Natural Killer Cells and Childhood Cancer – PediaCast 517

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Show Notes

Description

• Dr Dean Lee visits the studio as we consider natural killer (NK) cells. Learn how scientists genetically modify and grow these cells in the lab with the aim of helping kids fight cancer. We hope you can join us!

Topics

• Natural Killer (NK) Cells
• Childhood Cancer

Guest

• Dr Dean Lee
  Principal Investigator
  Center for Childhood Cancer and Blood Diseases
  Nationwide Children’s Hospital

Links

• The Abigail Wexner Research Institute at Nationwide Children’s Hospital
• Center for Childhood Cancer and Blood Diseases at Nationwide Children’s Hospital
• Lee Lab at the Center for Childhood Cancer and Blood Diseases – Nationwide Children’s
• How Our Immune System Works – PediaCast 462
• Genomics 101: An Introduction to Next-Generation Sequencing – PediaCast CME 075
• Optimizing the Body’s Natural Cancer Killers – Pediatrics Nationwide

Transcription

Announcer 1: This is PediaCast.

[Music]

Announcer 2: Welcome to PediaCast, a pediatric podcast for parents. And now, direct from the campus of Nationwide Children's, here is your host, Dr. Mike.

Dr. Mike Patrick: Hello, everyone, and welcome once again to PediaCast. It is a pediatric podcast for moms and dads. This is Dr. Mike coming to you from the campus of Nationwide Children's Hospital. We are in Columbus, Ohio. It's Episode 517 for May 5th, 2022. We're calling this one "Natural Killer Cells and Childhood Cancer". I want to welcome all of you to the program.

0:00:56

So, we have a really interesting episode for you this week, especially if you enjoy the science side of our conversations, which I know many of you do because one of our most popular episodes at the height of the COVID-19 pandemic was one called "How Our Immune System Works". And if you've missed that one, I will put a link to it in the show notes for this episode, 517, over at pediacast.org so you can find it easily.

Today's episode sort of build off that one as we consider a particular type of cell in the immune system, one called natural killer cells, also known as NK cells. Because these cells don't really like to be referred to as killers, so scientist made a softer less controversial name for them, NK cells. However, they really are killers and they kill other cells in the body. And in particular, they kill cells infected with viruses because remember, viruses hijack cells and turn them in to virus-producing machines or factories. So, natural killer cells destroy the factory by killing the cell.

0:02:06

Well, it turns out NK cells also kill cancer cells which is pretty cool because that provides opportunities for isolating these cells, growing more of them in the lab, genetically modifying them to be more efficient and effective at tracking down cancel cells and killing them while living non-cancer cells alone, which is something that chemotherapy and radiation is unable to do. So, there's still much work to be done but we are definitely making progress with these natural killer cells or NK cells especially in the treatment of cancer.

And our guest today is an expert on NK cells, Dr. Dean Lee:. He is a principal investigator with the Center for Childhood Cancer and Blood Diseases at Nationwide Children's Hospital. And his lab has developed techniques for working with this natural killer cells with the aim of using them to fight childhood cancer.

0:03:05

So, we'll having an interesting and science-y conversation today, yes, but we would also break down the terminology and explain things as we go. Dr. Dean Lee: will be here soon but, first, let's cover our usual quick reminders. Don't forget, you can find PediaCast wherever podcasts are found. We're in the Apple and Google podcast apps, iHeart Radio, Spotify, SoundCloud, Amazon Music, and most other podcast apps for iOS and Android, including a new one, a Goodpods. We are now in the Goodpods app.

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0:04:03

I want to remind you the information presented in every episode of our program is for general educational purposes only. We do not diagnose medical conditions or formulate treatment plans for specific individuals. If you have a concern about your child's health, be sure to call your healthcare provider. Also, your used of this audio program is subject to the PediaCast Terms of Use Agreement which you can find at pediacast.org.

So, let's take a quick break. We'll get Dr. Dean Lee: settled into the studio and then we will be back to talk about natural killer cells. It's coming up right after this.

