Timed sequential treatment with cyclophosphamide, doxorubicin, and an allogeneic granulocyte-macrophage colony-stimulating factor - secreting breast tumor vaccine: A chemotherapy dose-ranging factorial study of safety and immune activation

Leisha A. Emens, Justin M. Asquith, James M. Leatherman, Barry J. Kobrin, Silvia Petrik, Marina Laiko, Joy Levi, Maithili M. Daphtary, Barbara Biedrzycki, Antonio C. Wolff, Vered Stearns, Mary L. Disis, Xiaobu Ye, Steven Piantadosi, John H. Fetting, Nancy E. Davidson, Elizabeth M. Jaffee

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Granulocyte-macrophage colony-stimulating factor (GM-CSF) -secreting tumor vaccines have demonstrated bioactivity but may be limited by disease burdens and immune tolerance. We tested the hypothesis that cyclophosphamide (CY) and doxorubicin (DOX) can enhance vaccine-induced immunity in patients with breast cancer. Patients and Methods: We conducted a 3 x 3 factorial (response surface) dose-ranging study of CY, DOX, and an HER2-positive, allogeneic, GM-CSF-secreting tumor vaccine in 28 patients with metastatic breast cancer. Patients received three monthly immunizations, with a boost 6 to 8 months from study entry. Primary objectives included safety and determination of the chemotherapy doses that maximize HER2-specific immunity. Results: Twenty-eight patients received at least one immunization, and 16 patients received four immunizations. No dose-limiting toxicities were observed. HER2-specific delayed-type hypersensitivity developed in most patients who received vaccine alone or with 200 mg/m2 CY. HER2-specific antibody responses were enhanced by 200 mg/m2 CY and 35 mg/m2 DOX, but higher CY doses suppressed immunity. Analyses revealed that CY at 200 mg/m2 and DOX at 35 mg/m2 is the combination that produced the highest antibody responses. Conclusion: First, immunotherapy with an allogeneic, HER2-positive, GM-CSF-secreting breast tumor vaccine alone or with CY and DOX is safe and induces HER2-specific immunity in patients with metastatic breast cancer. Second, the immunomodulatory activity of low-dose CY has a narrow therapeutic window, with an optimal dose not exceeding 200 mg/m2. Third, factorial designs provide an opportunity to identify the most active combination of interacting drugs in patients. Further investigation of the impact of chemotherapy on vaccine-induced immunity is warranted.

Original languageEnglish (US)
Pages (from-to)5911-5918
Number of pages8
JournalJournal of Clinical Oncology
Volume27
Issue number35
DOIs
StatePublished - Dec 10 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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