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.

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.

• Authors: 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
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 27 Issue 35 Pg. 5911-8 (Dec 10 2009) ISSN: 1527-7755 [Electronic] United States
• PMID: 19805669 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

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

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Breast Neoplasms (drug therapy, immunology, secondary, therapy)
• CD4-Positive T-Lymphocytes (immunology)
• Cancer Vaccines (administration & dosage, adverse effects, 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, blood, genetics)
• Humans
• Immunization Schedule
• Immunotherapy, Adoptive
• Middle Aged
• Receptor, ErbB-2 (immunology)
• Time Factors
• Transfection
• Treatment Outcome