Researching new ways to treat graft-versus-host disease

[00:00:00] Host Amber Smith: From Upstate Medical University and Syracuse, New York I'm Amber Smith. This is "HealthLink on Air." Graft-versus-host disease 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.

[00:00:28] Mobin Karimi, MD, PhD: Thank you for having me.

[00:00:30] 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?

[00:00:44] 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 have 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..

[00:01:35] 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?

[00:01:42] Mobin Karimi, MD, PhD: So graft-versus-host disease has one of the highest rates of mortality after cancer. So a lot of time 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 graph-versus-host disease. And with graft-versus-host disease, anywhere between 20% to 70% of the population might die from this condition. Uh, 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 as a very bad skin rash, gastrointestinal system gets damaged significantly, people develop diarrhea, and that diarrhea becomes 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.

[00:03:34] 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?

[00:03:46] Mobin Karimi, MD, PhD: So what happens is the donor T cells that we injected with the stem cells in order to engraft the stem cells, because if you don't give them the stem cells, the patient might die from the 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 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.

[00:04:45] Host Amber Smith: Can you walk us through how graft-versus-host disease is treated today?

[00:04:50] 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 drug. 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 you, the cells do not produce cytokines, but in the same time, it can clear tumor, and they can also clear viral infection.

[00:05:58] Host Amber Smith: How common is graft-versus-host among people who have a transplant?

[00:06:03] Mobin Karimi, MD, PhD: The range is pretty wide, anywhere between 20% to 75% It's based on the genetic makeup of the donor and the recipient, how far they are from each other.

[00:06:14] Host Amber Smith: So are physicians able to predict who will develop graft-versus-host?

[00:06:19] Mobin Karimi, MD, PhD: There is 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 different mouse. We can kill GVHD, we can target the cancer, but when it comes to the patient, it's much more than that. So the prediction, a lot of work has been done to 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 recipient's body, and then with the hope that they might not reject the organ or they might not reject the T-cell transplanted. But it's a big problem. Also a lot of people ask the question, 'why don't they use the 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 a 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 comes back it 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.

[00:08:24] 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 Upstate. 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?

[00:08:44] Mobin Karimi, MD, PhD: So our lab set up is that we study signaling, T cell signaling and K cell signaling, and we use graft-versus-host disease as a readout. For example, T cells are the one 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 graph versus tumor, or graft-versus-leukemia. So that is the goal of the the research is to 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 cells to do one thing and not do another thing -- that is our research focus.

[00:09:57] 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?

[00:10:06] 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 attenuated the TCR (T cell receptor) signaling, we might not 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 dysfunctional. It might not do anything. So we've been working on this molecule called ITK. So if we get rid of ITK, if we remove the 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 ones that cause anti- tumor response.

[00:11:33] Host Amber Smith: So it's not as simple as just getting rid of ITK. You can't entirely get rid of it.

[00:11:37] 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 problems is developing drugs and developing small molecules or developing anything against either T-cell mediated diseases, could be auto immunity, 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 tyrosine. Tyrosine is a signaling protein that connects adopter molecule with the kinases. So what we did is we mutated each one of them in the mouse. So we switched tyrosine for another molecule.And when we target 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 ofa viral infection, and they can get rid of the tumor. So the most important thing was where do you target this kinases? So we did this in the mouse model, and we've proven that also by we got similar results that we got 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 and those mice cannot clear the virus and cannot clear 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.

[00:14:24] 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. 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."