Developing Inhibitory Chimeric Antigen Receptors for Mitigating CAR T Cell On-Target, Off-Tumor Toxicity
Chimeric antigen receptor T cell (CAR T) therapy has shown extraordinary success in the treatment of hematological malignancies. However, its application to solid tumors has been largely limited by the immunosuppressive tumor microenvironment and toxicities. Because most CAR targets are tumor associ...
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| Format: | Dissertation |
| Language: | English |
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ProQuest Dissertations & Theses
01-01-2023
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| Online Access: | Get full text |
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| Summary: | Chimeric antigen receptor T cell (CAR T) therapy has shown extraordinary success in the treatment of hematological malignancies. However, its application to solid tumors has been largely limited by the immunosuppressive tumor microenvironment and toxicities. Because most CAR targets are tumor associated antigens, they are also expressed on normal tissues that are killed by CAR T cells in a process known as on-target, off-tumor toxicity. To mitigate this toxicity and increase specificity, Boolean logic gates have been applied to CAR T cells to regulate activity based on multiple antigenic signals. The AND-NOT-gate utilizes an inhibitory chimeric antigen receptor (iCAR) to downregulate T cell activation after normal tissue antigen recognition. Our study found that an iCAR with a single PD-1 domain shows a kinetic delay in inhibition. This delay can be ameliorated by increasing the avidity but not the affinity of the iCAR. Alternatively, the PD-1 domain can be replaced with alternative inhibitory domains from BTLA, LAIR-1, and SIGLEC-9. To further enhance inhibition, we developed a dual-signaling inhibitory CAR (DiCAR) that combines the PD-1 domain with one of these alternative domains. These DiCARs are more efficient at inhibiting cytotoxicity than an iCAR with a single PD-1 domain. Furthermore, preliminary studies have shown that these DiCARs can inhibit cytotoxicity in vivo. |
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| ISBN: | 9798380851114 |