[Music]

0:05:07

Dr. Mike Patrick: Dr. Dean Lee: is a principal investigator with the Center for Childhood Cancer and Blood Diseases at the Abigail Wexner Research Institute at Nationwide Children's Hospital. He's also a professor of Pediatrics at the Ohio State University College of Medicine. Dr. Lee has a special interest in our body's natural killer cells, which are an important part of our immune system's response to viral inspection and cancers.

Turns out, natural killer cells can be genetically engineered in the lab to respond more effectively to some cancer cells which holds promise as a treatment for cancer when that is highly selective of the cells we want to eliminate, more specifics on the science of that in a moment. But first, let's meet our guest Dr. Dean Lee:. Thank you so much for stopping by the studio today.

Dr. Dean Lee: Thanks, Mike. Glad to be here.

Dr. Mike Patrick: I really appreciate you taking time out of your busy schedule to join us. I think a good place to start would just be a definition. What exactly are natural killer or NK cells?

0:05:59

Dr. Dean Lee: So we have variety of kinds of white blood cells in our blood and those have all kinds of different functions. You can broadly split them into cells that are of what we call myeloid lineage, the neutrophils and monocytes and cells that are lymphoid lineage. In the lymphoid category, there's B-cells and T-cells. Lots of people know about those. Those are the cells that respond when you get a vaccine.

And then, there's NK cells. And NK cells are called that, very creative name-calling, right, because they had this natural ability to kill cancer just when you look at them in a dish.

So, B-cells and T-cells have to be trained. You get a vaccine, you train those cells to recognize chickenpox and for the rest of their lives, the B-cells and the T-cells that responded will only recognize chickenpox. NK cells don't really look at specific things. They look at general science of safety and danger and therefore look at naturally occurring pieces that tell them that the cell is dangerous and will kill those cells without ever having been trained to do so.

0:07:06

Dr. Mike Patrick: And that would include cells that are making virus because when we get sick with the virus, those cells turn into little factories, making more virus. So the NK cells will attack those cells and kill them to stop the factory. But then, they can also recognize there's something different about this cell that is a cancer cell and attack those as well.

Dr. Dean Lee: In both cases, the cells are stressed. So the virus puts a lot of stress on a cell to be manufacturing all those virus particles, so in terms of metabolism and sometimes even in terms of DNA damage and in terms of internal recognition of these foreign nucleic acids and foreign proteins. So the stress then causes what we call stress receptors to come up on the surface. And an NK cells sees those stress receptors and says, "There's something wrong with you. You're not behaving normally."

Cancer does a similar kind of stress. It induces defects in the DNA. There's lots of mechanisms for not repairing DNA in cancer and metabolic stress because cancer cells are just really growing fast and put it in a kind of a stress on the cell. And this is the same kind of stress receptors, stress ligands on the surface that the NK cells can see.

0:08:19

Dr. Mike Patrick: So these are really the first cells that often respond to problems because, as you mentioned, so the T-cells have to make more of themselves in order to respond to a certain invader, like a virus or a cancer. And the B-cells have to start making antibodies. And there's sort of a delay in that process. So those NK cells really are the first line of defense of the immune system, right?

Dr. Dean Lee: Yeah, important for bridging the time that it's going to take for the T-cells and B-cells to respond and also for setting up the kinds of signals that tell the B-cells and T-cells that something needs to be responded to.

So, they're sort of the first wave of the Green Berets, not only did they clear out space for the rest of the troops to come in, but they also send out the signals that everything is ready and this is where we need to go.

0:09:06

Dr. Mike Patrick: During the COVID-19 pandemic, people heard new words like cytokines. Is that the chemicals that are being used as signals to recruit other immune system cells to come in and help with the fight?

Dr. Dean Lee: Right. So, variety of cytokines that are what we call pro-inflammatory or set up those signals that says this is the right place to have an inflammatory response.

Dr. Mike Patrick: I just want to point people to a podcast that we did sort of at the height of the COVID-19 pandemic called the How Our Immune System Works. It was PediaCast episode 462 and I'll put a link to that in the show notes for this episode 517 over at pediacast.org because it really give a big overview and then the natural killer cells were a part of that talk. And now we're going to really focus in on those particular cells.

