Ovarian cancer surgery; a diabetes drug without side effects; a disease that can threaten transplant patients: Upstate Medical University's HealthLink on Air for Sunday, Dec. 12, 2021
Rinki Agarwal, MD, who specializes in treating gynecological cancers, discusses the surgery that may prevent ovarian cancer in women at high risk for the disease. Chemistry professor Robert Doyle, PhD, tells about efforts to develop a diabetes drug that has no side effects. And researcher Mobin Karimi, MD, PhD, explains his work on graft-versus-host disease, a rare condition that can threaten people who undergo transplants.
Host Amber Smith: Coming up next on Upstate's "HealthLink on Air," a gynecologist discusses the surgery that may prevent ovarian cancer in women at high risk for the disease:
Rinki Agarwal, MD: A number of things have been tried in the realm of screening, prevention or risk reduction using surgery. And of those, the most effective method has been to remove the ovaries and fallopian tubes.
Host Amber Smith: A chemistry professor tells how he's developing a diabetes drug without side effects:
Robert Doyle, PhD: As soon as we did that, we saw no nausea, no vomiting, no weight loss, but nice maintained glycemic control.
Host Amber Smith: And a researcher explains his work on a rare condition called graft-versus-host disease, which can threaten people who undergo transplants:
Mobin Karimi, MD, PhD: Graft-versus-host disease is one of the highest rates of mortality after cancer.
Host Amber Smith: All that, plus a visit from The Healing Muse, coming up after the news.
This is Upstate Medical University's "HealthLink on Air," your chance to explore health, science and medicine with the experts from Central New York's only academic medical center. I'm your host, Amber Smith. On this week's show, a chemistry professor shares how he's developing a diabetes drug without side effects.
Then a researcher explains his work on a condition that can affect people who undergo transplants. But first, a gynecologist tells about a study of how to prevent ovarian cancer in women at high genetic risk for the disease.
From Upstate Medical University in Syracuse, New York, I'm Amber Smith. This is "HealthLink on Air." Gynecologic oncology researchers are testing a surgery that may help women who have a high genetic risk for developing ovarian cancer. Here to tell about this study is Dr. Rinki Agarwal. She's an associate professor of obstetrics and gynecology at Upstate and also the medical director of the Upstate Cancer Center's gynecologic oncology program.
Thank you for your time, Dr. Agarwal.
Rinki Agarwal, MD: Thank you for having me, Amber. Besides that, I also want to mention that I am the director for the genetics program for the Upstate Cancer Center. And I served in that capacity as a board-certified geneticist, so this study that we are here to talk about and focus on is very near and dear to me from both avenues of my training.
Host Amber Smith: It sounds like it ties together nicely because the study focuses on women who know they are at an increased risk for ovarian cancer. Can you explain how a woman would know what her risk is?
Rinki Agarwal, MD: So women may come to get this information through multiple streams. Hopefully the way it would work for a majority of women at risk would be because they have familial risk that was identified.
And that information was shared by family members with patients at risk, and they go through testing. The other way that women find out about the risk is because they've had cancer themselves, either breast cancer or ovarian cancer, and they are going through the process of evaluating the reason for getting the cancer, and go through testing and that's the other significant way. In our practice, we see a very large number of patients who are coming to us for evaluation on the genetic side of my practice because of their strong family history. And we evaluate them, and then we end up identifying patients who are at risk, and then they are referred to the different specialties that would address those risks and help them manage that, understand the risk and manage it from there.
Host Amber Smith: Well, let me ask you about which family members. So are we talking about a mother or a sister or an aunt or a cousin who had ovarian cancer? Is that it, or is it just your parents?
Rinki Agarwal, MD: So really it can come from either side of the family. It can be maternal or paternal risk or through those lineages. And you can have people who have known risk in siblings, either parent or in extended family, aunts, uncles or cousins. And there is enough general awareness of the relationship between the genetic predisposition genes and the cancer risks to flag those for most practitioners so that patients will get that information. And then we encourage them to share it with family members.
Host Amber Smith: Now, why does this study look at surgery as a potential solution?
Rinki Agarwal, MD: So to understand that I would like for us to go back to some of the background and say, why is this study necessary?
And why is it surgery that's part of the study. OK, so where we are right now is essentially about 20 years of knowledge synthesized into development of the study. So on one side, and we're going to talk about. Understanding ovarian cancer risk. And in that with the identification of major, respect to genes, such as the BRC one and two genes where mutations would give people increased risk.
We've known that from going back to the mid-'90s, and that has led to development of strategies for managing risk, and a number of things have been tried in the realm of screening prevention or risk reduction using surgery. And of those, the most effective method has been to remove the ovaries and fallopian tubes.
