Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 29, Pages 10660-10665Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1312789111
Keywords
T-cell therapy; beta-1,3-glucan; fungus; adoptive immunotherapy
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Funding
- MDACC Cancer Center Support Grant (CCSG) [CA016672]
- Cancer Center Core Grant [CA16672]
- National Institutes of Health (NIH) [R01 CA124782, CA120956, CA141303]
- NIH [R33 CA116127, P01 CA148600]
- Burroughs Wellcome Fund
- Cancer Prevention and Research Institute of Texas
- Chronic Lymphocytic Leukemia Global Research Foundation
- Defense Advanced Research Projects Agency (Defense Sciences Office)
- Department of Defense
- estate of Noelan L. Bibler
- Gillson Longenbaugh Foundation
- Harry T. Mangurian, Jr. Fund for Leukemia Immunotherapy
- Institute of Personalized Cancer Therapy
- Leukemia and Lymphoma Society
- Lymphoma Research Foundation
- MDACC's Sister Institution Network Fund
- Miller Foundation
- National Foundation for Cancer Research
- Pediatric Cancer Research Foundation
- William Lawrence and Blanche Hughes Children's Foundation
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Clinical-grade T cells are genetically modified ex vivo to express chimeric antigen receptors (CARs) to redirect their specificity to target tumor-associated antigens in vivo. We now have developed this molecular strategy to render cytotoxic T cells specific for fungi. We adapted the pattern-recognition receptor Dectin-1 to activate T cells via chimeric CD28 and CD3-zeta (designated D-CAR) upon binding with carbohydrate in the cell wall of Aspergillus germlings. T cells genetically modified with the Sleeping Beauty system to express D-CAR stably were propagated selectively on artificial activating and propagating cells using an approach similar to that approved by the Food and Drug Administration for manufacturing CD19-specific CAR(+) T cells for clinical trials. The D-CAR(+) T cells exhibited specificity for beta-glucan which led to damage and inhibition of hyphal growth of Aspergillus in vitro and in vivo. Treatment of D-CAR(+) T cells with steroids did not compromise antifungal activity significantly. These data support the targeting of carbohydrate antigens by CAR(+) T cells and provide a clinically appealing strategy to enhance immunity for opportunistic fungal infections using T-cell gene therapy.
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