Serum Vascular Endothelial Growth Factor and Fibronectin Predict Clinical Response to High-Dose Interleukin-2 Therapy

Abstract

Purpose High-dose interleukin-2 (IL-2) induces durable therapeutic responses in a small subset of patients with metastatic melanoma and renal cell carcinoma, but simple pretreatment predictors of response have not been identified. Patients and Methods To identify predictive biomarkers of clinical response, sera from patients treated with high-dose IL-2 were collected for analysis using a customized, multiplex antibody-targeted protein array platform that surveyed expression of soluble factors associated with tumor immunobiology. Soluble factors associated with clinical responses were analyzed using a multivariate permutation test, and survival outcomes were determined using Kaplan-Meier and log-rank tests. Results A training set from 10 patients identified 68 potentially relevant soluble factors that were then tested in an independent validation set of 49 patients. Class comparison revealed a cluster of 11 biomarkers that were associated with therapeutic outcome. Vascular endothelial growth factor (VEGF) and fibronectin were identified as independent predictors of response. In particular, high levels of these proteins were correlated with lack of clinical response and decreased overall survival. Conclusion Serum VEGF and fibronectin are easily measured pretreatment biomarkers that could serve to exclude patients unlikely to respond to IL-2 therapy.

Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model

“…12 Furthermore, high serum levels of VEGF in patients treated with interleukin-2 or ipilimumab are correlated with a lack of clinical response. 13,14 Proangiogenic factors suppress the function of immune cells at different levels, including inhibition of DC maturation, induction of an M2 phenotype in macrophages, inhibition of T-cell activation and recruitment of myeloid-derived suppressor cells (MDSCs). [15][16][17][18] Anti-angiogenic treatment was shown to mature and normalize the structure of intratumoral blood vessels, to enhance the leukocyte-endothelial interaction, to increase the number of tumor-infiltrating leukocytes and to reduce the number of MDSCs within the tumor.…”

'OMICS': state of the art in vitro techniques employed in surgical research

“…Samples of many fluids, such as blood or urine, can be obtained in considerable large amounts with minimal or non-invasive methods. For example, a recent analysis of sera from metastatic melanoma patients (10 patients in the discovery set and 49 patients in the validation set) identified a cluster of 11 biomarkers that could predict clinical response to IL-2 therapy [13]. A study with a total of 366 urine samples was able to identify and validate a set of 22 polypeptide masses which can be used in the diagnosis of urothelial carcinoma [14].…”

Immunothérapie des cancers

“…Expression tumorale une néoangiogenèse importante, ont été associées à une résistance à l'immunothérapie [19].…”