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Interview: Dr. Eli Lewis, PhD, Ben-Gurion University of the Negev

The Future of Islet Transplantation

Steve Freed: Please give tell us a little bit about yourself, and your field of interest.

Dr. Eli Lewis: I studied in the medical school at Ben-Gurion University of the Negev (BGU) in Israel. During medical school, I was infatuated by medical research. I then completed a Masters and PhD in immunology. The area that I was studying was transplantation. While I was studying transplants, I focused on the role of the tissue that is transplanted in creating the immune response, it’s kind of an innovative view of immunology especially back then, the fact that the tissue actually plays a role. I then went on to do my postdoctoral fellowship in Denver, Colorado. I came back to open my at in BGU six years ago.

The focus of the lab is adjusting tissue damage in the bigger picture, with implications on immune tolerance. Tissue damage actually plays a role in type 1 diabetes and in islet transplants, but it is often overlooked and very understudied. So, if you were expressing disappointment from research in diabetes, it is maybe because there was at least one stone that was left unturned, and that is the role of the islets, as actual players in this game. They actually call up the immune system, they attract the immune cells. The damage that the islets go through actually perpetuates the progression of the disease. It looks that we finally have something close enough to address, at least in that area, and results in addressing tissue damage look very promising.

SF: How did you get started in preventing the destruction of the beta cells, and working on a possible cure for type 1 diabetes? In my family, I have a lot of people with type 1 diabetes, so I’ve always had an interest in it. Why did you get involved and turn your research in that direction?

Dr. Lewis: I grew up with a friend who had type 1 diabetes. I was so proud of him because he was able to inject himself, something a kid looks at as being a superhero. The research later wasn’t even to do with diabetes. It was transplants, but islet transplantation is something specific that drew my attention. It was this newer field which looked very promising, and I thought the impact could be on a lot more patients with type 1 diabetes if we could succeed with islet transplants. That opened the door to type 1 diabetes research for me, because part of transplant immunology actually overlaps with what happens in the pancreas to islets during type 1 diabetes. So whether we transplant the islets or just attack them, it’s always the islets facing the immune system.

SF: Obviously, you are familiar with the Edmonton protocols, but, you decided to work with pig islets, which is kind of a stretch, really, when you talk about using human islets. I know that if we were to transplant all the type 1 diabetics, there wouldn’t be enough islets in the world to cover them. Was that one of the main reasons that you started to look at pig islets?

Dr. Lewis: That is exactly one of the reasons. Islet transplants have gone from promise in the year 2000 to disappointment later; and now there is a comeback. I have just come back from a meeting here in Houston Medical Center, with a human islet transplant center head. It looks like we are all the way back now to the center of attention, because, in my opinion and as I mentioned before, the stones that were left unturned can be found in the Edmonton protocol. The protocol is missing some anti-inflammatory aspects and some tissue-protective aspects. It’s very focused on the immune system, and doesn’t address the tissue that suffers, and the tissue that actually now evokes more of the immune response. We had incredible results with islet transplants in animal models, and we are now waiting for clinical trials to start with islet transplants in humans using our therapeutic approach. In the meanwhile, considering what you mentioned, that there are never going to be enough human islets to reach all the patients in need, the field of pig transplants was unfortunately left on the back burner for a long time. It’s been held back by regulatory authorities because they were afraid that pig viruses might start seeping into our system. In the past two or three years however, the FDA finally approved a clinical trial with pig islets into humans, after proving that there is no danger to us. That’s why I felt that it’s worth addressing that area, it is probably going to be the source of islets.

SF: But wouldn’t you think that we have enough problems with rejection of human transplants, wouldn’t there be more of a problem with pig islets, with inflammation and rejection?

Dr. Lewis: It depends. There are many differences in favor of pig islets over human islets. For example, pigs can be genetically modified. You can take pig islets and remove from these islets many elements that are targets for the immune system, which is something you cannot do in human donors. In addition, the mechanism by which the immune system attacks human islets from a donor compared to a different species, is a different mechanism. It’s not just more of the same. It’s really a different arm of the immune system altogether. Being that different is actually an advantage, because we were able to cross that obstacle with a little creative work by our team at BGU. It’s something that’s actually not studied in regular human transplants, because that’s not the arm of immune response that is being examined. We were able to find benefit in the fact that we use pig islets, or any other species-to-species experiments. Lastly, consider that the transplants can be literally scheduled, and the timing then does not rely on the time of organ donation and its compatibility. Again, it’s only been held back by the problematic idea that maybe pig organs could be bad for us, not because it’s impossible, and they have since been proven not to pose such a threat.