As we think about cancer, how is it that the NK cells then respond? So they've attached to the cancer cell. They send out signals. What else do they do?

0:10:02

Dr. Dean Lee: Cytokines are proteins that are sort of loosen the blood to create signals that can travel. And they can either signal other cells to come and sort of attract those other cells to the area. Or they can activate responses that are in local cells or they can suppress responses. So we have some cytokines that actually calm things down, some cytokines that activate things.

NK cells produce a little bit of both depending on the circumstances. And the primary cytokines that they release are ones that are going to attract the rest of the immune system to come in. But they also have some cytokines that have killing ability themselves. There are receptors on virus infected cells and cancer cells that are what we call death receptors. And when NK cells make those cytokines, they can travel around and trigger any of those cells that have those receptors open.

0:10:58

The second arm of what NK cells do are to specifically release granules of toxins to a cell to intentionally kill one cell. So rather than traveling around and interacting with any cells that have those receptors, these are targeted release of almost like little payloads to the cancer cell or virus-infected cell.

And those contain mostly two proteins. One is  what is called perforin. Again, a really creative name because it perforates cells or pops a hole in a cell. And then granzyme that goes in through the hole and initiate a whole cascade of events for cell death. So the perforin and granzyme side doesn't need a receptor, doesn't need something on the cell that says it's going to be sensitive but cytokine part does.

Dr. Mike Patrick: And when we heard about those cytokine storms that maybe have been related to severe COVID, that's when you have a lot of those cytokines that cause immune system to react and up the immune system and not as many of the ones that sort of calm things, right?

Dr. Dean Lee: Right, right.

0:12:04

Dr. Mike Patrick: Now, in a perfect world then, this would just kill every cancer cell in our body but, obviously, that doesn't always work out. So cancer cells do have some means to avoid the effects of NK cells, right?

Dr. Dean Lee: So, the natural way that NK cells see those, like I mentioned before, is those stress ligands that get recognized by the receptors on the NK cell, and cancers can learn to shut those stress receptors down and over time build up enough of the suppressive cytokines that make the NK cells a little bit dysfunctional. So once they're in a tumor, they can't function as well.

For the first part, as far as helping the NK cells recognize better, it goes back to your comment at the beginning about genetically modifying them. So there are ways that we can enhance how an NK cell can see a specific target, either with antibody or with those genetic engineering.

0:13:01

On the suppressive side, there are ways that we can make the NK cells feel better in those suppressive environments and maintain their function and not be as sensitive to that suppression.

Dr. Mike Patrick: I just want to point out that this is inside of our bodies sort of a natural selection process, right? I mean, cancer cells aren't really smart enough to say, "Oh, I need to start making something that's going to make the NK cells not work. It's just the ones that happen to start doing that, then the NK cells aren't going to be as effective. And so those particular cells are the ones that going to multiply and become kind of resistant. And it's sort of the same thing when we talk about natural selection on an organism level. It's the same kind of thing happening. It's just inside our body.

Dr. Dean Lee: It turns out we actually probably develop cancer a lot more than we think we do but our body takes care of it. And occasionally, you get one that has somehow mutated in just the right way to escape that. And so finding ways to overcome that escape then is sort of the next wave of what we need to do with those cells.

0:14:00

Dr. Mike Patrick: And so basically, once you genetically engineered those cells to overcome any resistance that a cancer cell might have, then you can infuse those in the body and those NK cells can go take care of the cancer. But the problem is getting enough those NK cells, right? Tell us about that problem?

Dr. Dean Lee: So, we've known about NK cells since the 1970s but our knowledge about them compared to other lymphocytes like the T-cells and B-cells is probably 15 to 20 years behind. And in part because we didn't have a good way to grow them.

So, for T-cells, we've known four or five different ways to grow them since the early 70s, early 80s and B-cells, the whole idea of monoclonal antibodies was we learned a way to immortalize B-cells and make them live in a culture dish for decades. And that was in the 1980s.

But NK cells were tough. They just don't seem to grow and responds to the same kind of signals and if you can't grow the cells in the lab, you can't study them very well. And if you can't study them, you don't know how they work. And if you don't know how they work, then nobody cares about them.

