Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection

Pappanaicken R. Kumaresan, Pallavi R. Manuri, Nathaniel D. Albert, Sourindra Maiti, Harjeet Singh, Tiejuan Mi, Jason Roszik, Brian Rabinovich, Simon Olivares, Janani Krishnamurthy, Ling Zhang, Amer M. Najjar, M. Helen Huls, Dean A. Lee, Richard E. Champlin, Dimitrios P. Kontoyiannis, Laurence J N Cooper

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

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-ζ (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 β-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.

Original languageEnglish (US)
Pages (from-to)10660-10665
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number29
DOIs
StatePublished - Jul 22 2014
Externally publishedYes

Keywords

  • Adoptive immunotherapy
  • Fungus
  • T-cell therapy
  • β-1,3-glucan

ASJC Scopus subject areas

  • General

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  • Cite this

    Kumaresan, P. R., Manuri, P. R., Albert, N. D., Maiti, S., Singh, H., Mi, T., Roszik, J., Rabinovich, B., Olivares, S., Krishnamurthy, J., Zhang, L., Najjar, A. M., Huls, M. H., Lee, D. A., Champlin, R. E., Kontoyiannis, D. P., & Cooper, L. J. N. (2014). Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection. Proceedings of the National Academy of Sciences of the United States of America, 111(29), 10660-10665. https://doi.org/10.1073/pnas.1312789111