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Ligand-restricted synNotch switches enable precision cell therapy.

Xuyang Li1, Dan Hu2

  • 1Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205, USA; Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Lustgarten Dedicated Laboratory for Pancreatic Cancer Research and the Bloomberg~Kimmel Institute Cancer Genetics and Genomics Research Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Trends in Immunology
|January 28, 2025
PubMed
Summary

Engineered T cells with synNotch circuits precisely target brain tumors, expressing therapeutic payloads only at the tumor site. This localized treatment eliminates tumors without systemic side effects, offering enhanced efficacy for neuroinflammation and brain cancer.

Keywords:
chimeric antigen receptor (CAR)immunosuppressionsynNotch circuit

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Area of Science:

  • Immunology
  • Synthetic Biology
  • Neuroscience

Background:

  • Unwanted immunity and neuroinflammation pose significant challenges in treating brain conditions.
  • Current therapies often lack specificity, leading to systemic side effects and limited efficacy.

Purpose of the Study:

  • To engineer T cells with synNotch transcriptional circuits for precise, antigen-triggered payload expression.
  • To evaluate the efficacy and safety of this localized therapeutic approach in mouse brain tumor models.

Main Methods:

  • Development and implementation of synNotch transcriptional circuits in T cells.
  • In vivo testing in mouse models of brain tumors to assess payload delivery and therapeutic effects.
  • Evaluation of off-tumor toxicity and systemic immunosuppression.

Main Results:

  • SynNotch circuits enabled location-specific payload expression in response to tumor antigens.
  • Successful elimination of mouse brain tumors was achieved with localized T cell activity.
  • No observed off-tumor toxicity or systemic immunosuppression.

Conclusions:

  • SynNotch engineered T cells provide a precise method for localized immunotherapy in the brain.
  • This approach demonstrates potential for improved efficacy in treating brain tumors and neuroinflammation with enhanced safety profiles.