4.6 Article

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

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PLOS ONE
卷 7, 期 4, 页码 -

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PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0032614

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资金

  1. NIH/NCI [K01-CA111402, RO1-CA123396, R01 CA 112358]
  2. Brad Kaminsky Foundation
  3. Cranium Crusaders
  4. Miles for Hope Foundation
  5. Northwest Biotherapeutics, Inc.
  6. Eli & Edyth Broad Center of Regenerative Medicine and Stem Cell Research at UCLA
  7. STOP Cancer Foundation
  8. Ben & Catherine Ivy Foundation
  9. American Brain Tumor Association
  10. NIH [CA16042]

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Purpose: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. Experimental Design: 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.

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