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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 switch proteolysis. With the aim to develop improved second-generation switch systems, we here analyze the possibility space of both the immune cell receptor docking and inhibitory signaling domains that allow control over T cell activity. Importantly, these analyses demonstrate that the inhibitory domains that most potently suppress antigen receptor signaling in primary human T cells are not derived from inhibitory receptors, such as PD-1 and BTLA, that are endogenously expressed in T cells, but include ITIM/ITSM containing inhibitory domains derived from receptors present in myeloid cells. In addition, we demonstrate that physical proximity of the inhibitory domain to the antigen receptor is crucial to efficiently suppress T cell activation, as only switch designs that employ SH2 domains directly interacting with ITAM motifs in antigen receptors efficiently and reversibly inhibit T cell functionality. These data demonstrate the flexible and interchangeable nature of immune cell signaling domains, and inform the design of a synthetic proximity-based switch system with a superior dynamic range.

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