Tamarah Westmoreland, MD, PhD, Pediatric Surgeon at Nemours Children’s Hospital in Orlando, Florida, and Joseph Mazar, MD, Research Scientist at the same hospital, talk about using the Zika virus to cure childhood cancer.
Interview conducted by Ivanhoe Broadcast News in 2024.
Can you tell me a little bit about neuroblastoma?
Westmoreland: Neuroblastoma is a tumor that we see in children. It can occur in the abdomen above the kidney in the adrenal gland. That’s one of the more common places. It can also occur along the spinal cord along the nervous tissue, and it’s of what’s called neural crest origin. It can represent up to 15% of cancer deaths in children.
Is it a pretty aggressive cancer?
Westmoreland: It depends on the type of risk that the patient has. And what I mean by that is, patients can have lower-risk tumors or intermediate-risk tumors. And in general, these patients do quite well but if the patient has high-risk neuroblastoma, their survival at five years is approximately 50%. So these are the patients that my lab focuses on.
What is the traditional treatment?
Westmoreland: For high-risk neuroblastoma, it’s actually quite involved and involves chemotherapy, radiation, surgery, tra- bone marrow transplant. So it is very involved and still only with approximately 50% survival at five years. And that’s why, again, we focused on looking at novel therapies.
Is this an adult cancer, or tumor, as well? Is it always kids? Is it a certain age that it usually develops?
Westmoreland: So it’s primarily children, and it’s usually your younger children, your toddlers around that age. You can see it in older children, occasionally in teenagers, but in all likelihood, it’s probably been there. And so like I said, most commonly, it’s in that toddler age group.
You are leading the study on using the Zika virus. Can you tell me about that?
Westmoreland: A few years ago, Zika virus was an issue in Miami, and there were multiple infections and papers were coming out. And so in 2016, a paper came out looking at Zika virus but within the paper, it noted that immature neurons were sensitive to Zika viral exposure but mature neurons were not. And Dr. Mazar and I looked at this paper and we’re already studying neuroblastoma. And so we recognize that neuroblastoma is an immature neuron or a neuroblast and that really kicked off the whole study, initially looking in just cell culture, and these are human tumors that we were able to obtain from the children’s oncology group, and we published that in 2018, and the study currently is building on that.
Can you give me a little idea about Zika from mosquitoes, and is it the one that causes unborn babies’ brains not to develop?
Westmoreland: So Zika virus is a virus that is spread by mosquitoes and there is a congenital Zika viral syndrome, and that’s where a fetus is exposed to Zika virus. And as you mentioned, that those children can have issues with their brain development. Well, we’re not surprised by that because immature neurons are sensitive to exposure to Zika virus just like neuroblastoma, which involves immature neurons or neuroblast is sensitive. However, in the baby who was born in the child, and the adult, if you have exposure to Zika virus, the symptoms are very mild. Many times you don’t even know you have it or you can have cold-like symptoms for a couple of weeks and then it fully clears. So really, when the neurons are mature that they show resistance to Zika viral exposure.
When you did this study, did you inject just the plain Zika virus into a mouse?
Westmoreland: Yes. So we did not modify the virus. As a matter of fact, this is what’s called index strain or original strain of Zika virus. And what we did after growing the tumor on the flank of the mouse is we injected the virus at the edge of the tumor, and the virus itself spread across the tumor to kill the tumor. And what was left was primarily scar.
When you say that, it’s more than that because tell me the difference in the study from the tumors that it got a saline treatment to the tumors that got the Zika virus.
Westmoreland: So the tumors that received the saline treatment or the control, those tumors grew, and I mean, they grew significantly during the same time period that the tumors that did receive Zika virus were shrinking in size. As a matter of fact, we did what’s called survival studies. So we exposed the tumor to either Zika virus or saline and followed them over time. And even after that last control mouse left the study because of the increased size of the tumor, and the Zika viral treated tumor was shrunk to almost nothing. We followed them past that to confirm that we were not seeing recurrence of the tumor. And this was only after one injection of Zika virus.
What makes Zika virus different than any other virus that you could use?
Westmoreland: Viruses have been studied and continued to be studied as potential therapies. The unique nature of the Zika virus is that its symptoms are very mild and so you don’t have to modify this virus. As a matter of fact, those of us who have gone to Miami or live in Florida very well may have been exposed to Zika virus and didn’t even realize it.
What’s next for this?
Westmoreland: When we are looking for translation of this research to help children. I think about how do I make the mouse more like a child. And one way to do that is working with a mouse with an intact immune system and studying that and we actually currently have those studies going. And then also to grow the tumor in a similar location to a child so above the kidney and instead of on the flank of the mouse. So we- we actually have those studies ongoing right now.
Can it work for any kind of tumor then?
Westmoreland: So we know that Zika is working in neuroblastoma because neuroblastoma expresses a protein on its cell surface. It’s called CD24, and Zika is serving almost like a smart missile to that CD24 positive cell. So other tumors that do express CD24 have the potential to be treated by Zika virus and our lab has looked at other tumors and are studying those right now.
What would those be?
