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

• Published in: PloS one 2012-04, Vol.7 (4), p.e32614-e32614
• Main Authors: Fong, Brendan, Jin, Richard, Wang, Xiaoyan, Safaee, Michael, Lisiero, Dominique N, Yang, Isaac, Li, Gang, Liau, Linda M, Prins, Robert M
• Format: Article
• Language: English
• Subjects: Adult; Aged; Algorithms; alpha-Glucosidases - immunology; Antigens; B cells; Biology; Blood; Brain cancer; Brain Neoplasms - mortality; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Brain research; Cancer therapies; Cancer Vaccines - administration & dosage; CD25 antigen; CD3 antigen; CD4 antigen; CD69 antigen; CD8 antigen; Cell activation; Cell Extracts - immunology; Cell survival; Chemotherapy; Clinical trials; Clinical Trials, Phase I as Topic; Continuity (mathematics); CTLA-4 Antigen - genetics; CTLA-4 Antigen - metabolism; CTLA-4 protein; Cytokines; Cytometry; Data processing; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - transplantation; Drug dosages; Experimental design; Female; Flow cytometry; Glioblastoma; Glioblastoma - mortality; Glioblastoma - pathology; Glioblastoma - therapy; Gliomas; Hazards; Health hazards; Humans; Immunoregulation; Immunotherapy; Kaplan-Meier Estimate; Lymphocyte Activation; Lymphocyte Count; Lymphocyte Subsets; Lymphocytes; Lymphocytes T; Male; Markers; Medical innovations; Medical prognosis; Medical research; Medicine; Melanoma; Middle Aged; Monitoring; Neurosurgery; Partitioning; Patient outcomes; Patients; Peripheral blood; Pretreatment; Prognosis; Proportional Hazards Models; Statistical models; Survival; T cell receptors; T cells; T-Lymphocytes, Regulatory - metabolism; Treatment Outcome; Trees; Tumors; Two phase; Vaccination; Vaccines
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0032614

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. 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. 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. 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.