Sensitive and adaptable pharmacological control of CAR T cells through extracellular receptor dimerization
| Autor: | Wai-Hang Leung, Joel Gay, Unja Martin, Tracy E. Garrett, Holly M. Horton, Michael T. Certo, Bruce R. Blazar, Richard A. Morgan, Philip D. Gregory, Jordan Jarjour, Alexander Astrakhan |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Antigen Targeting medicine.medical_treatment T cell Recombinant Fusion Proteins T-Lymphocytes Antigens CD19 Lymphocyte Activation Immunotherapy Adoptive 03 medical and health sciences Mice 0302 clinical medicine Cancer immunotherapy Antigen Protein Domains Cell Line Tumor Neoplasms medicine Extracellular Animals Humans Receptor Promoter Regions Genetic Sirolimus Receptors Chimeric Antigen Chemistry General Medicine Xenograft Model Antitumor Assays Chimeric antigen receptor Cell biology 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Female Signal transduction Protein Multimerization Single-Chain Antibodies Research Article |
| Zdroj: | JCI insight. 5 |
| ISSN: | 2379-3708 |
| Popis: | 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 comprised 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 anti-tumor potency compared to 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 re-targeting modules, potentially extending antigen targeting. Overall, this novel regulatable CAR design has exquisite drug sensitivity, provides robust anti-tumor responses, and is uniquely flexible for multiplex antigen targeting or retargeting, which may further assist the development of safe, potent and durable T cell therapeutics. |
| Databáze: | OpenAIRE |
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