Antigen-dependent inducible T cell reporter system for PET imaging of breast cancer and glioblastoma

Shin, J.; Parker, M.; Zhu, I.; Alanizi, A.; Rodriguez, C.; Liu, R.; Watchmaker, P.; Kalita, M.; Blecha, J.; Luu, J.; Wright, B.; Lapi, S.; Flavell, R.; Okada, H.; Tlsty, T.; Wilson, D.; Roybal, K.

doi:10.1101/2022.02.16.480729

bioRxiv · 10.1101/2022.02.16.480729

Antigen-dependent inducible T cell reporter system for PET imaging of breast cancer and glioblastoma

Shin, J.·Parker, M.·Zhu, I.·Alanizi, A.·Rodriguez, C.·Liu, R.·Watchmaker, P.·Kalita, M.·Blecha, J.·Luu, J.·Wright, B.·Lapi, S.·Flavell, R.·Okada, H.·Tlsty, T.·Wilson, D.·Roybal, K.

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Abstract

For the past several decades, chimeric antigen receptor T cell (CAR T) therapies have shown promise in the treatment of cancers. These treatments would greatly benefit from companion imaging biomarkers to follow the trafficking of T cells in vivo. Using synthetic biology, we engineered T cells with a chimeric receptor SyNthetic Intramembrane Proteolysis Receptor (SNIPR) that induces overexpression of an exogenous reporter gene cassette upon recognition of specific tumor markers. We then applied a SNIPR-based positron emission tomography (PET) reporter system to two cancer-relevant antigens, human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor variant III (EGFRvIII), commonly expressed in breast and glial tumors respectively. Antigen-specific reporter induction of the SNIPR-PET T cells was confirmed in vitro using GFP fluorescence, luciferase luminescence, and the HSV-TK PET reporter with [18F]FHBG. T cells associated with their target antigens were successfully imaged using PET in dual xenograft HER2+/HER2- and EGFRvIII+/EGFRvIII-animal models, with > 10-fold higher [18F]FHBG signals seen in antigen-expressing tumors versus the corresponding controls. The main innovation described is therefore PET detection of T cells via specific antigen-induced signals, in contrast to reporter systems relying on constitutive gene expression.

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Shin, J., Parker, M., Zhu, I., Alanizi, A., Rodriguez, C., Liu, R., Watchmaker, P., Kalita, M., Blecha, J., Luu, J., Wright, B., Lapi, S., Flavell, R., Okada, H., Tlsty, T., Wilson, D., Roybal, K.. 2022-02-16. Antigen-dependent inducible T cell reporter system for PET imaging of breast cancer and glioblastoma. https://doi.org/10.1101/2022.02.16.480729

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