0:15:06

So, they kind of smolder along with a few people interested here and there. In mid 2000s, I was working on T-cells and we  generated some fetal cells to help the T-cells grow. And this was sort of a process for growing more T-cells. And every once in a while, those cultures we get overgrown with NK cells.

So my mentor at the time, he said, "Well, here's a couple of ideas. Why don't you play around with it and see if you can actually more consistently get them to grow and intentionally grow the NK cell part?" I was like, "Nah, nobody cares about NK cells. I'm a T-cell guy here." But I went ahead and did it.

And sure enough, we found kind of the secret sauce for getting these cells to grow. And now, on a very routine basis, we can get 2,000 to 3,000 times as many in a couple of weeks, 30,000 times in three weeks. So we have lots and lots of cells that we can generate in the lab not just as a study, but now to think about giving them to patients. Because if you can't grow them to a large enough numbers, they can't be effective. So, it help us on both sides, both on the studying side and on the therapy side.

0:16:08

Dr. Mike Patrick: So before you discovered this, you wouldn't really have enough NK cells to infuse into a patient. By the time that you had enough, the cancer would be more likely to be progressed and invasive and all those things because you need a lot of them quickly.

Dr. Dean Lee: The original studies that were done to deliver NK cells, we'd take a family member and put them on a machine called a apheresis machine where we would basically take all of their blood to cycle through the machine, separate out the white blood cells, give back all the platelets and plasma and red cells. And they'd be on that machine for four to five hours and give up as many as those white blood cells from your body as you could.

We take that and get rid of the T-cells because they actually cause some problems if you go between people. Put the rest of the culture in some cytokines that NK cells like to activate them overnight and then that's what we would give to patient as an NK cell therapy.

0:17:10

And it's a one-time shot. You couldn't keep doing this to the donor. And doing that, you could give somewhere around 30 million NK cells for every kilo of bodyweight of the patient.

So, it worked. It worked a little bit. We had some hints that they were doing some benefits but that was it. We couldn't beyond those numbers. Now instead of getting 20 million cells per kilo, we can easily give a 100 million, even more than that. I mean, give it multiple times. So we have several clinical trials where we've given six doses of a 100 million cells every time. So we're at 10 to 50 times as many NK cells as what we could give before.

Dr. Mike Patrick: Now, when you say the T-cells could create a problem, we think about blood types and that there's a problem with rejection when there's organ transplants. And since these are cells, are they coming from that person or just someone who has similar enough cell that won't be a problem? Or is that not an issue with NK cells at all?

0:18:14

Dr. Dean Lee: With NK cells is not an issue. For T-cells, it's the way they see the world. And so sometimes, I explain this a little bit like passports, that T-cells are really trained to see a very specific person inside a specific passport. And that's how they're trained.

And so, if you took that same picture and you put it in a different passport, they wouldn't recognize the person anymore because they go, "Oh, that's somebody who looks similar but they're from England. They're not from the United States." And so, they would sort of ignore them.

And the passport that I'm talking about is this protein called MHC. And it's present on all of our body cells and its job is to show the immune system what's inside. And as long as it's just showing self, showing "Yep, I'm just a normal pancreatic cell that you've always seen," there's no problem. The moment it shows that passport with a virus inside, that's when the T-cell can see it.

0:19:13

NK cells don't look at the picture. They're only looking to see that you have the passport. They just want to know that you actually are showing the rest of the immune system who you are and that you have sort of valid documentation.

So, there's a variety of these that NK cells see. And the way that they see them from one person to another is mostly on the being inhibited side, so they don't overreact to wrong passport. They just go, "You don't have the right one."

Dr. Mike Patrick: And so those proteins on the surface are sort of different for each person and specific to someone. And  your own immune system is trained to recognize that and say, "Hey, this is a normal cell. Don't attack this one." And so the NK cells are going to be able to do that in anybody. So, in other words you could just have an off-the-shelf product with NK cells and it doesn't really matter who they're from and they're going to help, as long as they're trained to fight whatever it is that you want them to fight.

