Award

Abstract The development of cell and gene therapies like Chimeric Antigen Receptor (CAR) T cells has necessitated new technologies that can monitor the biodistribution and trafficking pattern of these therapies in human patients. Imaging is particularly well suited to provide quantitative measurements of such therapies over time. Vellum Biosciences is a platform imaging company geared to fill this void in available technologies, providing repeatable, robust, and sensitive measures of genetic medicine in situ with clear applications in new drug development, clinical research, and eventually, clinical practice. Vellum’s technology is based on positron emission tomography (PET) radiotracer derivatives of the synthetic antibiotic trimethoprim (TMP) and engineered expression of its protein target E. coli dihydrofolate reductase (eDHFR). When eDHFR is expressed via a genetic medicine (e.g., cells harboring lentiviral or adeno-associated viral vectors or therapeutic mRNA), TMP radiotracers can be used to measure the expression of the protein products in any tissue within the body. Our strategy has been used to monitor the trafficking of CAR T cells targeting several types of tumors in rodents in collaboration with several different research groups at the University of Pennsylvania (UPenn) and a global pharmaceutical company. In this STTR phase 1, we propose the development of a GMP-compliant eDHFR viral vector that can be applied in a modular fashion to different cellular therapies to monitor their biodistribution over time. This “stand-alone” imaging vector dovetails with Vellum and UPenn’s on-going collaborative STTR Phase I grant focused on optimizing [18F]-FTMP production to provide a commercial supply of the radiotracer (R41EB034141). In Aim 1, we will evaluate the feasibility of using a stand-alone imaging vector format in vitro, which can then be applied to different cellular therapies in collaboration with the Penn Center for Cellular Immunotherapies (CCI). In Aim 2, we take the enabling steps to perform quality control measures and functional assessment of the vector both in vitro and in vivo and take the necessary steps to manufacture a GMP-compliant eDHFR lentiviral vector. This process has been initiated via an established relationship with a CRO to produce the IND-ready DNA plasmids in collaboration with the CCI and with the “line-of-sight” assistance of the Penn Vector Core for the future clinical grade lentivirus. Taken together, these short-term aims will provide the evidence base needed for the final justification and creation of eDHFR viral vectors that allow monitoring of investigational cell therapies in patients at UPenn. We envision that our approach will substantially impact our understanding of why a cell therapy product is successful or fails on an individual patient level using non-invasive imaging.