SF: So you feel that even though in the Edmonton trials, there hasn’t been a lot of success over long periods of time, because of the rejection problems and the inflammation that by using your protocols and using pig islets, that you have a feeling that you are at a better place as far as rejection, that it’s almost easier to prevent the rejection from a pig islet rather than a human islet? So my question is, why can’t we just use the same process, although you are saying it is a different mechanism of action? What would happen if we took your process and used it in the Edmonton protocols, or in a regular transplant patient?

Dr. Lewis: These are actually exactly the trials that we’ve just submitted for proposal to perform as human islet transplant clinical trials. I hope they will be accepted now, considering that we have three clinical trials that have just ended with type 1 diabetes and that hold very promising results. Human islet transplants are still my first choice. In the meanwhile, you can’t really discover things in one week, so we have the pig islet transplant study in parallel for when it can ultimately be considered for human trials.

SF: So you are waiting for approval to use your process in the human transplants?

Dr. Lewis: Yes. I just came back from two transplant centers, one in UCSF and one in Houston, which one of them has already submitted this protocol and the other is considering it. They are very optimistic; they are very eager to try this. Now that we see the bigger picture, we do realize that we were missing an entire area unaddressed in the treatment protocol.

SF: In your protocols, the ones that you are almost finished with, it’s only for type 1s. What kind of stipulations do you have for these patients? What requirements did you have for them to enter into the study, such as how long had they had diabetes — a week, a month, a year?

Dr. Lewis: Exactly. The inclusion criteria were in the three trials in Israel, Colorado, and Harvard, pretty similar. You had to be within one year of diagnosis, recent onset type 1 diabetes. Age was not an issue as this drug is so safe that the FDA approved its use for youngsters. In Israel for example it was age four years and above, as long as you were within one year of diagnosis, with residual, at least, non-zero levels of C-peptide. Over twenty individuals in each center, and all had stayed with the trial to its completion. There were no dropouts.

SF: How long has it been going on with the initial patients?

Dr. Lewis: Two years in the three different centers independently.

SF: So you are coming to these conclusions after two years?

Dr. Lewis: Yes, it’s the point that we chose to stop, and look at the results. It’s not because it’s not worth following. But for the trial to make the next turning point, you have to stop and look at the results, and maybe change the dose or timing. At this point right now, we are going to advance into another two trials with modified dosage, and try to optimize the protocol.

SF: What kind of time frame do you have for the publication of your first set of trials?

Dr. Lewis: I hope shortly. Usually, these things take several months.

SF: OK, so before the next ADA meeting. This is obviously for type 1 diabetes patients. Are there any thoughts on whether this would be effective for type 2s, although type 2 is a different disease, insulin resistance rather than immune destruction of islet cells.

Dr. Lewis: On the one hand it is a different disease, but there is a lot of overlap, especially when you look at the islets. There is a whole trend now to consider that islets actually play an important role in type 2 diabetes. When they function improperly, they can actually cause type 2 diabetes. So there is still kind of an area there worth targeting. In addition, we have data that show that when islets are damaged in type 2 diabetes, because there is too much glucose and fatty acids circulating for too long of a duration, the patients reach the point when they need insulin injections, they can’t make their own anymore. In our studies we found that there, also, we can protect the islets. We think that when islet function is lost under any condition, whether it’s type 1 diabetes or advanced type 2 diabetes, or whether it’s because of some side effect of drugs (I’ve noticed you posted an extensive list, we’re examining three of these!), there’s psychiatric drugs and even immunosuppressive drugs that actually cause diabetes, and other insults, all these are basically what we study; how to protect islets from damage. It looks like we have a very powerful approach across the different pathologies to protect islets.

SF: I work with a number of physicians that are very knowledgeable about type 1 diabetes, and some of them even have type 1 diabetes. I asked them for an input for what kind of questions I can ask you, to see if I can stump you along the way. One of the questions came up, what if another wave of immune attacks come along with most diabetics. How are the islets protected, because just like the Edmonton protocols, they thought they had stopped one type of attack, and guess what, another type of attack comes in, and that one is taken care of, and then another type of attack comes in. Have you looked at that?