Westmoreland: One is hepatoblastoma, which is a tumor that’s in the liver. We also study diffuse intrinsic pontine glioma, which is a deadly brain tumor in children.
Are these all tumors that happened in children and is there a certain type of protein that is more common in children then?
Westmoreland: Well, that protein is important in development. And so normally though it’s turned off later, once for example, the nervous tissue has developed. So it’s not that the protein is in children, it’s that the protein is in developing tissue.
Anything else?
Westmoreland: I would say, I think basic science research and translational research is very important. And we do not have this in a clinical trial yet. However, clinical trials happen because of translational research, and we are very hopeful and we hope that this also gives families hope as they’re the ones, the children, and the families, they are dealing with this on a daily basis.
Do you feel like it’s amazing that you might be on the cutting edge of, maybe, destroying this tumor?
Westmoreland: I think it’s a little unreal. But, I’m very thankful and hopeful along with my families. I have a very close relationship with my families of children with cancer, and that is what I dedicate my career to.
Zika virus is not something that I think comes to mind when it comes to saving lives?
Mazar: Right. No, I wouldn’t have thought so myself. Actually, so this entire idea came about in 2016. And so we found a paper that was published based upon the epidemic in South America. And what they showed in that paper was that. So the original idea for Zika virus came from a paper that was published in 2016, and this was about the epidemic in South America. And what was peculiar is that they discovered that normal mature neurons were completely unaffected by the virus. But neurons that were developing, so we call them neuroblasts, they were hypersensitive. And so the neuroblasts were killed by the virus even when mature neurons were in the same location. So this virus was not a generalized infecting virus. It was very specific. It’s a smart missile. It was targeting certain cells and only those. So I went to Dr. Westmoreland and said, well, we have been working for years on a potential therapy for neuroblastoma. Well, neuroblastoma is simply a disease of these immature neurons called neuroblasts that become cancer. So they are differentiating cells that have not matured. And so I asked her, well, if neuroblasts are sensitive to the virus, would neuroblastoma also be sensitive to the virus? And so we spent the next few years studying that and found overwhelmingly, neuroblastomas are wiped out by this virus very quickly and very efficiently. And so that’s what started the entire project.
What makes it? Tell me about CD24.
Mazar: Sure. CD24 is a gene, it’s a protein that appears on the surface of cells, but it only appears on the surface of cells when they are developing. So think of it as their teenage years. But once they become adults, they get rid of CD24. They don’t need it anymore. And so for example, in this case, neurons which are mature, they don’t express it anymore. They don’t have it. But neuroblasts who are these differentiating the teenagers, they have that marker, and that appears to indicate sensitivity to the virus. So when you have that marker, those cells get infected, they get killed and very quickly. So the real shock and surprise of this study is the fact that when we form these tumors in mice, and these are human tumors, and they have this marker, and we introduce the virus, the tumors get eliminated and the mice are untouched because the mice are predominantly mature cells. So you can see a gradient as the virus is basically burning its way through the tumor, completely eliminating it, and the surrounding tissue is perfectly fine. The mice are perfectly healthy. They don’t even know that anything is happening at all.
When you’re working with the child, I’d have to think that there’s more developing cells?
Mazar: Actually, that’s not really true. At any one time, we have a very small percentage of cells in our body that are developing. But the thing is that they’re disseminated throughout our entire body. Zika does not have some magic way to appear next to a developing cell. It has to find it, has to be in direct contact. So at any one time, we have very few actual cells in development in any one tissue. But the tumor is 100% a developing cell. And so this is why the virus is able to eliminate the tumor, but the host actually then eliminates the virus because those mature cells resist it.
Was it surprising to you to have something like this that’s actually natural?
Mazar: Yes.
To come in and wipe something out?
Mazar: We never expected anything like this. Even when we saw it in cells, which was very impressive, the fact that in an animal, that the virus itself is almost entirely innocuous. So in human beings, it’s 80% asymptomatic. So most people that have Zika, you wouldn’t even know you had it. You have no symptoms whatsoever. You’re totally healthy. In the mice, it’s the same thing, but the tumors have no resistance to it and so they get completely wiped out, and it’s very quick. We normally see within 7-10 days. The mice are monitored for another 4-5 weeks just to see if there are disease symptoms, or if the cancer could potentially recur. And overwhelmingly, there’s no recurrence. The tumor is killed, it doesn’t come back, and the mice stay healthy the whole time.
Interviewer: And the last, you just said a week from a tumor, a full sized tumor to just scar tissue?
Joseph Mazar: Yeah. So this was actually something we worked with one of our pathologists actually at Nemours and so we gave him the tissue, and this was blinded. So he had no idea what it was, or what we were looking for. And we simply said, tell us what you think it is and what happened. And he came back to us and said, well, it appears at some point, this was a mass, potentially a cancer, but all it is now is just dead tissue. It’s a scar. But there’s no cancer anymore.
Does that even amaze you and you’ve seen a lot?