And the people have studied that and the literature supports that there is tremendous value and a significant reduction in risk when you do the surgical interventions, whereas we're not great at screening and prevention using medical modalities. OK, so that's on one end. Then as we've gone on, biological assessments of the precursors for ovarian cancer, going back decades, have not really shown us a true precursor lesion in the ovary, as you see in multiple other cancers. You can take examples of breast or colon cancer, and you see precursor lesions. We never really saw those in the ovary.
And then in the last decade, decade and a half or so, we found that there are precursor lesions that are present in the fallopian tubes. So that's led to the belief that the genesis may not be in the ovary at all, but maybe in the fallopian tubes to start with. So that now brings us to a functional understanding of what these organs are doing, where you can draw on our knowledge of the different organs.
We're talking about two different things here. The fallopian tube, which is essentially connecting the uterus to the ovary and allowing for transit of egg and sperm and fertilization within the fallopian tube. But beyond that, it doesn't really have functions beyond fertility preservation. It doesn't have functions for hormonal activity for the female.
On the other hand, the ovaries produce eggs, but they also produce hormones. And they're what we know now from drawing on large studies of things like the Women's Health Initiative that we've had now available to us for review for the last 20 years or so, that the hormones coming from the ovaries are significantly impactful in preserving health for women.
And that's pretty much for every body system you can think of. In the short term, that can be things like mood, sleep disturbances, sexual function, and in the long term, it can range from cholesterol management, heart disease, cognitive function, bone health and other impacts, so you are coming to the realization that there is risk source, maybe the fallopian tube, and the ovary is potentially a source, but may just be a bystander that gets involved in the cancer process.
And then the ovary has significant functional benefit for the individual. And you're giving up on that when you take the ovaries out.
Host Amber Smith: If you were able to let a woman keep her ovaries, you would like that. As long as you can assure her that her risk for ovarian cancer is removed by taking the fallopian tubes out.
Rinki Agarwal, MD: Exactly. So you're basically taking all of this functional information, the pathologic information that we've gained over time, to say we have risk, we have the source of risk. We have benefit of this other organ. Can we truly preserve it or time its removal such that you get most of the benefit before it's surgically removed?
And that brings us to the study, the salpingo-oophorectomy to reduce the risk of ovarian cancer study.
Host Amber Smith: Let me ask you before we get into that, if we think that most ovarian cancers start in the fallopian tubes, while we stopped calling it ovarian cancer?
Rinki Agarwal, MD: It depends on what kind of philosophy you have. We're not going to walk away from calling it ovarian cancer for a long time.
A lot of the studies that we know about treatment of the disease literature is all going to call it ovarian cancer. In the end, there is significant involvement of the ovaries with the disease, whether it's arising from the fallopian tube or the ovary. And we can't completely eliminate the ovary as a primary source of the cancer.
So in a purist sort of a way, I would say that, yes, we may, at some point get to a point where we can differentiate and call them for what they are, based on their genesis. So we may have fallopian tube cancers that are a major category and ovary cancer is a minor category rather than the reverse, which is as it exists right now. They are similar enough in our understanding of how they behave that for the purposes of our current treatment and discussions, they are considered the same.
Host Amber Smith: This is Upstate's "HealthLink on Air." I'm your host, Amber Smith, talking with Dr. Rinki Agarwal about a study that is looking for women at high genetic risk for developing ovarian cancer. So what can you tell us about this trial? I know it's sponsored by the National Cancer Institute. What is it set up to do?
Rinki Agarwal, MD: In short, it's called SOROCk, which stands for Salpingo-Oophorectomy to Reduce the risk of Ovarian Cancer.
And it is a study that is available currently for enrollment at Upstate. And it's sponsored by NRG Oncology (a research organization), which is part of the National Cancer Institute Community Oncology Research Program. So it's a national study to evaluate the strategy for managing risk in patients who have an identified mutation in a BRCA1 gene for future development of ovarian cancer.
Host Amber Smith: So how many women are you looking for, and what are their ages?
Rinki Agarwal, MD: For the study nationally, they're looking to enroll just under 2,300 women between the ages of 35 to 50. And they would be looking to have certain things to include patients in the study. They have to have a known mutation in the BRCA1 gene, and they still have their fallopian tubes
Host Amber Smith: And is there anything that would disqualify someone from participating?
Rinki Agarwal, MD: Well, people who already have ovarian or fallopian tube cancer as the start of where they gathered this information would not be candidates for this study, but pretty much everybody else. And if the fallopian tubes have already been removed as part of some prior surgical process, those patients would be excluded.
But otherwise, everybody else is a candidate for it.
