title: Redirection of genetically engineered CAR-T cells using bifunctional small molecules.
abstract: Chimeric antigen receptor (CAR)-engineered T cells (CAR-Ts) provide a potent antitumor response and have become a promising treatment option for cancer. However, despite their efficacy, CAR-T cells are associated with significant safety challenges related to the inability to control their activation and expansion and terminate their response. Herein, we demonstrate that a bifunctional small molecule "switch" consisting of folate conjugated to fluorescein isothiocyanate (folate-FITC) can redirect and regulate FITC-specific CAR-T cell activity toward folate receptor (FR)-overexpressing tumor cells. This system was shown to be highly cytotoxic to FR-positive cells with no activity against FR-negative cells, demonstrating the specificity of redirection by folate-FITC. Anti-FITC-CAR-T cell activation and proliferation was strictly dependent on the presence of both folate-FITC and FR-positive cells and was dose titratable with folate-FITC switch. This novel treatment paradigm may ultimately lead to increased safety for CAR-T cell immunotherapy.
authors.affiliation: California Institute for Biomedical Research , 11119 North Torrey Pines Road, Suite 100, La Jolla, California 92037, United States.
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Kim
authors.forename: Jennifer S Y
authors.initials: JS
authors.lastname: Ma
authors.forename: Hwayoung
authors.initials: H
authors.lastname: Yun
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Victor
authors.initials: V
authors.lastname: Chi
authors.forename: Danling
authors.initials: D
authors.lastname: Wang
authors.forename: Ashley
authors.initials: A
authors.lastname: Woods
authors.forename: Lance
authors.initials: L
authors.lastname: Sherwood
authors.forename: Dawna
authors.initials: D
authors.lastname: Caballero
authors.forename: Jose
authors.initials: J
authors.lastname: Gonzalez
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.forename: Travis S
authors.initials: TS
authors.lastname: Young
authors.forename: Chan Hyuk
authors.initials: CH
authors.lastname: Kim
mesh_terms: D060846:Cell Engineering; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D005492:Folic Acid / Q000737:chemistry* / Q000378:metabolism*; D058972:Folic Acid Transporters / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007624:KB Cells; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism
chemical_list: D058972:Folic Acid Transporters; D011948:Receptors, Antigen, T-Cell; D005492:Folic Acid; D016650:Fluorescein-5-isothiocyanate