Engineered T cell-based imaging for glioblastoma and CAR-T cell tracking

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Molecular biology, genomics, and immunology are revolutionizing modern medicine by uncovering key molecular markers in human diseases. Imaging technologies that can directly visualize these markers, such as immune- positron emission tomography (immunoPET), are at the forefront of such innovation, reshaping current medical practice. In this proposal, we take advantage of both the superior targeting specificity of monoclonal antibodies (mAb), and the amplification inherent in cell signaling by developing a T cell-based imaging method. Using synthetic biology, we will develop engineered T cells with an antibody-derived chimeric receptor called “SNIPR” that has an antigen-recognizing single-chain variable fragment (scFv) as an extracellular domain and an engineered transcription factor as an intracellular domain. Upon binding its target antigen, SNIPR releases its transcription factor, which migrates into the nucleus and induces the overexpression of various exogenous reporter gene(s). This approach is fully customizable and versatile, and most importantly, can greatly enhance sensitivity through multiple rounds of signal amplifications. The main goals of this proposal are to establish the preclinical groundwork for SNIPR-PET in (1) visualizing early glioblastoma and (2) tracking activated CAR T cells. In Aim 1, we will refine SNIPR T cells targeting EGFRvIII and optimize SNIPR-PET reporter imaging strategies. In Aim 2, we will apply SNIPR-PET to the molecular imaging of glioblastoma and compare its sensitivity and specificity with antibody-based immunoPET. In Aim 3, we will image CD8+ therapeutic T cells, establish a correlation between PET signals and tumor response, and enhance T cell penetration into brain tissues. The developed technologies will allow non-invasive monitoring of biological/immunological responses within tumors, as potential biomarkers of successful therapy. This collaborative proposal between Immunology, Radiology and Neurosurgery will provide a versatile and customizable tool allowing cancer detection and treatment using engineered T cells. Our proposal reflects a close interdisciplinary collaboration between Drs. Kole Roybal, (Immunology), David Wilson (Radiology), and Hideho Okada (Neuroradiologic Surgery) at UCSF. Dr. Jaehoon Shin, an interventional radiologist and molecular biologist, is another primary driver of this project- integrating molecular biology, genomics, synthetic biology and biomedical imaging. We believe that our successful execution of the proposed work will greatly impact human health by introducing novel T cell-based imaging to detect early cancers and to enhance the safety profile of therapeutic T cells.