Mazar: Completely blows my mind. I’ve been doing science research for 30 years. I’ve never seen anything like this. You simply don’t. There’s really no experimental conditions I’ve seen that can produce such a selective response with basically no side effects at all. So that’s why we feel that this study is so unique. You have human tumors that are being eliminated rapidly, efficiently, no recurrence, and no side effects. I don’t know how to beat that.
What’s next for this?
Mazar: So there are a couple of different studies that we’ve wanted to do as follow ups. So one of the questions is, what is the immune response to Zika? Within the paper, there’s actually quite a bit of information on that, but there are some gaps, and so we’re working on those as well. Generally speaking, we just want to know how is the immune response on a person, a mouse, that thing, responding to the presence of the virus. And so far, the answer has been really nothing. The anti viral response from a host. So we all have this, mice have it, we have it, appears to eliminate the virus on its own. And so most of those questions have actually been answered, but there’s plenty more we want to do. Another is, what is the combination benefit with chemotherapy? So in other words, we’re not saying that you’re getting rid of chemotherapy, but what if we could as a combination, limit the amount that’s needed because chemotherapies can be very toxic, but it has an additive effect. Small amounts are much more tolerable than long term. And so if this is done as a complimentary study, we can cut that time down considerably. And so the long term effects of that would be cut down as well. There are other studies we want to do. One is called orthotopic. What that means is you put the tumor precisely where you would find it in a human being. You try to mimic human conditions as much as possible. So that’s something we’re actually preparing to do this summer. We’ve done actually with human tissue, and so we know that with human tissue, so for example, we had a sample that was resected here, so surgically removed from a patient at Nemours. They took that sample, went to pathology, pathology acquired what they needed from it, gave us the rest. On the same day, we took it to the lab, we put it in a dish, we added Zika virus and within five days, it was completely destroyed. So we know that this is not simply cultured cells or mouse models, we literally took a tumor from a patient the same day treated it and showed that the tumor could be completely eliminated. So now it simply comes down to in a human being, while it’s still in them, that study needs to be done.
What will the immune system do?
Mazar: Potentially but, I mean, Zika is not a new disease, it may be newer to the media, but it’s been around 70 years and typically speaking, an average year, there are as many as 2 to 300,000 people infected with Zika globally. So we know it’s a very mild disease, this is the reason why it is that it was such a shock in 2015 when they saw fetal effects but before that, everybody considered this was a trivial disease and it wasn’t worth their attention. So we know that once a person is literally born and from the age of birth and on, Zika is overwhelmingly a mild disease, if at all, overwhelmingly asymptomatic and only about maybe 20% symptomatic, and those are cold-like symptoms. They’re not long term, so once you get rid of it, about eight to 12 days, it’s gone. So as a disease goes, this is a perfect storm. We have about as mild a disease as possible for people and yet as aggressive as possible for the cancers. That’s a combination that I have never seen in the field of cancer treatment.
Would this only work in children?
Mazar: Oh, no.
Across the board?
Mazar: So we studied neuroblastoma because Nemours is a pediatric hospital, so our specialty and our focus is always going to be on children. That being said, we know that it works in other systems because CD24, this marker that identifies sensitivity, it’s not unique to neuroblastoma, it’s actually on developing cells throughout the body, so there are plenty of systems that use CD24 during development and once cells reach development, they stop using it, so it’s a very narrow window. So in any person at any one time, the number of cells that are sensitive is few and they are disparate, they’re separated within our body. The tumor, on the other hand again, is 100% CD24, and so all of it is sensitive, so that’s why it is as a treatment, we recommend its use as a local. This is not something that’s intended to be systemic because it would dilute.
You would just put it right in the tumor, right?
Mazar: Right into the tumor. So in oncology, one of the first steps for treating a cancer, a solid tumor is induction therapy, and then followed by that, what’s called bridge therapy. Well, the euphemism for those techniques is local control. That’s exactly what we’re saying. The very first steps for treating a solid tumor is to introduce locally. Well, that’s exactly how Zika works best. So we actually also studied in mice to see, well, we introduce it locally, but does it spread everywhere? It’s a virus. Why wouldn’t it? What turns out, not really actually, it does it terribly. So we find more than 10,000 times more virus at the tumor than anywhere else in the host and in fact, within 10-12 days, there’s almost no detectable amount of virus left anywhere except the tumor. So it’s capable of spreading, but it doesn’t take very well in fact, it takes badly and so the body seems to eliminate it beautifully, whereas the tumor can’t.
Anything we’re missing?
Mazar: The mouse before control is here. So that’s Week 9 of the tumor being grown inside the mouse. This is at Week 11 when we use a control, so this means that we’re just giving it saltwater, saline. And this is at Week 11 when we give it the virus and so you can see from the color, that’s the size of the tumor and the depth of the tumor, so the red is the deepest part. This is all that’s left after Zika virus with just two weeks.
And then over here is the histology showing the treatment effect of how Zika virus has killed the tumor, so that looks very nice the way that’s laid out there.
Mazar: So at this Week 11, these samples were removed, and this is what the tumor looks like when it is given a control, so no virus, and this is what happens to it when you give it virus and so all of this light pink is dead. So the virus has basically burned its way through and effectively eliminated the tumor.
END OF INTERVIEW
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