“The concept is based on the notion that cancer cells have different biophysical properties, (size, shape, stiffness, etc.) from normal healthy cells,” said Lee, the Billy and Audrey L. Wilder Professor in Cancer Immunotherapeutics. “If you can hit cancer cells with the right frequency, inducing harmonic resonance, you can selectively kill those cells.” Lee said the principle behind harmonic resonance is not unlike the opera singer who can break a glass with her voice.
“What we’re doing is finding the harmonic resonance for specific cancer cells, to ‘shatter’ them so they are destroyed. Since this is a totally new way to target cancer based on biophysical properties, cancer cells cannot mutate to become resistant to this therapy — which is called ‘oncotripsy,’” he said. “And sound waves can be transmitted innocuously through healthy tissue. We can potentially transmit sound waves to the brain and only selectively resonate the cancer cells. It’s a very targeted therapy.”
Lee partnered with Caltech’s Michael Ortiz, Ph.D. Lee’s lab contributed a number of cancer cell lines, but also many normal cells to advance the research.
To further the research, Lee applied for biomedical research grants that allowed him to secure postdoctoral fellow Jian Ye, Ph.D., and visiting scholar Caroline Hoffman, M.D., an ear, nose and throat cancer surgeon from the Institut Curie in Paris. “Caroline found out about our work and contacted me, interested in helping us move this project forward. She joined us for a year in late 2019,” Lee said.
A pilot instrument was built on the Duarte campus to mirror the one at Caltech, enabling Lee, Ye and Hoffman to test samples right in the lab without having to transport them back and forth between Duarte and Pasadena.
An important element of this approach is how it kills cancer cells, Lee explained. “Cells can die in different ways. Most common is a process called apoptosis, or programmed cell death. It’s also called cell ‘suicide.’ Most cells in our body die in this way, and it is an ordered cell death. The immune system ignores apoptosis, and it is immunologically silent. On the other hand, if a cell is killed by trauma or by a virus (such as the COVID-19 coronavirus), the immune system is triggered — called ‘immunogenic cell death.’”
Engaging the immune system
Lee said his research posits that the kind of low-emitting sound wave they are experimenting with will kill a cancer cell in an immunogenic way. This is good, because it may also engage the immune system to fight the cancer.
Over time, Lee and his team expanded the repertoire of cancer cell lines being tested, drawing samples from humans and mice to include colon and breast cancer. They also tested a variety of healthy human cells, including immune cells, to check how the treatment affects these cells.
The hope, Lee says, is that the ultrasound will kill cancer cells in a specific way that will also engage the immune system and arouse it to attack any cancer cells remaining after the treatment. “This is critical because it means that we can combine oncotripsy with immunotherapy to potentially cure patients — even with metastatic cancer.”
If ultrasound can be used to cause cell death in a way that the body’s immune system recognizes as injury, instead of as apoptosis, this could lead to the site of the tumor being flooded with white blood cells that could attack remaining cancer cells. So far, all of the testing has been done in cell cultures in petri dishes, but Lee said his team plans to expand the testing to solid tumors and, eventually, living animals.
A one-two punch
“Our plan is to start to increase complexity — everything up to now has been on cell lines and cultures. Now we want to start putting cells into three dimensions to create 3D cells and matrices and using organoids,” Lee said, explaining that organoids are miniaturized and simplified versions of organs produced in vitro to create realistic micro-anatomy. Lee said the team is already doing some nonhuman testing, with the hope to go to in-human clinical trials in the next few years.
“We don’t have to kill every last cancer cell for this to be a successful innovation,” Lee said. “If we can bring the immune system into the equation, your own cells do the rest. Even if we’re able to kill 70 to 80% via oncotripsy, the patient’s immune system will mop up what’s remaining. My ultimate hope is that this treatment will be combined with immune-based therapy for a one-two punch to beat cancer.”