Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy.
OBJECTIVE
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.


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.


CONCLUSIONS
Serum VEGF and fibronectin are easily measured pretreatment biomarkers that could serve to exclude patients unlikely to respond to IL-2 therapy.
Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Warren G Magnuson Clinical Center, NIH, Bethesda, MD, USA.
Marianna
M
Sabatino
Seunghee
S
Kim-Schulze
Monica C
MC
Panelli
David
D
Stroncek
Ena
E
Wang
Bret
B
Taback
Dae Won
DW
Kim
Gail
G
Deraffele
Zoltan
Z
Pos
Francesco M
FM
Marincola
Howard L
HL
Kaufman
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D016000:Cluster Analysis; D005260:Female; D005353:Fibronectins / Q000097:blood*; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D008875:Middle Aged; D018579:Patient Selection; D011237:Predictive Value of Tests; D011446:Prospective Studies; D040901:Proteomics; D011994:Recombinant Proteins / Q000627:therapeutic use; D015203:Reproducibility of Results; D018570:Risk Assessment; D012878:Skin Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D017211:Treatment Failure; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D055815:Young Adult
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D005353:Fibronectins; C508594:IL2 protein, human; D007376:Interleukin-2; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A