Multimodular Optimization of Chemically Regulated T Cell Switches Demonstrates Flexible and Interchangeable Nature of Immune Cell Signaling Domains.

ABSTRACT: Immune cell-based therapies can induce potent antitumor effects but are also often associated with severe toxicities. We previously developed a PD-1-based small molecule-regulated reversible T cell activation switch to control the activity of cellular immunotherapy products. This chemically regulated and SH2-delivered-inhibitory tail (CRASH-IT) switch relies on the noncovalent interaction of switch SH2 domains with phosphorylated ITAM motifs in either chimeric antigen receptors or T cell receptors. After this interaction, the immunoreceptor tyrosine-based inhibition motif/switch motif (ITIM/ITSM) containing PD-1 domain present in the CRASH-IT switch induces robust inhibition of T cell signaling, and CRASH-IT-mediated suppression of T cell activity can be reversed by small molecule-induced

SUBMITTER: Sahillioglu AC 

PROVIDER: S-EPMC10112874 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature