Programming T cells for Early Cancer Detection with Customized Protease-Activatable Receptors

Area of Science:

• Biotechnology
• Immunology
• Oncology

Background:

• Early cancer detection significantly reduces mortality, but current biomarkers lack sensitivity for early-stage disease.
• Endogenous tumor-shed biomarkers often fail to detect minimal residual disease or very small tumors.
• Developing novel strategies for highly sensitive and specific cancer detection remains a critical unmet need.

Purpose of the Study:

• To develop and validate OncoSCOUT, a T cell-based cancer detection strategy utilizing protease-activatable receptors (PARs).
• To engineer PARs that conditionally recognize tumor cells and release a detectable synthetic biomarker in urine.
• To assess the sensitivity and specificity of OncoSCOUT for detecting small tumor burdens in vivo.

Main Methods:

• Engineered T cells expressing synthetic Notch receptors (PARs) with protease-cleavable linkers were designed.
• A library of HER2-targeted PARs was screened in a HER2-positive cancer xenograft model.
• OncoSCOUT's detection capability was evaluated against established biomarkers like CA 15-3 and circulating tumor DNA (ctDNA).

Main Results:

• OncoSCOUT demonstrated improved spatial specificity and reduced off-tumor activation by requiring both protease activity and tumor antigen recognition.
• Multiple HER2-targeted PAR variants were identified and enriched in HER2-positive tumors.
• OncoSCOUT detected tumor burdens as small as 10-30 mm³ with superior sensitivity compared to CA 15-3 and a 20-plex ctDNA assay.

Conclusions:

• OncoSCOUT represents a promising new strategy for early cancer detection, leveraging engineered T cells and synthetic biomarkers.
• The system's ability to detect minute tumor volumes offers a significant advancement over current diagnostic methods.
• Further development of OncoSCOUT could lead to improved patient outcomes through earlier intervention.