Circulating Regulatory T Cells (Cd4(+)Cd25(High) Cd127(Low)) Decrease In Breast Cancer Patients After Vaccination With A Modified Her-2/Neu Hla Class Ii Peptide (Ae37) Vaccine
CANCER RESEARCH(2011)
摘要
Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL
BACKGROUND : Regulatory T cells (TReg) are elevated in breast cancer patients with the number of TReg cells being inversely associated with clinical outcome. We are conducting a prospective, randomized phase II trial of the HER-2/ neu peptide vaccines GP2 and AE37. GP2 is an HLA-A2+ -restricted peptide (HER-2/ neu aa: 654–662) capable of eliciting a CD8+ cytotoxic T cell response directed against HER-2/ neu expressing tumors. AE37 is the Ii-Key hybrid of the HER-2/ neu peptide AE36 (HER-2/ neu aa:776–790) and is capable of stimulating CD4+ helper T-cells with anti-tumor activity. Given the ability of AE37 to activate CD4+ helper T cells, concern exists that unwanted stimulation of TReg cells may occur with vaccination; although, this was not seen in our phase I trial. We have sought to confirm this finding by evaluating peripheral TReg cell levels in patients from our larger phase II breast cancer vaccine trial.
METHODS : Node positive or high-risk node negative breast cancer patients with any level of HER-2/ neu expression rendered disease-free by standard treatments were enrolled. HLA-A2+ patients were placed in the GP2 arm and randomized to either GP2 + GM-CSF (immunoadjuvant) or GM-CSF alone. HLA-A2− patients were placed in the AE37 arm and randomized to either AE37 + GM-CSF or GM-CSF alone. Vaccinations were given as six monthly intradermal inoculations. CD4+CD25high CD127low (CD127low) TReg cell levels were measured before (R0), mid-series (R3), upon completion (R6), and at six (RC6) and twelve (RC12) months after completion of the vaccine series using antibody staining and flow cytometry analysis. p values were calculated using the Student's t -test.
RESULTS : TReg cells were measured in 65 patients in the AE37 arm (34 vaccine, 31 adjuvant) and 33 patients in the GP2 arm (17 vaccine, 16 adjuvant). Patients receiving the AE37 vaccine exhibited a decrease in CD127low TReg cells from baseline at all measured timepoints (R0=4.2, R3=3.7, p<0.01 ; R6=3.7, p=0.01 ; RC6=3.5, p<0.01 ; RC12=3.7, p<0.00001 ) while the randomized adjuvant patients demonstrated no decrease at any time point except from R0 to R3 (R0=4.3, R3=3.6, p=0.02 ; R6=4.1, p=0.58 ; RC6=3.9, p=0.06 ; RC12=3.9, p=0.21 ). In the GP2 arm, CD127low TReg cell levels did not change for either GP2 vaccinated patients (R0=3.6, R3=3.7, p=0.47 ; R6=4.1, p=0.67 ; RC6=4.3, p=0.56 ; RC12=4.3, p=0.16 ) or in randomized adjuvant patients (R0=4.4, R3=4.0, p=0.58 ; R6=4.4, p=0.95 ; RC6=3.8, p=0.25 ; RC12, p=0.59 ).
CONCLUSIONS : Administration of a CD4 T cell-eliciting HER-2/ neu peptide (AE37) vaccine to breast cancer patients induced a sustained decrease in circulating CD127low TReg cells. No such decrease was seen in randomized adjuvant-treated patients. Use of the CD8-eliciting, GP2 vaccine did not change circulating TReg cell levels.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-413. doi:10.1158/1538-7445.AM2011-LB-413
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关键词
vaccination,breast cancer,breast cancer patients,peptide
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