Dr. Lewis: We did start to look at it. Some of the individuals with type 1 diabetes that got treated with alpha-1 antitrypsin, in and out of the trials, some of them were off-label, actually went on a separate protocol: if there was any hint of glucose control worsening, then they got another round of treatment. This whole protocol is basically eight to twelve weeks, roughly dependent on which center employs it, and is then withdrawn and glucose control is followed. So some individuals went back to repeat the protocol when the suspicion arose that it’s worsening. Behind this is the idea that it is so safe, that there are no side effects. We are basically mimicking the condition where the body is known to protect itself from tissue damage. We are mimicking what the body would do if you had the flu. It actually has a way of protecting tissues from an injurious inflammatory overspill. There is no downside, maybe the only thing would be that you have to visit an infusion nurse every week for several times, or that you have to pay for the drug, but there are no side effects. The drug has been used for thirty years, at even higher doses with no side effects, non-stop for the entire life span of individuals with a particular genetic deficiency. Considering that fact, we don’t really need to limit the treatment. We need to just find the ideal treatment program. So, some of these individuals outside of the trials got what we call a ‘rescue’ dose; because they needed it.

SF: Do we know exactly, or without getting too technical, how the alpha-1 antitrypsin works?

Dr. Lewis: Yes, we are getting closer than ever. We have a lot of data regarding this, most never existed before recently. The lab at BGU is basically the most advanced and most experienced in investigating the molecule’s function. We have collected evidence on many levels: what alpha-1 antitrypsin binds to, how different cells respond to it, etc. There is a lot more momentum now than was before, but still we’re not there just yet. The good thing is, you see, when a diabetic individual is to consider an alternative therapy, an alternative approach like an islet transplant or any form of clinical trial, a lot of times there is a downside that’s greater than just getting insulin injections, and they just decide not to go there. This is one of the only examples we have now that diabetics actually didn’t have any dilemma, because there is no downside. They were fighting to get included in the trials, rather than having to be convinced. And the compliance was absolutely great. For the first time in a long time, I think, this is why I would consider it a breakthrough. One hundred percent compliance is not that easy.

SF: I understand. Do we know which T-cells are depleted, and how?

Dr. Lewis: Oh, you are really using technical words. None of the T-cells are depleted. In fact, it is even more interesting. T-cells are not targeted here. We know from several different, independent groups, that alpha-1 antitrypsin does not affect T-cells directly in any manner. These cells live with alpha-1 antitrypsin, they can respond and proliferate, but here we pull the rug out from under their feet, because they rely on the tissue to be damaged and inflamed. Even the most activated T-cell would be completely silent if it were attracted to an area that had no inflammation, and then it wouldn’t cause any damage. That’s why I started this interview when I said that I think finally we are treating the tissue, and allow the immune system to just kind of get dangerously close but altogether avoid an injurious response. The islet in these cases we mentioned is sending an SOS, and we don’t want it to send the SOS. We want the immune system to completely ignore the islets. The only way to do this is have the islets recover and become intact, with no inflammation. The T-cell is really not the target here.

SF: That’s great information, because that’s always been the focus of many of the research studies.

Dr. Lewis: We are talking about stones being unturned, everybody was looking ‘under the flashlight’. Everyone was looking at the T-cells and B-cells. I’m not sure if you know of this, but they depleted T-cells from kids, didn’t really show much benefit. It was kind of a disappointment. It turns out that T-cells don’t just work alone. The T-cells completely need the other cells and the tissue to participate. So, they are not the best target, especially not if you need a therapy that has no side effects. Two days ago there was an event that I was giving a lecture to type 1 patients. One of them was a kid, I think 11 years old. I started to describe transplants, and to ask whether or not they would consider it, because we are practically going to destroy a lot of cells by immunosuppression. This kid was so cool, he said, “Oh, so you are going to turn us into an HIV patient.” This is one very sharp kid. I don’t want to neutralize the immune system. I don’t think that is the approach. I think the approach is to change the tissue in a manner that the immune system no longer considers it an authentic threat.

SF: That is certainly different than what’s going on out there. A question, do pig islet cells provide the same insulin response as human islets? Do we know that?

Dr. Lewis: You know people were getting pig insulin for the first fifty years of the drug, before it was made synthetic. It’s close enough. And I wouldn’t go to a donor mouse to give you islets, you need something that roughly parallels the patient by body weight. So that’s one of the considerations for the choice of pigs.

SF: What do we know about the use of alpha-1 anti-trypsin when it comes to possibly increasing the risk of cancers? It seems to be a major focus in every drug that comes out now. It’s been available for a while.

