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In Vitro Tumor Cell Rechallenge For Predictive Evaluation of Chimeric Antigen Receptor T Cell Antitumor Function
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In Vitro Tumor Cell Rechallenge For Predictive Evaluation of Chimeric Antigen Receptor T Cell Antitumor Function

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Logic-Gated ROR1 Chimeric Antigen Receptor Expression Rescues T Cell-Mediated Toxicity to Normal Tissues and Enables

Shivani Srivastava1, Alexander I Salter1, Denny Liggitt2

  • 1Program in Immunology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, D3-100, Seattle, WA 98109-1024, USA.

Cancer Cell
|March 20, 2019
PubMed

Insights

Engineered T-cells with synthetic Notch (synNotch) receptors target ROR1+ tumor cells selectively. This approach enables CAR-T cell therapy for solid tumors by preventing off-tumor toxicity in normal tissues.

Area of Science:

  • Immunology
  • Oncology
  • Biotechnology

Background:

  • CAR-T cell therapy faces challenges in solid tumors due to off-tumor toxicity.
  • Targeting tumor-associated antigens like ROR1 can lead to severe adverse effects in normal tissues.

Purpose of the Study:

  • To develop a more selective CAR-T cell strategy for solid tumors.
  • To engineer T-cells that can distinguish between tumor and normal cells expressing ROR1.

Main Methods:

  • Utilized synthetic Notch (synNotch) receptors for conditional CAR expression.
  • Designed synNotch receptors targeting EpCAM or B7-H3 on ROR1+ tumor cells.
  • Evaluated CAR-T cell efficacy and toxicity in mouse models.

Main Results:

  • SynNotch receptors enabled ROR1 CAR expression exclusively in tumor cells.
  • Achieved significant tumor regression without inducing bone marrow failure.
  • Demonstrated safety when tumor cells were spatially separated from normal ROR1+ cells.

Conclusions:

  • SynNotch receptor technology enhances CAR-T cell selectivity for solid tumors.
  • This strategy mitigates off-tumor toxicity by targeting tumor-specific antigens.
  • Safe and effective CAR-T cell therapy is feasible for solid tumors with appropriate targeting strategies.
Keywords:
B7-H3ROR1T cellschimeric antigen receptorcombinatorial antigen recognitionimmunotherapylogic gatingmesenchymal stem cellsynthetic Notch receptorstoxicity

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