0:20:07

Dr. Dean Lee: That's our goal. So far, all our studies we've done have been, like I said with family members, initially by that apheresis process and then secondly, by expanding them, like I mentioned. But now that we understand better how well we can expand them and what we think are kind of ideal genetic characteristics for NK cells.

We're working on another approach to really look through the entire country and use the same group that does bone marrow matching. The MNDP has worked with us for the last two years to identify people who have the right kind of MHC molecules and cure to make ideal NK cells. And we're harvesting large amounts of NK cells from them, splitting them up in a bank and from one individual, we can now make enough NK cells to treat 20, 50 or even 100 people.

Dr. Mike Patrick: That is amazing. So, what do you think in terms of how far off are we from having a product like that? I mean, I know you can't predict the future but I mean are we talking about a decade or shorter than that?

0:21:09

Dr. Dean Lee: Well, we've treated our first six patients over at OSU with these off-the-shelf universal donor product. We have our first trials open here at Nationwide to treat kids. I think we'll treat our first one in the next couple of months. And then it will just be a matter of seeing whether they actually do work the way that we intended. If it works out that they're as effective as we hope, then the next path is really to find can they be made efficiently by a company distributed, delivered to multiple hospitals? And can we expand the delivery mechanism for those?

Dr. Mike Patrick: Now, we talked about genetically modifying T-cells in order to make them more efficient and effective at a particular cancer. How do you go about genetically modifying a cell?

And I will point out that we did an episode of PediaCast CME which is our Continuing Medication Education podcast, but  folks can, we'll put a link to this one in the show notes as well. It was Genomics 101: an Introduction to Next Generation Sequencing.

0:22:11

And we did try to explain things as we went along because even primary care docs like myself, this is all still very foreign. We learned about it at medical school like a long time ago and then forgot about it. So I think we did a pretty good job of explaining as we went.

So folks who are interested in genomics and genetic sequencing and sort of how cells could potentially be modified, that would definitely be a good episode to listen to if you're interested in that. But for your purposes, you're really just swapping out DNA, right, because it's a code for what proteins get made and get shown on the surface.

Dr. Dean Lee: Yeah. So, for the NK cells, there's two things we'd like to do. There are some genes we'd like to get rid of. The ones that kind of calm the NK cells down, we want to make them not sensitive to those things inside the tumor. And the other is to put in new receptors that allow them to specifically target the tumor or give them new function.

0:23:07

Both of them are similar approaches. They're both considered genetic engineering, whether you're genetically engineering a way from a gene or towards a new gene. But most of our experience in medicine has been with adding new genes. And so we start with that maybe 15, 18 years ago, because we have lots of experience engineering T-cells. So CAR T-cells that we use now as a commercial product to cure leukemia in our kids is used by adding one of those genes to a T-cells.

Unfortunately, it's a good thing I guess from biology perspective but because NK cells are the first responders to viruses, they have very high turned on mechanisms for sensing viruses and they would rather die than be infected. So we did a whole bunch of work trying to get the same viruses that would help us engineer a T-cell to work for NK cell and none of them work.

0:24:06

In the last four years, the growth of things that we're doing in the lab and there's a new approach called CRISPR that Meisam Kararoudi in my lab was able to adapt and learned how to get rid of a gene. So rather than putting in a virus, you can put in little small pieces of RNA and protein that target a particular gene and able to make cuts in it. And that the NK cells tolerate fine.

And then, if you follow that with a new piece of DNA that has the right signals on the ends to insert, you can put in that new gene at the same place that you just cut out the old one.

And that's actually working really well. We're getting very nice 80 to 90% efficiency. It's a very careful controlled editing, unlike some of the other viruses where you don't really know where it went. Here, you actually can tell the gene exactly where you want it to be in the genome.

0:25:02

Dr. Mike Patrick: And how do you figure out even what gene to add? Do you just look at NK cells that you know work and then look at their genome to see how they're different, then maybe one that doesn't work and compare? And that's how you figure it out? I'm just using the knowledge that I learned in Genomics 101 episode to try to wrap my brain around how do you know what gene to put in to begin with?

