Dr. Zhen Xu describes a rat study where histotripsy was deliberately used to break up only 50 to 75 percent of an aggressive liver tumor (hepatocellular carcinoma), to test the worst-case fear that mechanically disrupting tumor tissue might spread cancer rather than contain it. Instead, in 9 of 11 treated rats the remaining, untreated tumor tissue disappeared entirely, while untreated control rats died within two to three weeks. This unexpected result led Xu to collaborate with cancer immunologist Cliff Cho to investigate whether histotripsy was triggering a systemic immune response rather than just local tissue destruction.
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Cancer normally evades the immune system by suppressing the local immune response and escaping natural cell-death pathways, which is why cancers like pancreatic or brain cancer often go undetected until late stages.
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Xu describes histotripsy as liquefying tumor cells into acellular debris that the body absorbs through normal metabolism, releasing tumor antigens into the bloodstream rather than leaving intact tumor matter behind.
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Xu and her team are still studying how to tune histotripsy parameters to maximize this immune effect and potentially combine it with drugs to move from local tumor destruction toward systemic cancer treatment.
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The first paper reporting this immune effect was published around 2020, and Xu describes the immune mechanism as a largely unexplored new research area.
1,362 words · auto-generated from the episode video
38:16And also another, uh, just a little quick thing, uh, that people, most people don't know the reason we started liver cancer was because my former PhD student, uh, Eli Wasasich, and he's actually now a professor at Virginia Tech. He was doing PhD with me and we're doing his literacy. He came into my office, uh, uh, after he came in as a new student and he said, I have to do liver cancer as my PhD dissertation, uh, because my mother died of liver cancer when I was a little kid. And, uh, this is, you know, I, I just have to do it. And I, I, I was like, yes, absolutely.
38:59Right. You know, how can you, how can you decline? So, so we started doing liver cancer work and then the whole field is like, okay, first you crazy woman want to do non-invasive surgery. Now you want to use a mechanical non-invasive way to treat cancer. Everybody was freaking out because what if you disrupt cancer cells, and you just help spread the tumor and the cancer everywhere. Yeah. Yeah. You're just like, you're like stirring it up and then, and then it goes everywhere. Yeah. So everybody had this huge concern that histotripsy will actually increase the chance of metastasis because it's mechanically break up tissue.
39:43But what happened is it's not mechanically breaking up tissue. histotripsy is mechanically breaking up the tumor cells, but regardless there was this big concern. So we had to go and do experiments. So what did is we actually had a rodent model and the first actually set of study was in rats where they had liver tumor and we intentionally treat 50 to 75% of the tumor and say, okay, in a worst case scenario, not only break up the tumor, we left something behind. Now we follow them long-term to see if we increase the metastasis rate, right?
40:25Like look for any kind of cancer within the lung at different locations and within the liver in different locations and outside the liver. And it was, and we started our experiments. I still remember we had two batch, one is control mice and one is treated by histotripsy, 11 in each batch. Control mice all died within two to three weeks. It's a super aggressive type of HCC, the hepatocellular carcinoma, primary liver tumor after tumor inoculation. The 11 rats treated, nine of them, not only the tumor didn't
41:08spread, the remaining tumor was just gone. We're like looking for it everywhere. We couldn't find it and we're like, what happened? Why did the residual tumor go away? Because we didn't treat that. And that was completely... That was a completely surprising finding. We were all shocked. Yeah. And where I guess something must be going on. So then I, you know, reach out to Cliff Cho who is this clinical scientist, a surgeon and a cancer immunologist. Now we did this study that you just talked about that paper and he help us looking to measuring all kinds of immune response.
41:48So it turned out that cancer, it does two things very well. And again, I'm also an engineer, so I'm doing this really basic chart. So why is that cancer heights, right? And that's why, you know, you have the patients who is cancer, supposedly a foreign thing come in, our body should kill it. But for cancer, especially surgeon cancer, like pancreatic cancer, brain cancer, you don't even find them until it's very late stage, because it hides so well. Yeah. It like suppresses the immune response around it. Right. And then it also escapes the pathway that body kill it. So what happens with histotripsy is that we disrupt the tumor cells with bubbles
42:33and open up the cell memory, allow the tumor engine to come out. And that's the first step. And the body, and that histotripsy, actually, you know, if you look at texture, it's literally liquefied this tumor into this acyclic debris, then the body absorb it, absorb it through metabolism process. So it doesn't stay there, go to bloodstream, right? So tumor energy come out, and then the body start looking for things. And not only just at the location of the treatment, because it's circulating in the body. So immune system is just circulating and looking for tumor everywhere. And also we trigger this immunological cell death.
43:15So it really start this whole immune cycle. And then the body is helping now really stimulate this immune response and use our immune response to attack the other tumors as well. And, and it, of course, is a process can vary a lot from tumor to tumor, patient to patients, and also with histotripsy to parameters you use can be different. We do, we do see in small fraction of the patients that we treat one tumor, other tumor shrinking, and the we're in the process of studying, how do we really optimize our patient parameter to maximize the immune
43:59response for that patient and combined with drugs, so that we expand this non-invasive focal surgery to eventually systemic cancer treatment. And only at that time we can talk about potential cure, right? And especially for advanced cancer stage. Yeah. Yeah. I mean, it was, it was absolutely incredible when I was reading this and yeah, as you said, I mean, you're a ultrasound engineer by heart. Um, and so you, you called up a collaborator, um, mentioned his name again. Yeah. So he, so, you know, how, how, how was that conversation?
44:39Like, was he at first, like, there's no way, or was he immediately like, I can maybe guess that a mechanism. Well, he doesn't know the mechanism, but he was very open-minded. Uh, he was doing, uh, looking at immune response induced by other forms of treatment, surgery, potentially other patients. And so he was like, okay, you know, let's take a look at least. Right. Um, but I think, uh, it just kind of show you how, um, you know, my career was a series of serendipity, uh, leading to surprising, uh, scientific discovery. And also, uh, I started it with ultrasound engineer, but along the way I
45:24learned so much. It was a continuous learning process over my whole career by working with many, many different collaborators and educating me and keep advancing this. And, and, and, and that's, you know, even though I have been working on only one thing for my entire career so far, uh, but it has been all extremely interesting. Um, and I think that's kind of how the scientific discovery, um, at least in my case goes, is like you, you find, uh, things, um, and, and then you lead to new things, uh, at, at, and I
46:06never, uh, just kind of, you know, ditch away any potential questions or anything. I always trying to, you know, keep an open mind, trying to address it. And if I don't understand, I try to look for and find someone who potentially can help me understand it and keep, and then that's how things get pushed forward. Yeah. And was he also at University of Michigan? Yeah, he was, uh, I was introduced to him because he, he, uh, was at University of Michigan and, and moved from Wisconsin and I had some friends from Wisconsin and now also, uh, uh, and then he also, uh, knew someone from HistoSonics company
46:46I co -founded. So, so really just a kind of different connections. Yeah. Yeah. Okay. Yeah. And now there are more considering knowledge is working on it. So it's really, really becoming this, uh, new field. And it really, uh, a lot of, um, answer question right now is, uh, kind of, this new field with a lot of unknown, uh, now, like we can really go in and explore. Yeah. I mean, this is pretty recent. This is 2020. So, you know, Yeah. And that's the first paper. Yeah. So, so, so it's a really, uh, really, it is a really new field and I invite everybody to call me.