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Non-Viral Engineering of Primary Human T Cells via Homology-Mediated End-Joining Targeted Integration of Large DNA Templates
Published on: May 9, 2025
Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors
Kole T Roybal1, Jasper Z Williams1, Leonardo Morsut1
1Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; UCSF Center for Systems and Synthetic Biology, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
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.
Insights
Engineered T cells can be customized using synthetic Notch (synNotch) receptors to improve cancer therapy. This technology allows precise control over immune responses, enhancing safety and effectiveness against tumors.
Area of Science:
- Immunology
- Synthetic Biology
- Biotechnology
Background:
- Therapeutic T cell efficacy is limited by natural immune responses, which can be toxic or insufficient to overcome tumor immunosuppression.
- Current engineered T cell therapies could be improved by precisely controlling their responses and safety profiles.
Purpose of the Study:
- To investigate the use of synthetic Notch (synNotch) receptors for sculpting custom immune cell responses.
- To demonstrate the potential of synNotch technology for enhancing T cell-based therapies.
Main Methods:
- Engineered primary T cells with synNotch receptors capable of antigen recognition.
- Inducing transcriptional activation in response to specific antigens via synNotch signaling.
- Analyzing custom cytokine secretion profiles, T cell differentiation, and payload delivery.
Main Results:
- SynNotch receptors enabled custom response programs in T cells, including tailored cytokine secretion.
- Demonstrated biased T cell differentiation and local delivery of therapeutic payloads like antibodies.
- SynNotch T cells successfully recognized antigens and remodeled local microenvironments.
Conclusions:
- Synthetic Notch receptors provide a versatile platform for engineering T cell functions.
- This technology can enhance the safety and efficacy of T cell therapies by customizing immune responses.
- SynNotch T cells offer a generalizable approach to target and modify disease-associated microenvironments.
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