Host Amber Smith: I want to let listeners know that they can call a local number to the Upstate Cancer Center to learn more about this trial at 315-464-8200, and if they have friends in other parts of the country, the National Cancer Information Center at 1-800-4CANCER, that's that's 1-800-422-6237, can also provide information. Can you walk us through what happens when someone joins the trial? Is this person going to meet with you or another doctor to help decide which surgery she'll have?
Rinki Agarwal, MD: Absolutely all four gynecologic oncologists in our practice are able to see patients and enroll them in the trial.
So they could certainly see me or one of the other physicians in the practice. And what would happen is that they would have an initial interview. They can come in with this information, or we're pretty much screening every patient that comes through that may be eligible for this trial to be considered for the trial.
They're given information and given some time to think about it. Now, the time to think about it is something that I encourage patients to do in the context of this particular scenario: They have a BRCA1 mutation; they're trying to manage their risk of ovarian cancer, and we're talking about risk management.
So that time to think about the study is something that I would consider a standard of care anyways. And once they've gone through the information and considered it, it's an option for them to proceed with enrolling for the trial. And then within the trial, it is patient choice on whether or not they would be in the arm of doing the current standard, which is to remove both tubes and ovaries after the age of 35, or if they were to choose the salpingectomy arm with a subsequent delayed oophorectomy at a later point after the age of 40 to 45.
So those would be the two arms that the patient. We enrolled in, but it would be patient choice.
Host Amber Smith: Does the trial pay for the surgery, or does the woman's health insurance cover the surgery?
Rinki Agarwal, MD: So the trial's intent is to collect information. The billing for the service is done through insurance. And the burden for the patient in terms of participating in the trial is predominantly that they are answering questions, they're allowing the trial to access their medical records, and they're allowing them to store a sample of blood for any biomarkers that we may find have utility for patients in the future. So those things would be covered by the trial, the maintenance of those records that they've collected, but the study would not cover the surgeries.
Host Amber Smith: What is the follow-up like? Are there visits after the surgery?
Rinki Agarwal, MD: There are visits after the surgery that are also considered standard of care. And that would be the points where we would assess for outcomes. How are they doing by way of quality of life preservation and the future risk of cancer, and that's all collected as part of standard of care, but would also be then given to the trial as long as the patient consents ,continues to consent to do so.
Host Amber Smith: How would you counsel women who joined this study to be on the lookout for signs or symptoms of ovarian cancer after they've had the surgery?
Rinki Agarwal, MD: So for lack of a better description, the signs and symptoms of ovarian cancer are relatively subtle, and it has been in the media called a silent disease. I do not believe that it's silent. It's more that you have to be aware because there is such subtlety to the signs and symptoms that you can frequently attribute those symptoms to other diseases before you think of ovarian cancer as the potential problem in a majority of those instances. So first to specify that there are some characteristics and symptoms that patients will have, if they have the disease and then, for what those symptoms may be. Frequently, more abdominal symptoms than symptoms elsewhere in the body.
And those can range from bloating, which we would define as just a sense of being very full or getting full too quickly. They find that they can't eat as much, but their abdomen or the belly feels very full. Abdominal pain or pressure change in how they're moving their bowels. And then other range of symptoms can be things like shortness of breath, loss of weight, and these are persistent. Anything that's lasting over a couple of weeks is something that would suggest that it requires further evaluation, and they can stem from numerous other potential differential diagnoses. But we, in this context, for this particular discussion, we're talking about patients where were identified at increased risk of ovarian cancer.
So for them to be thinking about this as a higher potential differential diagnosis would be important.
Host Amber Smith: What would you say are the benefits of a woman participating in a trial like this?
Rinki Agarwal, MD: So the benefit may not be evident to us for a few years, until these trial results are available to us. But the idea of the study is that with the counseling and with all of the information provided, the patients who choose something like the salpingectomy arm, by their own choice, are not committed to that alone. They can cross over to the salpingo-oophorectomy arm at any point. And even if they were to stay with salpingectomy arm, , have a planned oophorectoomy sometime in the future. We don't know what the answer of the ultimate findings of the trial is, but the trial has been carefully designed in order to minimize the risk of ovarian cancer or choose patients who are at the lowest risk of ovarian cancer and have the maximum benefit from retention of the ovaries. . So if in fact, the findings of this study showed that the salpingectomy-alone arm was good, then those patients would have gained from choosing that option along the way.
OK. And then there is the larger benefit. We're at a point where this is the logical next thing that we have to evaluate to minimize the impact of our recommendations on women's lives. So they would be contributing to our understanding and management of the risk tremendously by participating in this study.
