Product for sensitive imaging of cells in vivo

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In this Phase 2 application we aim to continue development and commercialization of a novel and sensitive magnetic resonance imaging (MRI) probe for the cell therapy tools market. We propose to implement first-into- man clinical translation of this technology to visualize the trafficking of tumor infiltrating lymphocytes (TILs) in head and neck cancer (HNC) patients. Celsense, Inc., manufactures imaging tools that provide quantitative assessment of in vivo cell trafficking. The Company’s core products are imaging agents based on unique perfluorocarbon (PFC) nanoemulsion compositions. Previously, in a collaboration between Celsense and Ahrens lab (UCSD), clinical use of a first-generation PFC nanoemulsion product was used to detect cell immunotherapy in cancer patients. Building on this work, we propose to develop next-generation imaging PFC nanoemulsion cell labels that incorporate a novel metal chelate (“FETRIS”) technology that yields dramatically improved sensitivity to detect immunotherapeutic cell products in vivo in clinical trials. Imaging initial cell biodistribution can provide crucial feedback regarding the localization, survival, optimal routes of delivery and therapeutic doses. FETRIS nanoemulsion is designed to be taken up by cells in culture, and following transfer to the subject, cells are detected in vivo using fluorine-19 (19F) MRI. The fluorine inside the cells yields cell- specific images, with no background signal. Images are readily quantified to measure apparent cell numbers at sites of accumulation. These 19F MRI methods have been demonstrated to be a safe tracking tool for various stem cells and immune cell types. By improving the sensitivity of 19F cell detection using FETRIS, we will lower the barriers for applying this technology to a wider range of cell therapy applications. A major effort is underway at UCSD to develop TIL therapy for HNC. Fundamental questions remain about tumor homing and cell survival of TILs in vivo. Up until now, we have been blind to the behavior of cells after infusion into patients. Importantly, TIL trafficking, as well as cell survival, may be predictive of responders versus non-responders to treatment. Imaging could provide real-time surrogate markers to gauge TIL tumor homing capacity and TIL survival in each patient, which could better inform therapeutic design and post-trial data analysis. The proposal has two Specific Aims: Aim 1 - TIL-FETRIS GMP cell preparation. (a) We will bolster manufacturing data and methods for a new FETRIS FDA Drug Master File (DMF). Additional engineering batches at ≥500 mL scale with release testing and accelerated stability studies will be produced. (b) Starting with the current UC San Diego TIL protocol, we will develop tissue culture protocols for TIL-FETRIS batches at clinical scale (>1×109 cells). We will establish a release criteria for acceptable TIL labeling and rigorously evaluate the degree to which PFC labeling induces potential alterations in TIL viability and phenotype in vitro. Aim 2 - Clinical use of CS-TILs in HNC patients. In a small HNC patient cohort (N=5), we will evaluate the safety and efficacy of using MRI to detect TIL-FETRIS. The 19F MRI will be used to assay putative CS-TIL tumor homing and survival longitudinally.