RT Journal Article
SR Electronic
T1 Sensitive manipulation of CAR T cell activity using a chimeric endocytosing receptor
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e000756
DO 10.1136/jitc-2020-000756
VO 8
IS 2
A1 Boning Zhang
A1 John Victor Napoleon
A1 Xin Liu
A1 Qian Luo
A1 Madduri Srinivasarao
A1 Philip S Low
YR 2020
UL http://jitc.bmj.com/content/8/2/e000756.abstract
AB Background Most adoptive cell therapies (ACTs) suffer from an inability to control the therapeutic cell’s behavior following its transplantation into a patient. Thus, efforts to inhibit, activate, differentiate or terminate an ACT after patient reinfusion can be futile, because the required drug adversely affects other cells in the patient.Methods We describe here a two domain fusion receptor composed of a ligand-binding domain linked to a recycling domain that allows constitutive internalization and trafficking of the fusion receptor back to the cell surface. Because the ligand-binding domain is designed to bind a ligand not normally present in humans, any drug conjugated to this ligand will bind and endocytose selectively into the ACT.Results In two embodiments of our strategy, we fuse the chronically endocytosing domain of human folate receptor alpha to either a murine scFv that binds fluorescein or human FK506 binding protein that binds FK506, thereby creating a fusion receptor composed of largely human components. We then create the ligand-targeted drug by conjugating any desired drug to either fluorescein or FK506, thereby generating a ligand-drug conjugate with ~10-9 M affinity for its fusion receptor. Using these tools, we demonstrate that CAR T cell activities can be sensitively tuned down or turned off in vitro as well as tightly controlled following their reinfusion into tumor-bearing mice.Conclusions We suggest this ‘chimeric endocytosing receptor’ can be exploited to manipulate not only CAR T cells but other ACTs following their reinfusion into patients. With efforts to develop ACTs to treat diseases including diabetes, heart failure, osteoarthritis, cancer and sickle cell anemia accelerating, we argue an ability to manipulate ACT activities postinfusion will be important.