David T. Rodgers1, Magdalena Mazagova1, Eric Hampton1, Yu Cao2, Nitya S. Ramadoss1, Ian R. Hardy1, Andrew D. Schulman1, Juanjuan Du1, Feng Wang1, Oded Singer1, Jennifer Ma1,3,4,5,6,7, Vanessa Núñez1, Jiayin Shen1, Ashley K. Woods1, Timothy M. Wright1, Peter G. Schultz1,2, Chan Hyuk Kim1, Travis S. Young1
1Department of Biology, California Institute for Biomedical Research, La Jolla, CA 92019;
2Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037
3Department of Infectious Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
4Fate Therapeutics, San Diego, CA 92121.
5Shriram Center, Stanford University, Stanford, CA 94305.
6University of Pennsylvania; and K
7Viral Vector Core, Weizmann Institute of Science, Rehovot 76100, Israel.
Tóm tắt
Significance
Chimeric antigen receptor T (CAR-T) cell therapy has produced promising results in clinical trials but has been challenged by the inability to control engineered cells once infused into the patient. Here we present a generalizable method of controlling CAR-T cells using peptide-engrafted antibody-based molecular switches that act as a bridge between the target cell and CAR-T cell. We show that switches specific for CD19 govern the activity, tissue-homing, cytokine release, and phenotype of switchable CAR-T cells in a dose-titratable manner using xenograft mouse models of B-cell leukemia. We expect that this method of tuning CAR-T cell responses will provide improved safety and versatility of CAR–T-cell therapy in the clinic.
