Programming T cells for Early Cancer Detection with Customized Protease-Activatable Receptors
Phuengkham, H.; Chen, Y.; Sivakumar, A.; Zamat, A. H.; Gamboa, L.; Mac, Q. D.; Lee, H. J.; Rogers, L. C.; You, J.; Steele, S. A.; Zhu, S.; Gollins, M. S.; Blazeck, J.; Qiu, P.; Kwong, G. A.
Show abstract
Early cancer detection has the potential to reduce cancer mortality, yet endogenous tumor-shed biomarkers lack sensitivity for early-stage disease. We report OncoSCOUT, a cancer detection strategy using T cells engineered with protease-activatable receptors (PARs) that conditionally recognize tumor cells and release a synthetic biomarker for detection in urine. These PARs comprise masked synthetic Notch receptors in which antigen binding is blocked by a peptide mimotope tethered via a protease-cleavable linker. We demonstrate that requiring both extracellular protease activity and tumor antigen recognition improves spatial specificity and minimizes off-tumor activation of PAR T cells in vivo. To identify tumor-selective PARs, we adoptively transferred a HER2-targeted PAR library displaying [~]160,000 unique 4-mer amino acid linkers and discovered multiple variants significantly enriched in a HER2-positive cancer xenograft model. Using a single customized PAR, we show that OncoSCOUT can detect total tumor burdens as small as 10-30 mm3 with significantly improved sensitivity than the protein biomarker CA 15-3 or a 20-plex circulating tumor DNA (ctDNA) assay.
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