Dr. Lewis: This is a good question. It’s the same question that applies to bacterial infections, or viral infections. We addressed this experimentally in the past couple of years, just to finally provide a solid answer. We found that, while I was looking to exclude that there is more susceptibility, we are actually blocking infections, and there is no advantage to tumors. We literally planted melanoma cells in animals, and discovered that when alpha-1 antitrypsin was elevated, the tumors did not evade the immune system and were destroyed. The immune system is not a target here, so the immune system was still responding to the tumors, it was still knocking down tumor growth. However, it was re-educated toward accepting islets. Bacteria have an interesting relationship with this molecule. Bacteria, as it turns out, need to damage the tissue in order for them to go in. When alpha-1 antitrypsin was present at higher levels, as we explored using direct lung infections and abdominal infections, bacteria just didn’t have their proper environment. They could not penetrate an area where these is no damage. So, we actually accidentally ended up studying also bacteria and cancer, which I vowed never to study, and now I have to explain these phenomena. It’s very positive in that manner. Again, our body makes this molecule all the time. We increase its levels when we are sick, endogenously. The liver does this. There is obviously a reason evolution chose this molecule to rise when we’re obviously in danger of excess injury. We are kind of stretching and increasing something that the body would have done otherwise and we are thinking that we’re doing this to compensate for the molecule being simply not enough, and not at the right time.

SF: So you really haven’t seen any side effects or major issues that would cause dropouts, because you haven’t had dropouts.

Dr. Lewis: No. It’s not the first time people used this drug, for one. People have been taking it for thirty years, because they have a genetic deficiency in it. They have below-normal levels of alpha-1 antitrypsin, just lower than normal, and when they get injected with alpha-1 antitrypsin, they actually supersede the usual circulating concentration by four to six times, on purpose, so that every week they can maintain above-normal levels. They are basically exposed to excessive levels, and there are no side effects reported. It’s pretty much what the body would generate, if it needed more. You don’t actually cross beyond what the body already has during sickness and illness.

SF: The philosophy is basically, if you have this autoimmune reaction to your islet cells, if you can keep the bucket half full, that you can get a cure. Are you looking to do a short period process, or are you still looking for the answers of how long someone might have to be on this treatment therapy? If they have to take three injections a day, have we really accomplished anything?

Dr. Lewis: This is a once-a-week protocol. We were not planning on increasing the frequency, because we think it’s too problematic to find an infusion nurse to do this whole thing more than once a week. We are sticking to this frequency in all the trials, at this point. But, the dosage is slightly changing. I think that within your question you are asking when will this be used, right? Are you really asking how long can we stretch these experiments before we can just proceed into giving alpha-1 antitrypsin to type 1 diabetes patients?

SF: Right.

Dr. Lewis: The answer is slightly problematic, because physicians already realize that it is safe enough to give, and they currently give it off-label to patients that appear to be applicable. This is outside trials. I’m thinking that what is going to happen now is that regardless of the next experiments, it’s just going to be used off-label. For it to become on-label, for the companies to officially commercialize it and say that it is indicated for type 1 diabetes, is going to take a couple more years. There are currently about the same number of people in the trials as outside the trials that have receive alpha-1 antitrypsin off-label because their physicians were convinced of its safety. We follow these individuals and we see results that reflect the ones collected in the trials.

SF: If you had to put together a percentage of your personal feelings, do you think you are 70% there, or 90% there, or 100% there?

Dr. Lewis: 85%.

SF: That’s pretty good. Another question I have, I’m Jewish, myself. I want to know, will this treatment be kosher?

Dr. Lewis: Completely. It is because it will save lives.

SF: Are you familiar with Dr. Yuval Dor’s research at the Hebrew University?

Dr. Lewis: Of course.

SF: Regeneration of beta cells is another area which has got a lot of interest recently. I’m familiar with his research and the enzyme he is using. Where do you feel that research might go?

Dr. Lewis: I think the answer is that there probably is not going to be one drug. We are probably going to have to combine therapies to have an actual serious effect. So, I think there is never any contradiction between parallel studies. If his method and my method complement each other, maybe even synergize, then it’s a win-win (us and patients all win). We do work together; there is to some degree some complementary between alpha-1 antitrypsin and the concept of regeneration. At least, it doesn’t block it; it allows it to work.

SF: That is an interesting concept, combination.

SF: Thank you for your time. Very interesting. Hopefully you’ll be presenting at the next ADA meeting in June, which is in Philadelphia, and hopefully we’ll be able to make contact then. Thank you.

Dr. Lewis: Thanks for the interview.

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