A Feasibility Study of Cyclophosphamide, Trastuzumab, and an Allogeneic GM-CSF-Secreting Breast Tumor Vaccine for HER2+ Metastatic Breast Cancer

被引:72
作者
Chen, Gang [1 ,2 ]
Gupta, Richa [1 ,2 ]
Petrik, Silvia [1 ,2 ]
Laiko, Marina [1 ,2 ]
Leatherman, James M. [1 ,2 ]
Asquith, Justin M. [1 ,2 ]
Daphtary, Maithili M. [1 ,2 ]
Garrett-Mayer, Elizabeth [9 ]
Davidson, Nancy E. [10 ,11 ]
Hirt, Kellie [1 ,2 ]
Berg, Maureen [1 ,2 ]
Uram, Jennifer N. [1 ,2 ]
Dauses, Tianna [1 ,2 ]
Fetting, John [1 ,2 ]
Duus, Elizabeth M. [1 ,2 ]
Atay-Rosenthal, Saadet [1 ,2 ]
Ye, Xiaobu [1 ,2 ,5 ]
Wolff, Antonio C. [1 ,2 ]
Stearns, Vered [1 ,2 ]
Jaffee, Elizabeth M. [1 ,2 ,3 ,4 ,7 ,8 ]
Emens, Leisha A. [1 ,2 ,6 ]
机构
[1] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA
[2] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA
[3] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21231 USA
[4] Johns Hopkins Univ, Sch Med, Dept Pharmacol, Baltimore, MD 21231 USA
[5] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21231 USA
[6] Johns Hopkins Univ, Sch Med, Program Pathobiol, Baltimore, MD 21231 USA
[7] Johns Hopkins Univ, Sch Med, Program Immunol, Baltimore, MD USA
[8] Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med, Baltimore, MD USA
[9] Med Univ S Carolina, Charleston, SC 29425 USA
[10] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA
[11] UPMC, Ctr Canc, Pittsburgh, PA USA
关键词
REGULATORY T-CELLS; ANTITUMOR IMMUNE-RESPONSE; PHASE-II TRIAL; MELANOMA PATIENTS; HYPERSENSITIVITY RESPONSE; MONOCLONAL-ANTIBODIES; PROLONGED SURVIVAL; SUPPRESSOR-CELLS; TRANSGENIC MICE; IMMUNOTHERAPY;
D O I
10.1158/2326-6066.CIR-14-0058
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccines are bioactive, but limited by disease burden and immune tolerance. Cyclophosphamide augments vaccine activity in tolerant neu mice and in patients with metastatic breast cancer. HER2-specific monoclonal antibodies (mAb) enhance vaccine activity in neu mice. We hypothesized that cyclophosphamide-modulated vaccination with HER2-specific mAb safely induces relevant HER2-specific immunity in neu mice and patients with HER2(+) metastatic breast cancer. Adding both cyclophosphamide and the HER2-specific mAb 7.16.4 to vaccination maximized HER2-specific CD8(+) T-cell immunity and tumor-free survival in neu transgenic mice. We, therefore, conducted a single-arm feasibility study of cyclophosphamide, an allogeneic HER2(+) GM-CSF-secreting breast tumor vaccine, and weekly trastuzumab in 20 patients with HER2(+) metastatic breast cancer. Primary clinical trial objectives were safety and clinical benefit, in which clinical benefit represents complete response + partial response + stable disease. Secondary study objectives were to assess HER2-specific T-cell responses by delayed type hypersensitivity (DTH) and intracellular cytokine staining. Patients received three monthly vaccinations, with a boost 6 to 8 months from trial entry. This combination immunotherapy was safe, with clinical benefit rates at 6 months and 1 year of 55% [95% confidence interval (CI), 32%-77%; P = 0.013] and 40% (95% CI, 19%-64%), respectively. Median progression-free survival and overall survival durations were 7 months (95% CI, 4-16) and 42 months (95% CI, 22-70), respectively. Increased HER2-specific DTH developed in 7 of 20 patients [of whom 4 had clinical benefit (95% CI, 18-90)], with a trend toward longer progression-free survival and overall survival in DTH responders. Polyfunctional HER2-specific CD8(+) T cells progressively expanded across vaccination cycles. Further investigation of cyclophosphamide-modulated vaccination with trastuzumab is warranted. (C)2014 AACR.
引用
收藏
页码:949 / 961
页数:13
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