A Feasibility Study of Cyclophosphamide, Trastuzumab, and an Allogeneic GM-CSF-secreting Breast Tumor Vaccine for HER-2+ Metastatic Breast Cancer
| Autor: | Tianna Dauses, Vered Stearns, Jennifer N. Uram, Elizabeth Garrett-Mayer, Gang Chen, Saadet Atay-Rosenthal, Justin M. Asquith, Nancy E. Davidson, Elizabeth M. Jaffee, Maithili M. Daphtary, Leisha A. Emens, Elizabeth M. Duus, Maureen Berg, Richa Gupta, Kellie Hirt, John H. Fetting, James M. Leatherman, Silvia Petrik, Xiaobu Ye, Marina Laiko, Antonio C. Wolff |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Oncology
Adult Cancer Research medicine.medical_specialty Cyclophosphamide Receptor ErbB-2 Immunology Antineoplastic Agents Breast Neoplasms Mice Transgenic CD8-Positive T-Lymphocytes Antibodies Monoclonal Humanized Cancer Vaccines Article Trastuzumab Immunity Internal medicine Cell Line Tumor medicine Animals Humans Hypersensitivity Delayed Neoplasm Metastasis skin and connective tissue diseases Survival analysis Aged business.industry Granulocyte-Macrophage Colony-Stimulating Factor Middle Aged medicine.disease Metastatic breast cancer Combined Modality Therapy Survival Analysis Clinical trial Vaccination Monoclonal Feasibility Studies Female business medicine.drug |
| Popis: | 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. (Clinicaltrials.gov identifier: NCT00399529) Cancer Immunol Res; 2(10); 949–61. ©2014 AACR. |
| Databáze: | OpenAIRE |
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