Abstract
Redirecting Tcells to attack cancer using engineered chimeric receptors provides powerful new therapeutic capabilities. However, the effectiveness of therapeutic Tcells is constrained by the endogenous Tcell response: certain facets of natural response programs can be toxic, whereas other responses, such as the ability to overcome tumor immunosuppression, are absent. Thus, the efficacy and safety of therapeutic cells could be improved if we could custom sculpt immune cell responses. Synthetic Notch (synNotch) receptors induce transcriptional activation in response to recognition of user-specified antigens. We show that synNotch receptors can be used to sculpt custom response programs in primary Tcells: they can drive a la carte cytokine secretion profiles, biased Tcell differentiation, and local delivery of non-native therapeutic payloads, such as antibodies, in response to antigen. SynNotch Tcells can thus be used as a general platform to recognize and remodel local microenvironments associated with diverse diseases.
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