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Drug platforms

Antigen-specific inhibitory chimeric antigen receptors (iCARs) as a self-regulating safety switch to constrain T cell-based therapies

Antigen-specific iCARs 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, page 1).

SciBX 7(2); doi:10.1038/scibx.2014.69
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;
doi:10.1126/scitranslmed.3006597
Contact: Michel Sadelain, Memorial Sloan Kettering Cancer Center, New York, N.Y.
e-mail:
m-sadelain@ski.mskcc.org