title: Cytokine responsiveness of CD8(+) T cells is a reproducible biomarker for the clinical efficacy of dendritic cell vaccination in glioblastoma patients.
abstract: BACKGROUND
  Immunotherapeutic approaches, such as dendritic cell (DC) vaccination, have emerged as promising strategies in the treatment of glioblastoma. Despite their promise, however, the absence of objective biomarkers and/or immunological monitoring techniques to assess the clinical efficacy of immunotherapy still remains a primary limitation. To address this, we sought to identify a functional biomarker for anti-tumor immune responsiveness associated with extended survival in glioblastoma patients undergoing DC vaccination.
  
  
  METHODS
  28 patients were enrolled and treated in two different Phase 1 DC vaccination clinical trials at UCLA. To assess the anti-tumor immune response elicited by therapy, we studied the functional responsiveness of pre- and post-vaccination peripheral blood lymphocytes (PBLs) to the immunostimulatory cytokines interferon-gamma (IFN-γ) and interleukin-2 (IL-2) in 21 of these patients for whom we had adequate material. Immune responsiveness was quantified by measuring downstream phosphorylation events of the transcription factors, STAT-1 and STAT-5, via phospho-specific flow cytometry.
  
  
  RESULTS
  DC vaccination induced a significant decrease in the half-maximal concentration (EC-50) of IL-2 required to upregulate pSTAT-5 specifically in CD3(+)CD8(+) T lymphocytes (p < 0.045). Extended survival was also associated with an increased per cell phosphorylation of STAT-5 in cytotoxic T-cells following IL-2 stimulation when the median post/pre pSTAT-5 ratio was used to dichotomize the patients (p = 0.0015, log-rank survival; hazard ratio = 0.1834, p = 0.018). Patients whose survival was longer than two years had a significantly greater pSTAT-5 ratio (p = 0.015), but, contrary to our expectations, a significantly lower pSTAT-1 ratio (p = 0.038).
  
  
  CONCLUSIONS
  Our results suggest that monitoring the pSTAT signaling changes in PBL may provide a functional immune monitoring measure predictive of clinical efficacy in DC-vaccinated patients.
authors.affiliation: Departments of Neurosurgery, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Everson
authors.affiliation: Departments of Neurosurgery, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Jin
authors.affiliation: Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Departments of Neurosurgery, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Safaee
authors.affiliation: Departments of Neurosurgery, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Rudi
authors.initials: R
authors.lastname: Scharnweber
authors.affiliation: Departments of Neurosurgery, University of California Los Angeles, Los Angeles, CA 90095, USA.|Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Dominique N
authors.initials: DN
authors.lastname: Lisiero
authors.affiliation: Departments of Neurosurgery, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Horacio
authors.initials: H
authors.lastname: Soto
authors.affiliation: Departments of Neurosurgery, University of California Los Angeles, Los Angeles, CA 90095, USA.|Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA.|Brain Research Institute, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Liau
authors.affiliation: Departments of Neurosurgery, University of California Los Angeles, Los Angeles, CA 90095, USA.|Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA.|Brain Research Institute, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.|Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Prins
keywords: Dendritic cells; Glioblastoma; Phospho-flow cytometry; T cells; Tumor immunity; pSTAT-5