Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2016 Oct 4

PMID 27693353

Citations 310

Authors

Kole T Roybal

Jasper Z Williams

Leonardo Morsut

Levi J Rupp

Isabel Kolinko

Joseph H Choe

Whitney J Walker

Krista A McNally

Wendell A Lim

Affiliations

Soon will be listed here.

Abstract

Redirecting T cells to attack cancer using engineered chimeric receptors provides powerful new therapeutic capabilities. However, the effectiveness of therapeutic T cells is constrained by the endogenous T cell 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 T cells: they can drive a la carte cytokine secretion profiles, biased T cell differentiation, and local delivery of non-native therapeutic payloads, such as antibodies, in response to antigen. SynNotch T cells can thus be used as a general platform to recognize and remodel local microenvironments associated with diverse diseases.

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