Host Amber Smith: Once again, the local phone number, if people are interested, is 315-464-8200, and that goes to the Upstate cancer center. My guest has been Dr. Rinki Agarwal.. She's an associate professor of obstetrics and gynecology and the medical director of the Upstate Cancer Center's, gynecologic oncology program, as well as the director of the Upstate Cancer Center's genetics program. I'm Amber Smith for Upstate's "HealthLink on Air."
How did a chemist get involved with diabetes research? Next on Upstate's "HealthLink on Air."
From Upstate Medical University in Syracuse, New York, I'm Amber Smith. This is "HealthLink on Air." Many of the people who have type 2 diabetes take medication that causes nausea, vomitingq and other side effects. A chemist at Syracuse University is developing a drug that would control blood sugar without the side effects.
Robert Doyle is a chemistry professor at SU and also an adjunct assistant professor at Upstate. Thank you for making time, professor Doyle.
Robert Doyle, PhD: It's nice to be here. Thank you.
Host Amber Smith: Before I ask you about your work, how did a chemist get involved in diabetes research?
Robert Doyle, PhD: Oh, that's a great question.
So my interest has always been in making things, not surprisingly, as a chemist, and the, I guess you could say epidemic, of type 2 diabetes and comorbid obesity. So these sort of diseases go hand in hand. It was really evident as a chemist who was coming up, the pharmaceutical industry that I'm involved with or would aspire to be involved with, were very driven by looking at ways, new ways to control blood glucose because of this huge problem that we were seeing worldwide.
Host Amber Smith: So, let me ask you because diabetes is a little complex to try to understand if you're not involved in the work that you're involved with. Can you give us a good layman's definition of glycemic control?
Robert Doyle, PhD: Sure. In essence, it means not having glucose levels in your blood that's too high and not having glucose levels in your blood that's too low. It really has to be a blood glucose that's in that "Goldilocks" zone, not too cold, not too high, not too low, right in that space between about 60 and 125 (mg/dL, or milligrams per deciliter). They're the sort of magic numbers.
Host Amber Smith: So there's a lot of existing medications already on the market for controlling blood sugar and trying to get into that sweet spot. But how do those work and why are they not doing everything that you would like them to do?
Robert Doyle, PhD: First of all, I will start by saying they are wonderful drugs and for the majority of patients who will take them, absolutely life-affirming, life-altering in all the right ways.
So they can work by increasing insulin secretion from your pancreas. So your pancreas is the organ that is responsible for controlling your blood glucose levels, keeping them at just the right level, and they will work to increase that insulin level, these drugs, to increase these insulin levels, so as to facilitate glucose uptake into your cells and where it needs to be.
So the big challenge with glucose dysregulation per glycemic control is the fact that you could be awash in glucose in your blood. And in fact, the classic type 2 diabetes patient will have very high levels of glucose, but their cells are starving for glucose. So the problem is they're like a teenager trying to get into a club. There's a bouncer in the way; he says no, and if you're not on the list, you don't get in, and you need the insulin pass to get you through the door. And so these drugs can work to elevate that amount of insulin, in patients who require that additional boost to help get that insulin into the tissues, into their cells, across the body.
Other ways to do it are simply to upregulate control mechanisms, whose job it is to protect these pathways that will either utilize the glucose, or again, drive this instant secretion and glucose uptake in cells. So they're all playing around. We're all playing around really the pancreas and insulin, or essentially helping the kidneys to flush glucose out of blood system.
So there's a myriad of different ways to do it. I mean, I don't want to get too technical about it, but there's a myriad of ways to do it, and they're all wonderful. They all work really, really well for the majority of patients. You can even actually just inject straight insulin, but that's only done in type 1 patients who cannot produce insulin directly themselves, the majority of patients with diabetes are type 2.
Host Amber Smith: So what about these medications might cause the side effects, the nausea, the vomiting, weight loss?
Robert Doyle, PhD: Yeah. And these are not my words, (they're) the words of the physician community, the darlings of current treatment for patients with type 2 diabetes are what are called GLP-1 agonists, andyou inject them into your body, so they have to be subcutaneously administered. You have to use a needle or syringe to administer them. And what happens is they go to your pancreas. And in concert with glucose level, they drive insulin secretion from your pancreas. And the really, really clever thing about this is that it models how we do it naturally.
And so, because it only works when glucose level is high to release insulin, you never have an overproduction of insulin or over-release of insulin, which means it never drops too low, either, and so it achieves that wonderful Goldilocks state of bringing down the high, but not bringing it down to achieve the incorrect low.
And so it really can bring about an excellent, what we call, metabolic norm. So something that's more akin to what let's call it a typical patient would have, or typical person would have in day-to-day blood glucose levels. The side effects are because of our quirky human physiology, the same receptor or target in the pancreas is actually also found in your lizard brain and your hindbrain, which is the little space between your ears and in the middle. But in that case, it doesn't work to release insulin because your brain doesn't release insulin. What it does in that case is it triggers appetite depression and nausea and in a lot of cases, vomiting, so it goes to a part of your brain which is designed to test essentially your body for poisons or drugs or unknown substances with a view to getting them out of your system, if you need to.
