Joo Ha Hwang, MD, PhD, is Professor of Medicine, Gastroenterology and Hepatology at Stanford University. He is also president of the International Society for Therapeutic Ultrasound, a partner organization of the Focused Ultrasound Foundation. Dr. Hwang became interested in focused ultrasound through his work with pancreatic cancer patients: He wanted to find a therapy that would prolong their lives or even cure them. Today he is more optimistic than ever about the possibility of using focused ultrasound to treat pancreatic cancer. Below is an edited transcript of our conversation with him.

Why are you so enthusiastic about this technology?
I've been in this field since 2000, so I've been actively doing focused ultrasound research for 18 years. Much of that research has been looking at enhancing drug delivery for pancreatic cancer using focused ultrasound. We have achieved great results, but the problem has been that there are no real effective chemotherapeutic agents. Even our best agents have very modest efficacy.

We have shown that focused ultrasound can increase the drug concentration into a tumor locally by 10 times, but it's always been tempered by oncologists saying, "This is a systemic disease and we know that these agents don't work very well for metastatic disease." My response has been, "As soon as an effective agent is identified to treat the systemic disease, then treatment of the primary tumor – local therapy – with either ablation or enhanced drug delivery may be effective and limit the need for surgical intervention, which has significant mortality and morbidity."

The reason the immune system story is so interesting is that we no longer need to treat the entire tumor – and that was always a big problem for focused ultrasound ablation. Now we may be able to use focused ultrasound noninvasively to treat just part of the tumor, which will up-regulate the immune response along with the administration of immune modulators.

So you use focused ultrasound to treat part of the tumor. What happens after that?
Pancreatic tumors have what is called "immune privilege," meaning they can evade the immune response. By administering focused ultrasound to part of the tumor, it has the potential to wake up the immune response by saying, "Hey immune system, there's a tumor right here!" The immune response then replies, "Oh, tumor right there."

A signal that triggers an immune response against tumor antigens is produced from ablation by focused ultrasound. The immune response can be further enhanced by the administration of new immunotherapy drugs to boost the immune response to attack the tumor. Not only does it attack the tumor where you target it with ultrasound, it also attacks it wherever it is in the body resulting in a systemic response.

One big problem with pancreatic cancer is that at the time of diagnosis there is what's called micrometastasis – meaning, the tumor has spread even though we can't see it on imaging. That's just the nature of pancreatic cancer. Immunotherapy may allow us to treat just part of the tumor to activate the immune response to attack the cancer where ever it may be in the body, and focused ultrasound is the best modality for doing this because it's noninvasive, it's cost-effective, it can be done on an outpatient basis, and it might not require sedation. If we can get all the pieces together from all the data we have, it may work. We just have to figure out what the right combinations are.

This really is the first time that I have felt that this might work. So, it really is exciting.

Immunotherapy

What was the moment when you thought to yourself, "Hey, this really might work?"
It's an evolution, but it's always something we thought about. There are reports going back 20 years where a patient got treated with focused ultrasound in one spot, and the tumor regressed in another spot. On the other hand, there are other stories where a tumor was ablated and it did the exact opposite and the tumor grew rapidly. Unfortunately, we don't understand all the mechanisms – but we're getting closer.

A lot of this is because we now have a dialogue. In the past, people in the focused ultrasound field didn't really interact with people in immunology. The Focused Ultrasound Foundation really did help in increasing awareness of this potential to the immunology community (PDF).

Maybe about five years ago we started to get people from the immunology community coming to focused ultrasound meetings, and they'd say "Hey, there might be something to this." And now I'd say a large percentage of our research has some component of immunology to it. It used to be all about ablation. Now the story is about how focused ultrasound can synergize with immunotherapy (PDF) and other therapies like chemotherapies to improve outcomes in patients with all forms of cancer.

Pancreatic cancer and glioblastoma are two of the deadliest – both without good therapies now. But that's also what makes this the ideal field to investigate. Since there aren't good options, the field is more receptive to novel therapies, as long as they make sense and are biologically plausible.

What's the timeframe for when we're using this regularly to treat pancreatic cancer?
We still need to do rigorous preclinical studies. There are so many permutations that need to be looked at in terms of the optimal target, the timing, which inhibitor or immune modulator we should be using. The parameter space is too large right now. There is too much that is not known. Fortunately, we have an idea of what the targets are. We just need to figure out the optimal approach in terms of which immunotherapy we use, when we give the immunotherapy, and when we do the focused ultrasound treatment.

Rigorous preclinical studies are still needed before we move to clinical trials. But I'm hoping we'll be doing the first focused ultrasound treatment in pancreatic patients in two years, best case. Worst case, it's five years. It might not be here in the US, and I wouldn't be surprised if in the next one or two years some investigators try to do these treatments outside the US, and we start hearing reports of these trials being done.

We often have a lot of the ideas and get funding from the National Institutes of Health to do the preclinical trials in the US, but the regulatory environment here is a little bit more challenging to translate this to clinical trials.

One of my first projects was to try to develop an endoscopic focused ultrasound system, and we're still working on that. With that system, it would have been extremely difficult to ablate the entire tumor. But if I'm just looking to ablate part of it, or disrupt part of it, focused ultrasound is the best way to do that. I already know of several devices out there that can do this. The technology is already there.

Now all we need to do is put the pieces together. It's just like a big puzzle. We just have to get everyone together – surgeons, oncologists, gastroenterologists, immunologists, radiation oncologists. If we are able to get everyone in the room it becomes pretty obvious once you educate everyone. We all want to cure pancreatic cancer.

I wouldn't be surprised if after this meeting [6th International Symposium on Focused Ultrasound] some of these people who have access to these devices and immunotherapies outside the US start doing it. We wouldn't do this in the US at this time because there's too much we don't know. But the story is there. It's compelling. And we just have to put it together correctly.

Additional Resources
Focused Ultrasound for Pancreatic Tumors
Webinar: Joo Ha Hwang – Focused Ultrasound for the Treatment of Pancreatic Cancer
Pancreatic Cancer Study Shows Potential Survival Benefit

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Joo Ha Hwang, MD, PhD, is Professor of Medicine, Gastroenterology and Hepatology at Stanford University. He is also president of the International Society for Therapeutic Ultrasound.

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