy. However, none have yet examined cytokine concentrations in parallel cohorts receiving either immunotherapy or targeted therapy.

Methods: In this prospective correlative study, we enrolled 56 patients who were planned for treatment with either a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or immune checkpoint inhibitor (ICI). Eligibility requirements permitted any RCC histologic subtype, International Metastatic Renal Cell Carcinoma risk classification, and line of therapy. Immunologic profile was assessed at baseline and after 1 month on treatment using a Human Cytokine 30-plex protein assay (Invitrogen). Clinical benefit was defined as complete response, partial response, or stable disease ≥6 months per RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria.

Results: Clinical benefit was similar between VEGF-TKI and ICI arms (65% vs 54%). Patients with clinical benefit from VEGF-TKIs had lower pretreatment levels of interleukin-6 (IL-6) (p=0.02), IL-1RA (p=0.03), and granulocyte colony-stimulating factor (CSF) (p=0.02). At 1 month, patients with clinical benefit from ICIs had higher levels of interferon-γ (IFN-γ) (p=0.04) and IL-12 (p=0.03). Among patients on VEGF-TKIs, those with clinical benefit had lower 1 month IL-13 (p=0.02) and granulocyte macrophage CSF (p=0.01) as well as higher 1 month VEGF (p=0.04) compared with patients with no clinical benefit.

Conclusion: For patients receiving VEGF-TKI or ICI therapy, distinct plasma cytokines were associated with clinical benefit. Our findings support additional investigation into plasma cytokines as biomarkers in metastatic RCC.

Keywords: biomarkers; cytokines; immunotherapy; tumor.

Figure 1

Associations between clinical benefit from vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) therapy and pretreatment interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and IL-1RA. Box contains values q1, median and q2. Whiskers expand out to 10th and 90th percentiles. P values are from the Wilcoxon rank-sum test. CB, clinical benefit; NCB, no clinical benefit.

Figure 2

Associations between on-treatment cytokine changes and clinical benefit either vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or immune checkpoint inhibitor (ICI) therapy. Box contains values q1, median and q2. Whiskers expand out to 10th and 90th percentiles. P values are from the Wilcoxon rank-sum test. CB, clinical benefit; GM-CSF, granulocyte macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; NCB, no clinical benefit.