So it's an evolutionary protective mechanism. These drugs go to your pancreas that are wonderful, but they also end up in the hindbrain and trigger these side effects by hitting the same receptors that are located in these two very distinct place. Pancreas glucose control, brain, weight loss, nausea, vomiting.
Host Amber Smith: So what was your idea for avoiding the side effects? Was it to avoid going to the brain at all?
Robert Doyle, PhD: Exactly. So if we could keep it out of the brain, particularly the hindbrain, you would get all of the peripheral effects, the pancreas effects, but you wouldn't get any of the brain effects. That was the theory. That was the hypothesis that we put forward, yeah.
Host Amber Smith: Well, do I understand correctly, your new drug is a combination of two molecules?
Robert Doyle, PhD: It is. It's what we call a conjugate. Yep.
Host Amber Smith: So what can you tell me about each of these molecules?
Robert Doyle, PhD: The idea, I guess. It was born of the fact that I was studying vitamin B12. This comes back full circle. And I was looking to see as a medicinal chemist where the vitamin B12 pathway actively transports vitamin B12.
And what I noticed using radioactive, radio-labeled vitamin B12 was that it really did not go to the brain at all, but it would still happily goes to the kidneys, the pancreas, the liver, etc. And so I thought if we put these GLP-1 drugs on the back, if you will, of vitamin B12 or vitamin B12-type compound, It might be like putting it on a specific bus or a specific airplane and saying you only fly this route.
So I'll only take you to those locations. So if you're on the No. 16 bus to downtown Syracuse, you get to go there. But if you're on the 16 bus and you want to go to Binghamton, you're on the wrong bus. And so we said no bus to the brain, only on the vitamin B12 route. And as a consequence, some of it still goes to the pancreas and obviously it's dose dependent. And so we worked to figure out how much we need to maintain a relevant level to trigger a glucose control, but no brain entry. And as soon as we did that, we saw no nausea, no vomiting, no weight loss, but nice, maintained glycemic control.
Host Amber Smith: So does your drug have a name?
Robert Doyle, PhD: Uh, no, we call it "corrinated." We call the technology"corrination" because vitamin B12 has a beautiful red color. It has this, what we call a corrin ring. So corrination is the obvious, sort of, term from this. So the drugs in this family are called glutides. So I guess we could call it "corriglutide," if we take it that far, but certainly we have just a generic internal moniker for it right now.
Host Amber Smith: Why was it tested in the musk shrew?
Robert Doyle, PhD: So, yeah, it's very unusual. So the musk shrew, first and foremost, looks like a rodent. It looks like a rat or a mouse, but it's actually a mammal. And in fact, it used to be, before the advent of more complex sequencing and DNA analysis, it used to be ranked as a pseudo primate.
So it was originally considered to be a really small creature related to a monkey. So in other words, we're primates -- very, very high-order evolutionary species, but it can do something as well that a rat and a mouse cannot do. They cannot vomit, so you can't actually do emetic studies, or vomiting studies -- my little boy calls it barf studies, and he likes to say, "Did you do more barfing studies today, Dad?"-- to do it, you need a species that can truly vomit.
And that's usually done in dogs, but here we have a small, rodentlike, higher-order mammalian model that can vomit that has the exact same pathway, the vitamin B12 pathway, that a human does. So in addition to rats and mice and guinea pigs, etc., not having the ability to vomit, they also don't have the same human vitamin B12 pathway.
So they ended up being completely incorrect as a model species for us to be able to do the work.
Host Amber Smith: So, this musk shrew was perfect for what you needed.
Robert Doyle, PhD: Well, you had to prove it. We actually had to study the vitamin B pathway in the shrew because it wasn't known, and confirm it actually had the human setup, and which we did.
And then my collaborators at Penn -- University of Pennsylvania in Philadelphia -- they are experts. In fact, they're one of only two colonies in the entire world -- the other is in Hong Kong --- that actually utilize musk shrews in this way.
Host Amber Smith: So the drug proved itself in the musk shrew.
Robert Doyle, PhD: Yes. And actually it did better than an actual FDA (Food and Drug Administration)-approved drug that's currently on the market, better in terms of its life span and its glycemic control.
And unlike that drug, it did not cause vomiting or weight loss.
Host Amber Smith: So what is the next step after you finish looking at how this performs in this species, what do you do after that?
