A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting breast tumor vaccine for HER2+ metastatic breast cancer

Gang Chen, Richa Gupta, Silvia Petrik, Marina Laiko, James M. Leatherman, Justin M. Asquith, Maithili M. Daphtary, Elizabeth Garrett-Mayer, Nancy E. Davidson, Kellie Hirt, Maureen Berg, Jennifer Uram, Tianna Dauses, John H Fetting, Elizabeth M. Duus, Saadet Atay-Rosenthal, Xiaobu Ye, Antonio C Wolff, Vered Stearns, Elizabeth JaffeeLeisha A. Emens

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)949-961
Number of pages13
JournalCancer immunology research
Volume2
Issue number10
DOIs
StatePublished - Oct 1 2014

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ASJC Scopus subject areas

  • Medicine(all)

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Chen, G., Gupta, R., Petrik, S., Laiko, M., Leatherman, J. M., Asquith, J. M., Daphtary, M. M., Garrett-Mayer, E., Davidson, N. E., Hirt, K., Berg, M., Uram, J., Dauses, T., Fetting, J. H., Duus, E. M., Atay-Rosenthal, S., Ye, X., Wolff, A. C., Stearns, V., ... Emens, L. A. (2014). A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting breast tumor vaccine for HER2+ metastatic breast cancer. Cancer immunology research, 2(10), 949-961. https://doi.org/10.1158/2326-6066.CIR-14-0058