Dr. Dean Lee: So the genes we're putting in are mostly ones that we've had about 20 years of experience building lots of labs around the world are looking at these genes called CAR, chimeric antigen receptors. And they're pretty consistent structures that are an outside piece that's from an antibody that tells you what to target and an inside piece that says what to signal. So, if we understand enough about NK cells to know what a good signal is to an NK cell, we can put those pieces on the inside so they get good signals.

0:26:00

And if we understand the tumor well enough to know what kinds of things marked that tumor as being tumor and what we can target on them, then we can put that on the outside of the protein. So that's really all a CAR is, is trying to tell a NK cell, "If you see this marker, kill that cell because that's a bad cell."

For the genes to take out, some of it has been by luck just finding them. Some of them have been genes that we know are a problem. Some of the suppressive pathways we've known about for 20 or 30 years and if you can get rid of the receptor to that, then you can eliminate the ability of the tumor to suppress the NK cells. So, we have pretty targeted ones that we can look for.

Dr. Mike Patrick: And so since they are so targeted and to a specific cancer, what cancer is right now have this therapy available?

Dr. Dean Lee: So, the only one that's been done in the clinical trial and published is CD-19 which is the same thing we target CAR T-cells for for a leukemia, also useful for lymphomas and some other blood cancers.

0:27:07

There are dozens of clinical trials that are available for solid tumors. None of them have had the kind of a dramatic effect that CAR T-cells have for leukemia. And some of that is because of the different ways that T-cells and NK cells behave.

So our first move into solid tumors with the CAR would be to put the CAR into the NK cells. And there's a couple of already pretty well-established target to try that with. One is called HER2. It's the same target that the breast cancer drug Herceptin is made for.

There's another one called GD2 and that's the target for an antibody using pediatrics for neuroblastoma dinutuximab. So we already have a little bit of experience with targeting those things in antibodies and it's not such a big leap then to tell the FDA we want to target that same thing with an NK cell.

0:28:05

Dr. Mike Patrick: Very interesting. Now, we still have chemotherapy and radiation which are not specific to the cancer cells. It's just going to kill or destroy any rapidly dividing cells in your body. And so it's going to just be harmful to normal cells as well, whereas the NK ones are going to be very specific for the cancer cells. But we're not at the point where you can only use NK cells, correct?

Dr. Dean Lee: Correct. So far, cell therapy has been remarkable in some settings like the leukemia that we mentioned, where essentially a single infusion of CAR T-cells induce a long-term cure for many patients. But not all by themselves. We still need to treat patients with a little bit of chemotherapy to get the patient ready for those cells.

And there are some other therapies that sometimes we need to add afterwards either to reduce some toxicity or help the cells to move along.

0:29:04

At some point, we may be able to do enough engineering of the cells that you don't need that initial chemotherapy but I don't entirely know that's the right approach. I think there are some ecopoise around how we think of what genetic engineering we're doing and we might be moving towards or a little bit over-engineering, right, because there's a small amount of chemotherapy that are really very easy, very inexpensive to give, very well tolerated that we shouldn't kind of throw out the baby with the bath water, so to speak.

Dr. Mike Patrick: That make sense. I mean, ultimately, we want good outcomes and so you got to figure out what the right combination of things is for the outcome that you want.

And you talked about over-engineering and I think in a lot of people's minds, that could be kind of scary thing thinking about taking someone else's blood genetically making the cells different and then infusing them into another person. So are there any dangers or risks involved with that process?

0:29:59

Dr. Dean Lee: There are. Any time you're making changes to the DNA, there's a possibility for changes that you aren't aware of. I think doing dangerous things to the DNA intentionally is much as likely. We know what we're targeting and both our own regulatory structures within the hospital, as well as the FDA, are very strict about what kinds of proof you have to give them, that you're making safe changes. But it's the unknown ones and there been a few, very few but some cases where, for instance, we were genetically engineering bone marrow to try to cure someone of immune deficiency and instead the engineering triggered the gene that cause leukemia.

So these kinds of things are very very carefully looked at. The FDA wants lots of data ahead of time to make sure that you know what you're engineering, that it's not close to need this other dangerous change and that you've done due diligence to make sure that you've got a product that is a safe as you can make it.