Robert Doyle, PhD: Well, because the data was so good. We actually did two major things. We wrote anRO1, which is the primary mode of acquiring health funding in the United States through the NIH, the National Institutes of Health, and the first submission, thankfully, they liked it enough to give us $3.4 million to pursue it over the next four years, which actually just began this past July, 2021. And we also, at the same time, and by we, I mean myself and my two collaborators at Penn, professors Matt Hayes and Bart De Jonghe, we spun out a company.
So we started a company called Cantius Therapeutics, and one of our lead pipeline drugs now will be this corriglutide, as you've now inspired me to name it (laughs). And so we will now, over the next 18 months, begin the process of acquiring the data we need to get what's called an IND, or investigative new drug, application to the FDA.
So it is something that we're actually very excited about it. And we have really, really good, interesting lawyers and businesspeople who've come on board now at Cantius, whose job it will be to guide the scientists who don't know the business and legal aspects of drug development through the next 18 months into this process.
And if the science holds up, that's where we should be in about 18 months.
Host Amber Smith: So this 18 month period -- at the end of that period, is that when this may be tested in humans?
Robert Doyle, PhD: Yes, at that point you can go into a phase one safety study just to make sure that it's tolerated and tolerated doses that you were clinically use.
And then our idea, the main focus for our work, to go back to my area, to come into, these are wonderful medications, the darling of research. They do have a limitation in that while a lot of type 2 (diabetes) patients do benefit from losing weight, that is absolutely true, some patients who have a comorbid disease like cystic fibrosis or HIV or cancer who are also type 2 diabetic, they cannot see their nutritional status suffer any further.
And so what you would like is to be able to offer them another tool in the toolbox to give them glycemic control, but without affecting their nutritional status. They want the glucose control. They do not want the weight-loss aspects. And of course that would also apply to lean type 2 diabetic patients. So this is more of a, a forgotten small percentage, if you will, that aren't able to benefit from these really wonderful drugs that would now be able to benefit from them. And we're focusing right now particularly on patients with cystic fibrosis who also have type 2 diabetes. And that is usually the case with patients with cystic fibrosis. They will eventually develop diabetes, unfortunately.
Host Amber Smith: This is very interesting. I appreciate you sharing this information with us.
Robert Doyle, PhD: Sure.
Host Amber Smith: My guest has been professor Robert Doyle. He's a professor of chemistry at Syracuse University and an adjunct assistant professor at Upstate. I'm Amber Smith for Upstate's "HealthLink on Air."
Next on Upstate's "HealthLink on Air": understanding graft-versus-host disease.
From Upstate Medical University in Syracuse, New York, I'm Amber Smith. This is "HealthLink on Air." Graft-versus-host disease (GVHD) is a rare condition that may develop after a person undergoes a bone marrow or stem cell transplant. A scientist in microbiology and immunology at Upstate has done considerable research on this condition, and he's agreed to tell us about it. My guest is Dr. Mobin Karimi. He's an assistant professor at Upstate -- and I thank you for making time for this interview.
Mobin Karimi, MD, PhD: Thank you for having me
Host Amber Smith: Now is graft-versus-host disease only a threat to people who had bone marrow or stem cell transplants, or could people who've received an organ transplant or blood transfusion also be at risk?
Mobin Karimi, MD, PhD: Graft-versus-host disease can be a risk in both people who received the bone marrow with the stem cells and mature T cells, and it also can be a risk with receiving a solid organ. The difference is that when a patient receives a stem cell, they also has to receive some mature T cells. So, these mature T cells, what they do is they help the engraftment. But in the case of solid organ transplant, what happens is that the patient's own T cells can reject the transplant and can cause graft-versus-host disease.
Host Amber Smith: I see. Well, tell us about this condition. What are the main symptoms of graft-versus-host, and why is it a danger?
Mobin Karimi, MD, PhD: So graft-versus-host disease is one of the highest rates of mortality afte cancer. So a lot of times, what happens when a patient goes under chemotherapy and radiation, we have to give them some mature T cells and stem cells to regenerate their immune system. And in order for the stem cells to engraft, those T cells help the engraftment, and those T cells also get rid of the minimum residual cancer cells that had been hiding anywhere.
So it's a great way to get rid of the cancer. But what happens is that within the first 100 days in a human, those donor T cells, if they are a mismatch, they can proliferate and they can produce this molecule called cytokines. And they're targeting the cancer cells, but they are also targeting the normal cells. So that's what constitutes a graft-versus-host disease.
And with graft-versus-host disease anywhere between 20% to 70% of the population might die from this condition, so historically people think of graft-versus-host disease as trading one disease for another disease. So there's a lot of possibility that the patient might not die from cancer, but they might die from graft-versus-host disease.
