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

J Clin Oncol. 2009 Dec 10;27(35):5911-8. doi: 10.1200/JCO.2009.23.3494. Epub 2009 Oct 5.

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/m(2) CY. HER2-specific antibody responses were enhanced by 200 mg/m(2) CY and 35 mg/m(2) DOX, but higher CY doses suppressed immunity. Analyses revealed that CY at 200 mg/m(2) and DOX at 35 mg/m(2) 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/m(2). 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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / immunology
  • Breast Neoplasms / secondary
  • Breast Neoplasms / therapy*
  • CD4-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / adverse effects
  • Cancer Vaccines / genetics
  • Cell Line
  • Combined Modality Therapy
  • Cyclophosphamide / administration & dosage
  • Dose-Response Relationship, Drug
  • Doxorubicin / administration & dosage
  • Drug Administration Schedule
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis*
  • Granulocyte-Macrophage Colony-Stimulating Factor / blood
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Humans
  • Immunization Schedule
  • Immunotherapy, Adoptive*
  • Middle Aged
  • Receptor, ErbB-2 / immunology
  • Time Factors
  • Transfection
  • Treatment Outcome

Substances

  • Cancer Vaccines
  • Doxorubicin
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Cyclophosphamide
  • ERBB2 protein, human
  • Receptor, ErbB-2