SBIR-STTR Award

This project aims to develop and commercialize a novel and highly sensitive MRI probe technology for the cell therapy tools market. This project will transfer technology invented in the academic lab of Dr. Ahrens at UCSD, to Celsense, Inc., an established company that offers imaging agents for visualizing the trafficking of cell therapies and inflammation in the body using magnetic resonance imaging (MRI). Overall, the Company?s products are tools that provide quantive data on the in vivo trafficking of cells. The core products of the Company are imaging agents based on unique perfluorocarbon (PFC) emulsion compositions. The Company generates revenue by international sales of its proprietary imaging agent products for clinical and preclinical use, as well as specialized software, licensing fees, and fee-for-service contracts. A common need for developers of cell therapies is a non-invasive means to visualize the biodistribution of cells following injection. Imaging of cell trafficking can provide crucial feedback regarding the persistence, motility, optimal routes of delivery and therapeutic doses. This same information can also help to overcome regulatory barriers. The PFC agents are designed to be taken up by cells in culture, and following transfer to the subject, cells are tracked 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. We and others have demonstrated that these methods can track a wide range of cell types including various stem cells and immune cell types. Importantly, a collaboration between Celsense and the Ahrens lab has demonstrated clinical use with this technology to detect cellular immunotherapy in cancer patients. Looking forward, improving the sensitivity of 19F cell detection will lower the barriers for using this technology in a wider range of biomedical applications. Recent preclinical results from the Ahrens lab demonstrate dramatically-enhanced sensitivity of fluorine MRI by the invention of a new class of molecules that combine highly fluorinated nanoemulsions with the magnetic properties of metals that are solubilized into the fluorous phase. The resulting 19F MRI detection sensitivity boost is conservatively estimated to be at least 8-fold at a clinical field strength of 3 T. These recent advances in imaging probe technology will fit perfectly into Celsense?s reagent product line. The goal of this project is to initiate this technology transfer and make the transformation to commercial product, initially for the preclinical market. The Specific Aims of this project are: (1) Chemistry optimization and scale-up; (2) Physical analytical characterization and stability testing of prototype nanoemulsion agent; (3) In vitro biological testing of cell uptake, cytotoxicity and cell phenotype in cells labeled with FETRIS; (4) Generation of in vivo preclinical MRI datasets in rodents for agent evaluation and marketing purposes. Our view is that the new FETRIS imaging probe technology will be attractive to customers due to its greatly enhanced sensitivity and image quality.

Project Terms:
Adoption; base; Biodistribution; Biological; Biological Testing; Cancer Patient; Catalogs; Cell Count; cell motility; Cell Survival; Cell Therapy; cell type; Cells; cellular imaging; Cellular immunotherapy; Chemistry; Clinical; Collaborations; Computer software; Contract Services; cytotoxicity; Data; data acquisition; Data Set; Dendritic Cells; design; Detection; Development; Disease; Dose; Emulsions; Evaluation; Family; Fee-for-Service Plans; Feedback; Fees; Fluorine; Fluorocarbons; Generations; Goals; Image; imaging agent; imaging detection; imaging probe; imaging properties; Immune; improved; In Vitro; in vivo; Inflammation; Injections; interest; International; invention; Iron; Label; Laboratories; Licensing; Life; Magnetic Resonance Imaging; Magnetism; Marketing; Measures; Mesenchymal Stem Cells; Metals; Methods; molecular imaging; nanoemulsion; Natural Killer Cells; neoplastic cell; novel; novel therapeutics; Phagocytes; Phase; Phenotype; Population; pre-clinical; Property; prototype; Provider; Publishing; Reagent; Relaxation; Research Personnel; Rodent; Route; Sales; scale up; Scanning; Scientist; Side; Signal Transduction; Site; Speed; stability testing; Stem cells; T-Lymphocyte; targeted delivery; Technology; Technology Transfer; Therapeutic; Time; tool; trafficking; United States Food and Drug Administration; uptake;

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.

Public Health Relevance Statement:
This project aims to develop next-generation magnetic resonance imaging (MRI) probe technology to detect therapeutic tumor infiltrating lymphocytes in head and neck cancer patients. Up until now, we have been blind to the behavior of cells after infusion into patients. The probe technology is used to image lymphocyte homing to tumor and persistence of the therapy which may be predictive of responders versus non-responders to treatment. This information can be used to help speed the adoption of these new therapies.

Project Terms:
Adoption; Affect; arm; base; Biodistribution; Biological Assay; blind; Cancer Patient; cancer therapy; cell behavior; Cell Count; cell preparation; Cell Survival; Cell Therapy; cell type; Cells; cellular imaging; Cellular immunotherapy; Clinical; clinical translation; Clinical Trials; cohort; Collaborations; commercialization; cytotoxicity; Data; Data Analyses; Dendritic Cells; design; Detection; Development; Dose; Elements; Engineering; Enrollment; Feedback; Fluorine; Fluorocarbons; Funding; Generations; Germ Cells; Head and Neck Cancer; head and neck cancer patient; Homing; Image; image reconstruction; imaging agent; imaging detection; Imaging Device; imaging modality; imaging probe; imaging properties; Immune; Immunotherapeutic agent; Immunotherapy; improved; In Vitro; in vivo; Infusion procedures; Injections; Institutional Review Boards; Investments; Iron; Label; Lymphocyte; magnetic field; Magnetic Resonance Imaging; Magnetism; Malignant Neoplasms; man; manufacturing scale-up; Measures; melanoma; metal chelator; Metals; Methods; Molecular; nanoemulsion; Natural Killer Cells; neoplastic cell; next generation; novel; novel therapeutics; Outcome; Patients; Pharmaceutical Preparations; Phase; Phenotype; pilot trial; Preclinical Testing; Preparation; programs; Property; protocol development; Protocols documentation; Publishing; Refractory; Reproducibility; responders and non-responders; Route; Safety; Signal Transduction; Site; Solid Neoplasm; Speed; Stem cells; Surrogate Markers; T-Lymphocyte; Technology; Testing; Therapeutic; Time; tissue culture; tool; trafficking; tumor; tumor infiltrating lymphocyte therapy; Tumor-Infiltrating Lymphocytes; United States National Institutes of Health; Work