February 1, 2012 (Vol. 32, No. 3)

Neil McKenna, Ph.D.

In vivo imaging, an umbrella term for a spectrum of technologies that facilitate visualization and quantitation of functional and anatomical events within a whole animal or person, is an area of intensive research and development. Many companies and academic centers are actively engaged in developing and refining methodologies to monitor a wide range of parameters, from larger scale measurements such as tumor size and morphology to subtle but critical indices at the cellular level, such as metabolism, subcellular dynamics, and motility.

Using these techniques, instead of more invasive methods, data points can be amassed on a much earlier time scale in a variety of contexts (e.g., monitoring the efficacy of drug candidates in clinical trials). Techniques commonly employed in in vivo imaging, depending upon the application, include magnetic resonance imaging (MRI), x-ray computed tomography (CT), positron emission tomography (PET), optical imaging, and more recently photo acoustic imaging (PAI).

GEN spoke to a number of scientists from companies and research laboratories, several of whom will present at this month’s Wellcome Trust “Mouse Models and Disease” conference about their in vivo imaging programs.

A major focus of research the laboratory of Kevin Brindle, Ph.D., at the University of Cambridge, is to develop imaging methods that guide therapy by allowing for the earlier evaluation of the efficacy of a drug in a particular patient in a clinical trial.

“Assessing the efficacy of an antitumor drug, for example, relies on tracking a decrease in tumor volume over time—a period of days or even weeks—and some cytostatic treatments don’t even have an impact in terms of tumor size,” said Dr. Brindle.

MRI is commonly used in the clinical setting to visualize internal structures. In a collaboration with GE Healthcare, Dr. Brindle’s lab is developing a novel MRI-based approach that boasts a 10,000-fold increase in sensitivity over conventional MRI methodologies.

The novel technique detects small carbon metabolites, which are present at a much lower concentration than water, which is the imaging target for conventional MRI.

“We take radiolabelled derivatives of these metabolites, such as pyruvate, and supercool them to just above absolute zero in order to align the spins in a field and give us a fabulous increase in sensitivity,” explained Dr. Brindle.

The rate at which individual cells metabolize the compound can then be correlated with the effect of the drug on those cells’ metabolism. “When we treat a tumor, we see that its metabolism is slowed,” he continued. “In some cases we can obtain very rapid feedback on drug action, on the order of 24–48 hours.”

Getting a jump on tumor cell response in this manner affords clinicians the opportunity to alter or adjust therapies much sooner than would normally be possible, which ultimately translates to improved therapeutic practice.

Dr. Brindle listed several advantages that his lab’s adaptation of MRI holds over PET, which is widely used in the clinical setting, particularly in the diagnosis of tumors of the prostate and brain.

“The glucose surrogate typically used in PET, fluorodeoxyglucose, isn’t taken up well by the prostate and is, in fact, preferentially taken up by the kidney, which limits the use of PET in prostate cancer,” he said.

Citing the high background glucose levels in the brain, Dr. Brindle went on to point out that it can be difficult to discern specific brain signals using PET.

Finally, the increased radioactive hazard that PET-based techniques carry limits the number of repeat exams that a clinician might run during early evaluation of a patient.

Dr. Brindle’s adaptation of MRI is currently being used in a prostate cancer trial under way at the University of California, San Francisco. It it is also slated for trials of glioma, lymphoma, and breast cancer.

“Its potential application isn’t limited to oncology,” he emphasized. “We are planning studies in cardiac imaging and kidney disease, so this could potentially have widespread application in the clinic.”

Innovative Techniques

Research at Animascope focuses on two main subdisciplines of imaging.

“One of our projects is aimed at developing innovative nuclear and optical imaging tracers for oncology and diabetes in the biomarker field,” said Arnaud Briat, Ph.D., CSO. “In the equipment field, Animascope is setting up a collaborative consortium to develop a new generation CT scanner based on an exclusive license recently acquired by Animascope in the preclinical, veterinary and human clinical fields.”

Animascope is also developing another project that aims to replace current invasive methodologies by x-ray imaging technology in the toxicology field.

“Longitudinal whole-system datasets generated by noninvasive imaging provide a platform for investigating the time course relationship between target, disease state, and therapeutic. This data can be extremely valuable in interpreting early clinical results,” noted Dr. Briat.

Soluble T-cell receptors (TCRs) are an entirely novel class of targeting agent for cancer and diabetes since they zero in on antigens not accessible to monoclonal antibodies. A recent TCR-based Animascope research project has garnered a Eureka label from the High Level Group of the EU’s European Innovation Institute, which recognizes groundbreaking research applications with significant potential for commercial success.

The application, ANIDIAG, is based on leveraging a SPECT (Single Photon Emission Computed Tomography) imaging platform to detect radiolabelled TCRs, which were developed by Immunocore, that have greatly enhanced affinity for target antigens and which have potential as therapeutic agents in cancer and type I diabetes.