TY - JOUR
T1 - Sensitive and adaptable pharmacological control of CAR T cells through extracellular receptor dimerization
AU - Leung, Wai Hang
AU - Gay, Joel
AU - Martin, Unja
AU - Garrett, Tracy E.
AU - Horton, Holly M.
AU - Certo, Michael T.
AU - Blazar, Bruce R.
AU - Morgan, Richard A.
AU - Gregory, Philip D.
AU - Jarjour, Jordan
AU - Astrakhan, Alexander
N1 - Publisher Copyright:
Copyright: © 2019 American Society for Clinical Investigation
PY - 2019/6/6
Y1 - 2019/6/6
N2 - Chimeric antigen receptor (CAR) T cell therapies have achieved promising outcomes in several cancers; however, more challenging oncology indications may necessitate advanced antigen receptor designs and functions. Here we describe a bipartite receptor system composed of separate antigen-targeting and signal transduction polypeptides, each containing an extracellular dimerization domain. We demonstrate that T cell activation remains antigen dependent but can only be achieved in the presence of a dimerizing drug, rapamycin. Studies performed in vitro and in xenograft mouse models illustrate equivalent to superior antitumor potency compared with currently used CAR designs, and at rapamycin concentrations well below immunosuppressive levels. We further show that the extracellular positioning of the dimerization domains enables the administration of recombinant retargeting modules, potentially extending antigen targeting. Overall, this regulatable CAR design has exquisite drug sensitivity, provides robust antitumor responses, and is flexible for multiplex antigen targeting or retargeting, which may further assist the development of safe, potent, and durable T cell therapeutics.
AB - Chimeric antigen receptor (CAR) T cell therapies have achieved promising outcomes in several cancers; however, more challenging oncology indications may necessitate advanced antigen receptor designs and functions. Here we describe a bipartite receptor system composed of separate antigen-targeting and signal transduction polypeptides, each containing an extracellular dimerization domain. We demonstrate that T cell activation remains antigen dependent but can only be achieved in the presence of a dimerizing drug, rapamycin. Studies performed in vitro and in xenograft mouse models illustrate equivalent to superior antitumor potency compared with currently used CAR designs, and at rapamycin concentrations well below immunosuppressive levels. We further show that the extracellular positioning of the dimerization domains enables the administration of recombinant retargeting modules, potentially extending antigen targeting. Overall, this regulatable CAR design has exquisite drug sensitivity, provides robust antitumor responses, and is flexible for multiplex antigen targeting or retargeting, which may further assist the development of safe, potent, and durable T cell therapeutics.
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U2 - 10.1172/jci.insight.124430
DO - 10.1172/jci.insight.124430
M3 - Article
C2 - 31039141
AN - SCOPUS:85070660965
SN - 2379-3708
VL - 4
JO - JCI insight
JF - JCI insight
IS - 11
M1 - e124430
ER -