Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 4, Issue 134, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3003330
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Funding
- NIH [CA111377]
- Juvenile Diabetes Research Foundation (JDRF) Collaborative Centers for Cell Therapy and the JDRF Center on Cord Blood Therapies for Type 1 Diabetes
- Breast Cancer Research Foundation
- Abramson Family Cancer Research Institute
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Regulatory T cells (T-regs) are key mediators of immune tolerance and feature prominently in cancer. Depletion of CD25(+) FoxP3(+) T-regs in vivo may promote T cell cancer immunosurveillance, but no strategy to do so in humans while preserving immunity and preventing autoimmunity has been validated. We evaluated the Food and Drug Administration-approved CD25-blocking monoclonal antibody daclizumab with regard to human T-reg survival and function. In vitro, daclizumab did not mediate antibody-dependent or complement-mediated cytotoxicity but rather resulted in the down-regulation of FoxP3 selectively among CD25(high) CD45RA(neg) T-regs. Moreover, daclizumab-treated CD45RA(neg) T-regs lost suppressive function and regained the ability to produce interferon-gamma, consistent with reprogramming. To understand the impact of daclizumab on T-regs in vivo, we performed a clinical trial of daclizumab in combination with an experimental cancer vaccine in patients with metastatic breast cancer. Daclizumab administration led to a marked and prolonged decrease in T-regs in patients. Robust CD8 and CD4 T cell priming and boosting to all vaccine antigens were observed in the absence of autoimmunity. We conclude that CD25 blockade depletes and selectively reprograms T-regs in concert with active immune therapy in cancer patients. These results suggest a mechanism to target cancer-associated T-regs while avoiding autoimmunity.
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