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         headline:Low-dose cyclophosphamide administered as daily or single dose enhances the antitumor effects of a therapeutic HPV vaccine
         description:Although therapeutic HPV vaccines are able to elicit systemic HPV-specific immunity, clinical responses have not always correlated with levels of vaccine-induced CD8+ T cells in human clinical trials. This observed discrepancy may be attributable to an immunosuppressive tumor microenvironment in which the CD8+ T cells are recruited. Regulatory T cells (Tregs) are cells that can dampen cytotoxic CD8+ T-cell function. Cyclophosphamide (CTX) is a systemic chemotherapeutic agent, which can eradicate immune cells, including inhibitory Tregs. The optimal dose and schedule of CTX administration in combination with immunotherapy to eliminate the Treg population without adversely affecting vaccine-induced T-cell responses is unknown. Therefore, we investigated various dosing and administration schedules of CTX in combination with a therapeutic HPV vaccine in a preclinical tumor model. HPV tumor-bearing mice received either a single preconditioning dose or a daily dose of CTX in combination with the pNGVL4a-CRT/E7(detox) DNA vaccine. Both single and daily dosing of CTX in combination with vaccine had a synergistic antitumor effect as compared to monotherapy alone. The potent antitumor responses were attributed to the reduction in Treg frequency and increased infiltration of HPV16 E7-specific CD8+ T cells, which led to higher ratios of CD8+/Treg and CD8+/CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs). There was an observed trend toward decreased vaccine-induced CD8+ T-cell frequency with daily dosing of CTX. We recommend a single, preconditioning dose of CTX prior to vaccination due to its efficacy, ease of administration, and reduced cumulative adverse effect on vaccine-induced T cells.
         datePublished:2012-08-04T00:00:00Z
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            name:Johns Hopkins School of Medicine
            address:
               name:Department of Oncology, Johns Hopkins School of Medicine, Baltimore, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Johns Hopkins Medical Institutions, Baltimore, USA
      name:Department of Pathology, Johns Hopkins School of Medicine, Baltimore, USA
      name:Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Johns Hopkins Medical Institutions, Baltimore, USA
      name:Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Johns Hopkins Medical Institutions, Baltimore, USA
      name:Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Johns Hopkins Medical Institutions, Baltimore, USA
      name:Department of Pathology, Johns Hopkins School of Medicine, Baltimore, USA
      name:Department of Oncology, Johns Hopkins School of Medicine, Baltimore, USA
      name:Ichor Medical Systems, Inc., San Diego, USA
      name:Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Johns Hopkins Medical Institutions, Baltimore, USA
      name:Milton J. Dance Jr. Head and Neck Center, Greater Baltimore Medical Center, Baltimore, USA
      name:Department of Pathology, Johns Hopkins School of Medicine, Baltimore, USA
      name:Department of Oncology, Johns Hopkins School of Medicine, Baltimore, USA
      name:Department of Obstetrics and Gynecology, Johns Hopkins School of Medicine, Baltimore, USA
      name:Department of Molecular Microbiology and Immunology, Johns Hopkins School of Medicine, Baltimore, USA
      name:Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Johns Hopkins Medical Institutions, Baltimore, USA
      name:Department of Oncology, Johns Hopkins School of Medicine, Baltimore, USA
WebPageElement:
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