So the first symptom in the human is a very bad skin rash, gastrointestinal system get damaged significantly, people develop diarrhea, and that diarrhea become bloody diarrhea. The liver gets damaged. The skin gets significantly damaged. The eyes get damaged. And if not treated, a patient might die from this.
Host Amber Smith: So it sounds like, correct me if I'm wrong, so the person who's receiving the transplant, if this develops, their body is rejecting the transplant or not happy with it in some way?
Mobin Karimi, MD, PhD: So what happens is the donor T cells that we injected with the stem cells in order to grab the stem cells, because if you don't give them the stem cells, the patient might from the radiation and chemotherapy. So those donor T cells proliferate so highly and they are the ones that are targeting the patient because those donor T cells are not developed in the patient's body.
So they consider the patient as a foreign entity, and they're targeting it. So if they were developed at the same time, or they were related by the genetic relationship they might not get rejected. But since they are totally different from each other, there was a greater chance that the donor cells might cause the graft-versus-host disease.
Host Amber Smith: Can you walk us through how graph-versus-host disease is treated today?
Mobin Karimi, MD, PhD: So graft-versus-host disease is based on the condition, whether it is acute graft-versus-host disease or chronic graft-versus-host disease. But the general treatment is an immunosuppressive drug. So what happens is that when a patient develops graft-versus-host disease, a physician treats them with any immunosuppressive drug.
What happens in that case is that that patient will always be on those immunosuppressive drugs. And they cannot be vaccinated against viruses like a flu or COVID or any other things. The patient could simply die from bacterial infection. They cannot clear a bacterial infection. There is a greater chance that the tumor will relapse right away, because T cells cannot fight back the minimum residual. So it is a great idea to modulate T cells signaling to the point where you achieve the immunosuppressive part, where your T cells do not produce cytokines, but at the same time, it can clear tumors, and they can also clear viral infection.
Host Amber Smith: How common is graft-versus-host among people who have a transient?
Mobin Karimi, MD, PhD: The range is pretty wide and I knew it'd be between 20% to 75%. It's based on the genetic makeup of the donor and the recipient, how far they are from each other.
Host Amber Smith: So are physicians able to predict who will develop graft-versus-host?
Mobin Karimi, MD, PhD: There's a lot of literature that the physician can predict the graft-versus-host disease, but those are not prominent science that guarantee that this will be GVHD or not GVHD. What happens is in the mouse model, we can generate a different mouse. We can kill GVHD, we can target the cancer, but when it's come to the patient, it's much more than that. So the prediction, a lot of work has been done ro recognize in the prediction. Other things that doctors are exploring is the possibility that what they do is they take some stem cells, stem cells alone, and transplant it from the donor to the recipient and let it go in the rcipient's body, qneqand then with the hope that they might not reject the organ, or they might not reject the T cells transplanted. But it's a big problem. Also, a lot of people can ask the question, "Why don't they use patient's own cells?" or a lot of people ask, "Why don't they use their -- like, if you have a twin sister and brother, or from mom to the patient or from dad to the patient from children -- because they were relatively closely related?"
So why we don't do that? The problem with that case is that if a cancer has happened and the bone marrow cells or the cancer was really like CML (chronic myleloid leukemia), AML (acute myeloid leukemia), that happened in the myeloid cells in the bone marrow. So if you transplant them, T cells or stem cells from the closest relative, the greater chance that they will relapse. And this time if they relapse, when the cancer come back and is much worse than the first time and it's aggressive.
So what happens is that if you use it from the less relative, from the less mismatch to the patient, they do not relapse the cancer, but they develop GVHD.
Host Amber Smith: This is Upstate's "HealthLink on Air." I'm your host, Amber Smith, talking about graft-versus-host disease with Dr. Mobin Karimi. He's an assistant professor of microbiology and immunology at ups.
So tell us about what you are focused on in your research. Have you and your colleagues found a way to eliminate graft-versus-host?
Mobin Karimi, MD, PhD: So our lab setup is that we study signaling, T cell signaling and K cell signaling, and we use graft-versus-host disease as a readout for those. For example, T cells are the ones that cause a disease., graft-versus-host disease, but the same T cells are required to get rid of the tumor. So if we can modulate the signaling that they will not cause graft-versus-host disease, but they can target a graft-versus-tumor or graft-versus -eukemia. So that is the goal of the research, is how can we module it this pathway for a T cell to do one thing but not the other.
And this has been pretty challenging to our time because you need the same T cells for engraftment to secure the engraftment of stem cells. You need the same T cells that get rid of the tumor cells, but the same T cells also cause graft-versus-host disease. So how do you make a T cell do one thing and not do another thing? That is our research focus.
Host Amber Smith: So that's what you're focused mostly on. Now I understand your team has developed a peptide to inhibit some of this?
