title: 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: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. emensle@jhmi.edu
authors.forename: Leisha A
authors.initials: LA
authors.lastname: Emens
authors.forename: Justin M
authors.initials: JM
authors.lastname: Asquith
authors.forename: James M
authors.initials: JM
authors.lastname: Leatherman
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Kobrin
authors.forename: Silvia
authors.initials: S
authors.lastname: Petrik
authors.forename: Marina
authors.initials: M
authors.lastname: Laiko
authors.forename: Joy
authors.initials: J
authors.lastname: Levi
authors.forename: Maithili M
authors.initials: MM
authors.lastname: Daphtary
authors.forename: Barbara
authors.initials: B
authors.lastname: Biedrzycki
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
authors.forename: Xiaobu
authors.initials: X
authors.lastname: Ye
authors.forename: Steven
authors.initials: S
authors.lastname: Piantadosi
authors.forename: John H
authors.initials: JH
authors.lastname: Fetting
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jaffee
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000235:genetics; D002460:Cell Line; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D006801:Humans; D007115:Immunization Schedule; D016219:Immunotherapy, Adoptive; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D019496:Cancer Vaccines; D003520:Cyclophosphamide; D004317:Doxorubicin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human