Thursday, January 16, 2014
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chimeric antigen receptors (iCARs) as a self-regulating safety switch to
constrain T cell-based therapies
could be used as a self-regulating safety switch to constrain T cell-based
therapies and avoid off-tumor toxicity. As proof of concept, T cells were
modified to include a tumor cell-specific, CD19-specific CAR and a prostate-specific membrane antigen
(PSMA; FOLH1; GCPII)-specific iCAR, which
contained inhibitory receptor signaling domains based on protectin D1 (PD1) or CTLA-4 (CD152). In cell culture and
in a mouse xenograft model, T cells expressing a CD19-specific CAR and a
PSMA-specific iCAR killed CD19+/PSMA-
cells but not CD19+/PSMA+ cells,
preventing off-target effects on PSMA+ cells.
In culture, the engineered T cells were suppressed when encountering CD19+/PSMA+ cells and
activated when next encountering CD19+/PSMA-
cells, indicating that iCAR suppression was temporary. Next steps include
designing CAR-based or T cell receptor (TCR)-based T cells that
express antigen-specific iCARs that target antigens downregulated on cells in
solid tumors but present on healthy cells (see Putting on the brakes,
Published online Jan. 16, 2014
Patent application filed on
the use of iCARs to protect normal tissues from off-target effects of
allogeneic or autologous
T cells; optioned to Juno Therapeutics Inc.
Fedorov, V.D. et al.
Sci. Transl. Med.; published online Dec. 11, 2013;
Contact: Michel Sadelain, Memorial Sloan Kettering Cancer
Center, New York, N.Y.
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