By Aaron Krol
March 14, 2016 | Last week, at the Molecular Medicine Tri Conference in San Francisco, Calif., Xcell Biosciences announced the commercial launch of the Avatar System, a cell incubator designed to mimic real-life microenvironments inside the human body. The platform takes aim at the problem of preserving primary tissue—cell samples collected directly from patients—for long enough to perform experimental or clinical tests, without distorting those cells’ physiology and genetic activity.
This problem, says the Xcell team, is particularly acute at a time when many molecular tests are moving beyond DNA to look at cells’ expression of RNA and protein, which can quickly be altered by their physical environments. “The message we’ve been hammering home is that cells cultured under different conditions are going to be behave very differently,” says Chief Scientific Officer James Lim—and that in turn affects how meaningful test results are for understanding diseases and, ultimately, treating patients.
Traditional cell culture incubators control only a few variables, notably CO2 concentration, temperature, and humidity. Few human cell types can survive and grow for long in the unnatural environments of these machines—and even the immortal cell lines that do fare well in incubators tend to acquire radical mutations over several generations in the lab. “The dogma, at least when I was in graduate school ten years ago, was that you could not maintain and grow primary tissue in culture,” says Lim. “They would die before you had the chance to perform any experiments.”
Xcell did not overturn that dogma itself. The burgeoning field of stem cell biology has led academics to develop new and improved culturing techniques to preserve these fragile cells, which tend to differentiate and lose their unique properties if not very carefully maintained. There has also been growing interest in characterizing the human microenvironments in which different cell types, especially cancer cells, thrive. Lim especially credits the work of Gregg Semenza at Johns Hopkins University and Rakesh Jain at Harvard for elucidating the balance of pressure, temperature, oxygen and carbon dioxide found in different tumor types.
The Avatar System is designed to make these discoveries practical to apply in the lab. “We took the basic principles from stem cell culturing, and applied them to primary tissues—specifically biopsies, fine needle aspirates, and peripheral blood,” says Lim. The technologies involved are eclectic: to control atmospheric pressure, Xcell adapted engineering from the diving industry. Yet together, they allow the Avatar to tune the conditions of cell cultures much more finely than a typical incubator. In particular, the platform can bring oxygen content as low as 0.1%―a level that might be found in a highly necrotic tumor core―without using the chemical treatments found in dedicated hypoxia workstations.
Lim says his company’s approach should let lab technicians keep most if not all cell types for longer, and with less damage, than they could with incubators. Early access customers, who have been using beta versions of the Avatar since late 2015, have focused especially on cancer samples, including circulating tumor cells from whole blood, and stem cells. Internally, Xcell has kept embryonic stem cells for more than two weeks without seeing differentiation, and has expanded other types of primary cells for as long as six months.
Many of the potential applications for the Avatar are in basic research. Academic scientists might use the system to more accurately measure the RNA and protein activity of tumors as they would appear in the body. Because the Avatar can be used to expand cell lines without their incurring major mutations, it may also be useful for getting full DNA profiles of very rare cell types like circulating tumor cells, whose DNA would otherwise be found only in trace amounts.
Users in the pharmaceutical industry might further adopt the platform for early, preclinical drug tests. “Pharma are really interested in whether their PDX [patient-derived xenograft] models or cell lines they’ve developed will respond to a set drug, or whether they express a drug target, in these culturing conditions,” says Lim.
However, the Xcell team is particularly excited about the clinical potential of their product, as a part of ex vivo diagnostic tests on patient samples. Presently, the Avatar is sold for research use only, but Xcell is coordinating with the University of California, San Francisco, on two planned clinical trials in cancer treatment. In these trials―which have institutional review board approval at UCSF but have not started recruiting―patients with pancreatic and prostate cancer would be randomized into groups where their tumors’ RNA expression would be regularly measured using either the Avatar or a traditional incubator. Oncologists would then bin patients into different treatment groups based on these RNA profiles, trying to assign targeted drug regimens where possible, and less aggressive treatments in more benign cancers.
Xcell envisions these trials as aiming for overall patient survival, perhaps in addition to quality of life indicators, a sign of the company’s confidence in the Avatar’s diagnostic value.
For now, laboratories that want to use the Avatar can order the device for research purposes. Xcell also provides culture media, device support, and guidance on the optimal conditions for different cell types―a body of knowledge the company expects to grow as more experiments are performed.