Mobin Karimi, MD, PhD: So previously many people have shown that if you can modulate T-cell signaling, that will cause less disease. So we had published previously, and other people have published, that there is a molecule called ITK.
ITK is a kinase that is required for T cell robust response against virus, against antigen, against any foreign things. So if we can attend attenuate the TCR (T cell receptor) signaling, we might not cros cause graft-versus-host disease. So the issue was where do we target T cell signaling? So if we can target it downstream, some other signaling might compensate for the signaling molecule that we target.
But if we've targeted upstream, it might make the T cells totally dysfunctionla. It might not do anything. So we've been working on this molecule called ITK. So if we get rdi of ITK, if we remove ITK, then the T cells do not cause the cytokine storm, which causes graft-versus-host disease, but they upregulate other molecules, and those are the one that anit-tumor response.
Host Amber Smith: So it's not as simple as just getting rid of ITK. You can't entirely get rid of it.
Mobin Karimi, MD, PhD: So what we wanted to do is, we wanted to look at -- and ITK is a kinase, so if you take 100 kinases, they will all look the same. One of the problem is that developing drugs and developing small molecules or developing anything against either T cell mediated diseases, could be autoimmunity, could be a graft-versus-host disease. It could be any possible thing. What happens is that when you target one kinase, by default, you will target another kinase. So, what we looked at is that, OK, we need to target ITK, but what is the signaling that activates ITK?
So what we looked at it, there is a, there was a molecule called SLP-76. SLP-76 is a molecule on the top of ITK. So when we removed the SLP-76, we didn't see any T cells in the mice. The mice do not make T cells. And the mice do not make NK (natural killer) cells. So SLP-76 has three important tyrosines. Tyrosine is a signaling protein that connect adopter molecule with the kinases.
So what we did is we mutated each one of them in the mouse. So we switch tyrosine for another molecule. And when we talk the SLP-76, in the position 145, the ITK was not phosphorylated. Basically the signal was the same. And those mice can clear LCMV (lymphocytic choriomeningitis virus) infection. They can clear virus, they can clear tumor, they can do anything, but they don't cause autoimmunity.
They don't cause graft-versus-host disease. So what we did is we tweaked the system enough that they will not cause autoimmune response, or they will not develop other immunity or graft-versus-host disease. But at the same time, they will be able to get rid of a viral infection, and they can get rid of the tumor.
So the most important thing was where do you target thes kinases? So we did this in the mouse model, and we've proven that also by we get similar results that we get rid of the ITK itself. If you remove it from the mice, it doesn't do anything. But some report has shown that if you target ITK, those mice cannot clear the virus and cannot clear that any other infection.
So that's what we, our idea was where to target this. Once we targeted, we were able to achieve the goal.
Host Amber Smith: Well, I know the basic research that you're working on and doing is really the building blocks toward getting closer to something that would take care of or treat graft-versus-host. So I appreciate you kind of bringing us into your laboratory today.
Mobin Karimi, MD, PhD: Thank
Host Amber Smith: My guest has been Dr. Mobin Karimi. He's an assistant professor of microbiology and immunology at Upstate Medical University. I'm Amber Smith for Upstate's "HealthLink on Air."
And now ,Deirdre Neilen, editor of Upstate Medical University's literary and visual arts journal, The Healing Muse, with this week's selection.
Deirdre Neilen, PhD: Dale Shank is the founding editor of the fictional journal Black Ice. Dale's work appears in Akros Review and the University of Portland Review. The poem "Apple Tree Time" celebrates life, friendship and aging with both wisdom and grace.
"Apple Tree Time"
A winter morning pruning apple trees
Is an exercise in aging.
We do not hear a clock ticking.
We cannot see the trees growing older.
Time can be counted as much by
the rhythms of branches being cut
As by words between us.
A winter morning pruning apple trees
Is an exercise in optimism.
As we work our way from Gravenstein
to Red Delicious to Northern Spy,
Cutting the gnarled, the dead, the misshapen limbs,
We believe, implicitly, we will be back
In the spring when the trees are in bloom
Or at least by fall when the apples are ripe.
We tell ourselves these cuts are kind,
a requisite for rejuvenation.
We tell ourselves time is an ally.
Host Amber Smith: This has been Upstate's "HealthLink on Air," brought to you each week by Upstate Medical University in Syracuse, New York. Next week on "HealthLink on Air": How have the children fared during the pandemic? If you missed any of today's show or for more information on a variety of health, science and medical topics, visit our website at healthlinkonair.org
Upstate's "HealthLink on Air" is produced by Jim Howe with sound engineering by Stephen Shaw. This is your host, Amber Smith, thanking you for listening.