Key Points
- Beyond his recent podcast episode, Dr. Cho shares more about his work, how histotripsy is impacting patients, and what is next for his research laboratory.
- Also, learn more about how the team at the University of Michigan is expanding access to this innovative therapy.
Dr. Clifford Cho is the C. Gardner Child Professor of Surgery at the University of Michigan. His professional focus is on cancer immunology and cancers of the liver and pancreas. His team is investigating the immunostimulatory effects of histotripsy, a method of using focused ultrasound to mechanically destroy target tissue.
We recently spoke with Dr. Cho about his work, the recent strides in using histotripsy for treatment, and what is next for his research laboratory.
Focused Ultrasound Work
When and how did you get interested in focused ultrasound?
I was introduced to the technology of focused ultrasound after I moved to the University of Michigan in 2016. Through a number of fortuitous connections, I was introduced to Zhen Xu, PhD, who is the co-inventor of histotripsy. At the time, Dr. Xu was looking for a clinical partner for her ongoing efforts to optimize histotripsy for the treatment of liver tumors. As she explained the mechanism of action of histotripsy to me, it occurred to us that this non-thermal tumor disruption could also have the effect of stimulating immune responses to tumor antigens released by treatment. We did a small pilot experiment to test this hypothesis in my laboratory, and the results were surprising and promising – and the research grew from there.
What are your areas of interest in focused ultrasound?
At this point, the ability of histotripsy focused ultrasound treatment to trigger anti-tumor immune responses has become the one and all-encompassing focus of our laboratory efforts. Having demonstrated this immunostimulatory effect, our laboratory is working to learn how this effect begins, testing ways in which we could make the effect stronger, and understanding how the tumor microenvironment is altered as a result of this effect.
What excites you most about histotripsy’s potential?
The real excitement is the fact that histotripsy is now a clinical reality. Now that it’s been approved for use against liver tumors, we’re seeing a rapid acceleration and accumulation of clinical experience, and that experience is validating some of the immune effects we have observed in the laboratory. With clinical adoption and the learning curve rising so rapidly, it feels like we’re all running in the same race and on the same team to make sure we learn as much as we can about the biological effects of histotripsy as quickly as we can, so that these insights can be simultaneously translated into what we’re doing in the clinic.
What are your funding sources?
Our research is currently funded by the National Institutes of Health and the Focused Ultrasound Foundation; in the past, we’ve also received funding from the University of Michigan and the US Department of Veterans Affairs.
Research Details
Who are your team members?
I’m fortunate beyond description to work with an amazingly talented and fun research team. Anutosh Ganguly, MSc, PhD, is a faculty research scientist with deep expertise in microscopy and cellular biology; he and I can spend hours speculating, scheming, and dreaming about histotripsy. Brian Song is the world’s greatest laboratory technician – a true workhorse capable of superhuman levels of effort who juggles multiple experiments and piles of data all the time. Heineken Queen Daguplo is an unbelievably talented graduate student who has already made herself an expert in the tumor microenvironmental implications of histotripsy treatment. In addition to this core of talent and creativity, we are fortunate to have a small army of highly trained and motivated University of Michigan students who allow us to be continually productive.
Who are your internal and external collaborators?
There is zero chance that we’d have any success if it were not for our close partnership with Dr. Xu’s University of Michigan biomedical engineering laboratory. She is the driving force behind much of the histotripsy research going on around the country, and I’m extremely fortunate to work with her. She and I co-mentor a number of graduate students who are using their studies to become experts in both biomedical engineering and immunology. I work in close collaboration with Michal Olszewski, DVM, PhD, an immunologist at the University of Michigan whose deep expertise in innate immunity has given us much good advice and guidance over the years. We’re quickly forming partnerships with like-minded focused ultrasound scientists at Virginia Tech and the University of Virginia – and now, as histotripsy is being performed in so many centers, we’re developing collaborations with clinicians around the country.
What are your greatest achievements? Any major disappointments?
My greatest achievement was one in which I played only a part – and that was the #HOPE4LIVER clinical trial. I was lucky to have served as co-Principal Investigator for this trial alongside my friend and colleague Tim Ziemlewicz, MD, a radiologist at the University of Wisconsin. The multicenter safety and efficacy trial explored the use of the HistoSonics histotripsy treatment platform for patients with primary and metastatic liver tumors. Along with a concurrent European trial, we demonstrated that histotripsy liver tumor treatment was effective and well-tolerated. These results prompted the US Food and Drug Administration (FDA) to grant clearance for this procedure in October 2023, ushering in the current era of clinical histotripsy.
What do you see as impediments to your success?
I would say that the biggest challenge has been the effort to accommodate patient demand. Well before the opening of our histotripsy program at the University of Michigan, we began receiving an enormous volume of referrals for treatment that overwhelmed our clinical capacity. In comparing notes with other centers, it appears that this has been a common challenge. Thankfully, we’re currently in the process of opening a second histotripsy site at University of Michigan Health-West in western Michigan, and this increased capacity will allow us to meet the clinical demand for this therapy.
What is your research wish list?
Our next goal is to transition our laboratory focus from treating experimental models (mouse tumors) with histotripsy to more clinical studies using patient tumor samples to validate and expand on our experimental observations. We’re organizing a combined effort between the University of Michigan Health-West and the Van Andel Institute to build a clinical translational research program that will allow us to do this. Beyond that, our wish is to expand the application of histotripsy to other tumors. This will happen after ongoing and pending clinical trials verify that histotripsy is also safe and effective against cancers of the kidney, pancreas, brain, and other sites – because, conceptually, there is almost no part of the body that could not be targeted by histotripsy.
Has the Foundation played a role in your work?
The Focused Ultrasound Foundation has been a critical part of our research work in two ways. The first has been through funding; because this is such a new field, the willingness of the Foundation to fund high risk research proposals has been instrumental to the advancement of focused ultrasound. The second has been through interpersonal connections; by creating such a vigorous and collaborative community of scientists, clinicians, and interested and supportive sponsors, I’ve been able to meet many helpful partners – all in a culture and atmosphere that have been amazingly enjoyable and encouraging.
Clinical Details
How many patients have you treated?
In the first few months of our clinical histotripsy program, we have already treated about 30 patients, and that number is increasing rapidly. Our experience is validating the results of our clinical trial: histotripsy is extremely accurate and effective, and amazingly well-tolerated. A common question we get from patients is whether they actually received their treatment – the absence of side effects after a procedure is something people with cancer are not used to experiencing.
Looking Ahead
What comes next?
I’m currently focused on building a second histotripsy clinical program in western Michigan. This program will be housed at University of Michigan Health-West and executed through the Cancer Network of West Michigan’s multicenter partnership – a collaboration of hospitals and health systems in the Grand Rapids region that is turning cancer care delivery from an arena of competition into an excuse for collaboration. Our vision is to evaluate and treat patients through the Cancer Network of West Michigan and to do this in scientific partnership with the University of Michigan and the Van Andel Institute, where our research laboratory will be able to use patient samples to conduct experiments that will help us understand and harness the immunobiological effects of histotripsy. This ambitious effort will take advantage of our past discoveries in the engineering and immunological aspects of histotripsy and merge them with our accelerating clinical experience and volumes – all with the goal of providing our rapidly expanding histotripsy clinical community with scientific and clinical insights to guide and direct the future of this field.