Ultimately, we're treating patients with cancer. So there is sort of accepted amount of risk that patients themselves are willing to take, knowing that they've got a bad disease and are wanting to try new things.

0:31:19

Dr. Mike Patrick: I mean, for all of these and really for any decision in our life, we think about risks versus the benefits and then make a decision based on that. I mean, even when we get in the car, the benefit of getting somewhere fast and the risk of an accident, you're still weighing the risk and benefit. And so, with these patients and families, I'm sure you go down that road of the risk of not doing it is that this cancer may not be treated with standard therapy and could be deadly. But the benefit of using this, you'd want that that   way the risk of using it, right?

Dr. Dean Lee: Right, right.

Dr. Mike Patrick: And kind of walking the family through that decision-making process and making the decision together.

0:31:55

Dr. Dean Lee: And we have a long history of doing that for all of medicine but very specifically in cancer therapy. We know that chemotherapy and radiation is toxic and hurts people. And so we do as much as we can to effect good cures and then we do as much as we can to back off from that and do as little damage as possible. So, it's always a little bit of trade-off. You're trying to do as much good as you can with as little bad as you can.

Dr. Mike Patrick: So what does the future hold for manufactured immune system products? Where do we go from here?

Dr. Dean Lee: So you've mentioned one of them and that's an off-the-shelf product. I think we're at the very beginnings of that for NK cells. There's a lot of work being done about doing that for T-cells as well. They're a little bit harder to figure out all the right pieces that have to be done to make them transferrable from one patient to another without problems but some good progress on that. So having something that is just readily available on the shelf that you can then infuse is one of the biggest sort of forward-looking pieces.

0:32:58

And that's because to do this kind of patient-specific manufacturing and engineering is not only expensive but it also takes time. And many of these patients don't have the time to wait. So, we have quite a lot of cases where we have patients who are wanting to get one of these new therapies but the amount of time that it takes for us to make it is longer than they can wait for their disease. So, it is both trying to reduce the cost, as well as capture those patients that otherwise wouldn't be able to get there.

Dr. Mike Patrick: In terms of insurance and coverage and for getting this kind of product, is that something you have to fight with insurance companies? Or because they're clinical trials at this point, their medicine is provided free of charge? How does that all work with the family because I'm sure that's probably a stress and strain on folks, too?

0:33:52

Dr. Dean Lee: For the ones that have been approved like the CAR T-cells, the insurance companies actually are really good about covering them, they are very effective and completely effective and have a really low level of toxicity to deal with, so their safety profile is high. And I think that everybody understands that even though they're expensive, so is not curing cancer and so is curing cancer poorly. So that part has not been very difficult. 

For the ones that are currently in research, those are almost uniformly paid for by the researchers or by the hospitals. We don't feel that it's ethically appropriate to charge somebody for something that's experimental. And so we build as many possible ways of covering that as possible.

And we get government grants, we get foundation grants, philanthropy that comes to the hospital. And in some cases, when it's part of an overall treatment package, we try to bundle that in with the other things that are standard just so that we can help move along better standard of care.

0:35:00

Dr. Mike Patrick: So when folks donate money to a children's hospital, these are the kind of things that that money goes toward helping provide this type of research and giving those medicines to children who need that.

Dr. Dean Lee: Absolutely.

Dr. Mike Patrick: Very, very important. I know you have a lab at Nationwide Children's, the Lee Lab. Tell us a little bit about that.

Dr. Dean Lee: So, all of it really started short after my training in building T-cell therapy. And as I mentioned, we've pretty quickly switch to NK cells mostly on a fluke. I've finally figured out how to grow them. When I moved here to Columbus, I only had one person who stayed with me who is a graduate student, so we had to kind of rebuild all those people. And now we're up to 10 or 12. There's a wide variety of fully trained staff scientists who have their PhD and finished post-graduate training. We have PhD students. There are technicians. Some of which are freshly out of college, fellows who are in their clinical training who want to come through and understand better about what our research lab does before they go back to the clinic. And even a couple of veterinarians.

0:36:12

Dr. Mike Patrick: Great. And we'll put a link to the Lee Lab at the Center for Childhood Cancer and Blood Diseases at Nationwide Children's Hospital so people can learn more about what you do.

