TY - JOUR
T1 - Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection
AU - Kumaresan, Pappanaicken R.
AU - Manuri, Pallavi R.
AU - Albert, Nathaniel D.
AU - Maiti, Sourindra
AU - Singh, Harjeet
AU - Mi, Tiejuan
AU - Roszik, Jason
AU - Rabinovich, Brian
AU - Olivares, Simon
AU - Krishnamurthy, Janani
AU - Zhang, Ling
AU - Najjar, Amer M.
AU - Huls, M. Helen
AU - Lee, Dean A.
AU - Champlin, Richard E.
AU - Kontoyiannis, Dimitrios P.
AU - Cooper, Laurence J.N.
PY - 2014/7/22
Y1 - 2014/7/22
N2 - 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.
AB - 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.
KW - Adoptive immunotherapy
KW - Fungus
KW - T-cell therapy
KW - β-1,3-glucan
UR - http://www.scopus.com/inward/record.url?scp=84904632405&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904632405&partnerID=8YFLogxK
U2 - 10.1073/pnas.1312789111
DO - 10.1073/pnas.1312789111
M3 - Article
C2 - 25002471
AN - SCOPUS:84904632405
SN - 0027-8424
VL - 111
SP - 10660
EP - 10665
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 29
ER -