title: A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting breast tumor vaccine for HER2+ metastatic breast cancer.
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.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Richa
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Petrik
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Marina
authors.initials: M
authors.lastname: Laiko
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: James M
authors.initials: JM
authors.lastname: Leatherman
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Asquith
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Maithili M
authors.initials: MM
authors.lastname: Daphtary
authors.affiliation: Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.affiliation: University of Pittsburgh Cancer Institute and UPMC CancerCenter, Pittsburgh, Pennsylvania.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Kellie
authors.initials: K
authors.lastname: Hirt
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Maureen
authors.initials: M
authors.lastname: Berg
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Uram
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Tianna
authors.initials: T
authors.lastname: Dauses
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: John
authors.initials: J
authors.lastname: Fetting
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Duus
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Saadet
authors.initials: S
authors.lastname: Atay-Rosenthal
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Xiaobu
authors.initials: X
authors.lastname: Ye
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Program in Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jaffee
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Program in Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland. emensle@jhmi.edu.
authors.forename: Leisha A
authors.initials: LA
authors.lastname: Emens
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D005240:Feasibility Studies; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D008822:Mice, Transgenic; D008875:Middle Aged; D009362:Neoplasm Metastasis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D016019:Survival Analysis; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D003520:Cyclophosphamide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab