Antigen-Dependent Inducible T-Cell Reporter System for PET Imaging of Breast Cancer and Glioblastoma

• Published in: Journal of Nuclear Medicine Vol. 64; no. 1; pp. 137 - 144
• Main Authors: Shin, Jaehoon, Parker, Matthew F L, Zhu, Iowis, Alanizi, Aryn, Rodriguez, Carlos I, Liu, Raymond, Watchmaker, Payal B, Kalita, Mausam, Blecha, Joseph, Luu, Justin, Wright, Brian, Lapi, Suzanne E, Flavell, Robert R, Okada, Hideho, Tlsty, Thea D, Roybal, Kole T, Wilson, David M
• Format: Journal Article
• Language: English
• Published: United States Society of Nuclear Medicine 01.01.2023
• Subjects: Animal models; Animals; Antigens; Biomarkers; Brain cancer; Breast cancer; Breast Neoplasms - diagnostic imaging; Breast Neoplasms - genetics; Cell Line, Tumor; Chimeric antigen receptors; Epidermal growth factor; ErbB-2 protein; Female; Fluorescence; Fluorine isotopes; Gene expression; Genes, Reporter; Glioblastoma; Green fluorescent protein; Growth factors; Humans; In vivo methods and tests; Lymphocytes; Lymphocytes T; Positron emission; Positron-Emission Tomography - methods; Proteolysis; Receptors; Reporter gene; T-Lymphocytes; Tumor markers; Tumors; Xenografts; Xenotransplantation; reporter; cancer antigens; CAR T; SNIPR; PET
• ISSN: 0161-5505; 1535-5667; 2159-662X
• DOI: 10.2967/jnumed.122.264284

For the past several decades, chimeric antigen receptor T-cell 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 on recognition of specific tumor markers. We then applied a SNIPR-based PET reporter system to 2 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 green fluorescent protein fluorescence, luciferase luminescence, and the HSV-TK PET reporter with 9-(4- F-fluoro-3-[hydroxymethyl]butyl)guanine ([ F]FHBG). T cells associated with their target antigens were successfully imaged using PET in dual-xenograft HER2+/HER2- and EGFRvIII+/EGFRvIII- animal models, with more than 10-fold higher [ F]FHBG signals seen in antigen-expressing tumors versus the corresponding controls. The main innovation found in this work was PET detection of T cells via specific antigen-induced signals, in contrast to reporter systems relying on constitutive gene expression.