There was also a great article in the magazine Pediatrics Nationwide called Optimizing the Body's Natural Cancer Killers and that's a great article. I'll put a link to that in the show notes as well.

And then tell us about the Center for Childhood Cancer and Blood Diseases. We've mentioned that a few times. What is that center all about?

Dr. Dean Lee: It's about childhood cancer and blood diseases. In our clinical practice, we divide people into  specialties. We have rheumatologist who study autoimmune diseases and doctors of infectious disease that study infections. And your cancer doctors and hematologists study blood diseases and cancers.

0:37:04

So, on the research side, I think it's very similar, right? We want to structure the kinds of research that we're attracting into groups of people who can work together and collaborate. And in many places, individual research labs like mine would really just be kind of an isolated island. We study NK cells and we study NK cell biology because we want to know how they work and we want to engineer them better to cure cancer.

But it's actually much more a productive for me to have a lab next to me that also studies the biology of osteosarcoma, for instance. That's the cancer that I want to treat. And if I only know how the NK cells work and I don't have somebody who is thinking about how the cancer works, then we missed out on half of the biology that's happening inside of a person.

So the CCBD is really structured to try and enable those kinds of interaction. Whether you are looking at drugs, chemotherapy radiation immune system genetics, that might be the science that you're doing, but we're all studying different aspects of the cancer itself.

0:38:16

Dr. Mike Patrick: Yeah, and collaborating amongst yourselves and then other centers and other children's hospitals and really sharing information and advancing the field together.

We really appreciate you stopping by and educating us about NK cells. Lots of links in the show notes this week. Some of them that I've already mentioned, Genomics 101 and Introduction to Next Generation Sequencing, PediaCast CME. And then the one How Our Immune System Works. So, if you're interested in genetics and genomics and the immune system, please check out those episodes. And again, we'll put the links in the show notes for you.

So, once again, Dr. Dean Lee:, principal investigator with the Center for Childhood Cancer and Blood Diseases at Nationwide Children's Hospital. Thank you so much for stopping by today.

0:39:00

Dr. Dean Lee: Thanks, Mike.

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Dr. Mike Patrick: We are back with just enough time to say thanks once again to all of you for taking time out of your day and making PediaCast a part of it. Really do appreciate that.

Also, thanks to our guest this week, Dr. Dean Lee:, principal investigator with the Center for Childhood Cancer and Blood Diseases at Nationwide Children's Hospital.

Don't forget you can find PediaCast wherever podcasts are found. We're in the Apple and Google podcast apps, iHeart Radio, Spotify, SoundCloud, Amazon Music, and most other podcast apps for iOS and Android, including that new one Goodpods. So, let be sure to check that one out.

Also our landing site pediacast.org. If you go there, you'll find our entire archive of past programs, along with our show notes, our Terms of Use Agreement, and that Contact page if you would like to suggest a future topic for the program.

0:40:13

Reviews are helpful wherever you get your podcasts. We always appreciate when you share your thoughts about the show.

And we love connecting with you on social media. You'll find us on Facebook, Twitter, LinkedIn, and Instagram. Simply search for PediaCast.

Also don't forget about our sibling podcast, PediaCast CME. That stands for Continuing Medical Education. It is similar to this program. We continue to turn the science up a couple notches and we do offer free Continuing Medical Education credit for those who listen including, not only doctors, but also nurse practitioners, physician assistants, nurses, pharmacist, psychologist, social workers, and dentist.

And since Nationwide Children's is jointly accredited by many professional organizations, it's likely we offer the exact credits you need to fulfill your states Continuing Medical Education requirements. Of course, you want to be sure the content of the episode matches your scope of practice.

0:41:01

Shows and details are available at the landing site for that program pediacastcme.org. You can also listen wherever podcasts are found. Simply search for PediaCast CME.

Thanks again for stopping by. And until next time, this is Dr. Mike saying stay safe, stay healthy and stay involved with your kids. So, long, everybody.

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Announcer 2: This program is a production of Nationwide Children's. Thanks for listening. We'll see you next time on PediaCast.