title: Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients.
abstract: OBJECTIVE
  Dendritic cell (DC) vaccines have recently emerged as an innovative therapeutic option for glioblastoma patients. To identify novel surrogates of anti-tumor immune responsiveness, we studied the dynamic expression of activation and inhibitory markers on peripheral blood lymphocyte (PBL) subsets in glioblastoma patients treated with DC vaccination at UCLA.
  
  
  METHODS
  Pre-treatment and post-treatment PBL from 24 patients enrolled in two Phase I clinical trials of dendritic cell immunotherapy were stained and analyzed using flow cytometry. A univariate Cox proportional hazards model was utilized to investigate the association between continuous immune monitoring variables and survival. Finally, the immune monitoring variables were dichotomized and a recursive partitioning survival tree was built to obtain cut-off values predictive of survival.
  
  
  RESULTS
  The change in regulatory T cell (CD3(+)CD4(+)CD25(+)CD127(low)) frequency in PBL was significantly associated with survival (p = 0.0228; hazard ratio = 3.623) after DC vaccination. Furthermore, the dynamic expression of the negative co-stimulatory molecule, CTLA-4, was also significantly associated with survival on CD3(+)CD4(+) T cells (p = 0.0191; hazard ratio = 2.840) and CD3(+)CD8(+) T cells (p = 0.0273; hazard ratio = 2.690), while that of activation markers (CD25, CD69) was not. Finally, a recursive partitioning tree algorithm was utilized to dichotomize the post/pre fold change immune monitoring variables. The resultant cut-off values from these immune monitoring variables could effectively segregate these patients into groups with significantly different overall survival curves.
  
  
  CONCLUSIONS
  Our results suggest that monitoring the change in regulatory T cell frequencies and dynamic expression of the negative co-stimulatory molecules on peripheral blood T cells, before and after DC vaccination, may predict survival. The cut-off point generated from these data can be utilized in future prospective immunotherapy trials to further evaluate its predictive validity.
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Brendan
authors.initials: B
authors.lastname: Fong
authors.forename: Richard
authors.initials: R
authors.lastname: Jin
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Safaee
authors.forename: Dominique N
authors.initials: DN
authors.lastname: Lisiero
authors.forename: Isaac
authors.initials: I
authors.lastname: Yang
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Linda M
authors.initials: LM
authors.lastname: Liau
authors.forename: Robert M
authors.initials: RM
authors.lastname: Prins
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism*; D019496:Cancer Vaccines / Q000008:administration & dosage*; D002457:Cell Extracts / Q000276:immunology; D017321:Clinical Trials, Phase I as Topic; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D005260:Female; D005909:Glioblastoma / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D006801:Humans; D053208:Kaplan-Meier Estimate; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D016896:Treatment Outcome; D014611:Vaccination; D000520:alpha-Glucosidases / Q000276:immunology
chemical_list: D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D002457:Cell Extracts; C509951:GAA protein, human; D000520:alpha-Glucosidases