High-Power Intravital Microscopy System Allows Tumor Blood Vessels to Be Seen in Real Time During Surgery

Study in patients with melanoma reveals unexpected tumor vasculature, key implications for systemic therapy

BUFFALO, N.Y. — A team of Roswell Park Cancer Institute (RPCI) researchers has developed and evaluated the first intravital microscopy system shown to be safe for use in humans. Writing in the journal Nature Communications, the scientists report that their proprietary technology enabled them, for the first time ever, to visualize tumor blood vessels in real time. In a small study involving patients with melanoma tumors, the researchers show that this approach to viewing malignancies in real time during surgery is not only feasible, but that it revealed unexpected findings about the vasculature of human tumors, with potentially significant implications regarding the delivery of cancer treatments such as chemotherapy and immunotherapy.

Intravital microscopy (IVM) is a technique for studying tumors at the cellular and subcellular level. Used previously only in animals, this approach has allowed research teams to assess an organism’s physiological responses to systemic cancer treatments like chemotherapy and immunotherapy, allowing them to see, for example, how lymphocytes interact with tumor vasculature.

A team led by Joseph Skitzki, MD, FACS, Chair of the Melanoma/Sarcoma Disease Site Research Group at Roswell Park, designed and constructed a mobile platform for performing IVM in humans in the operating room. While most surgical microscopes allow for 15X magnification, their IVM platform enables magnification of 100X or higher. In their newly published feasibility study, the investigators report their findings from IVM observation of the tumors of 10 patients with melanoma.

“We had to overcome some significant hurdles in order to develop our system, including issues with image stability, visualizing tumors in place, and generating contrast between the vessels and the tumor tissue. But we found ways to address those challenges, and in the course of our clinical trial were able to successfully measure tumor blood vessel diameters and densities in 90% of patients, and blood-flow rates in 70% of patients,” notes the paper’s first author, Daniel Fisher, PhD, an affiliate member of the Department of Surgical Oncology at Roswell Park.

The key findings of this analysis are that IVM can be performed safely in humans; that approximately 50% of tumor blood vessels are nonfunctional (not supporting blood flow) at any given time; and that human tumor blood vessels have much wider diameter than has been indicated by animal studies or pathological analyses of tumors to date.

“What we learned through this first study of intravital microscopy in humans challenges assumptions that have been made about human tumors, and has several important implications regarding drug delivery and immunotherapy. We may learn, for example, that more patients are good candidates for immunotherapy approaches than previously thought,” says Dr. Skitzki, who holds faculty appointments in the departments of Surgical Oncology and Immunology at RPCI.

The team plans to develop these findings through additional clinical and preclinical studies. The researchers note that while IVM was first evaluated in patients with melanoma, they expect that it will be applicable for any malignant tumor that is accessible by surgery.

This research by Dr. Skitzki and colleagues has been made possible in part by a generous donation from the Jennifer Linscott Tietgen Family Foundation, which is dedicated to supporting melanoma cancer research in memory of their daughter, Jennifer. The Foundation covered in full the cost of the intravital microscope, which was central to this work.

“When we lost Jennifer at a young age to melanoma, it was earth-shattering for our family,” the Tietgens say. “We knew we needed to do something to make a difference, and the best way we could think of was funding melanoma research projects. The Roswell Park melanoma team has an advanced understanding of this devastating cancer and is working tirelessly to improve diagnostic testing and treatment.”

The work was also supported in part by three National Institutes of Health grants: awards R01CA79765 and P30CA016056 from the National Cancer Institute (NCI), and R01AI082039 from the National Institute of Allergy and Infectious Diseases (NIAID).

The study, “Intraoperative intravital microscopy permits the study of human tumour vessels,” is available at nature.com/ncomms.