Recently, Dr. James Shapiro and a team of transplant surgeons at the University of Alberta in Edmonton transplanted islets into 10 people with type 1 diabetes. In previous studies, only eight percent of islet-transplant recipients have remained off insulin for one year. The Edmonton Protocol is the first study in which 100 percent of islet-transplant recipients have been insulin-independent for one year.
The keys to the success of the Edmonton Protocol are a new anti-rejection drug combination, the avoidance of steroids and the delivery of sufficient islets.
Recently, at the ADA Scientific Sessions in San Antonio, Texas, Diabetes Health publisher Scott King caught up with Dr. Shapiro to discuss the Edmonton Protocol.
Scott King: Am I right that part of the success was this new anti-rejection cocktail that does not involve steroids, because steroids are toxic for islets?
Dr. James Shapiro: That’s exactly right. In previous islets transplants, and there were a lot of them carried out in the world-over 400-they used to always use steroids and their success rate was 8 percent. What we have done here is gone from an 8 percent success rate to a 100 percent success rate in one easy step. Well, I wouldn’t say easy. It’s taken a lot of work and there have been a lot of challenges. There has been a huge team of people behind it, not only in Edmonton, Canada, but also in many other centers across the world like Dr. Camillo Ricordi and Dr. Bernhard Hering.
So what have we done? We’ve used a new anti-rejection cocktail that does not require steroids. We’ve used an anti-rejection cocktail that works in concert to stop the rejection systems from being activated. They are also very effective at stopping the auto-immune process that destroys islets in the first place.
King: So, what are some of the side effects? I know that parents are already calling us saying, “I want to sign my daughter up for this.” We know children are not eligible and you are looking for people that are suffering pretty badly from their diabetes.
Shapiro: We don’t know for sure what the long-term risks and side effects are. We can predict (based on countless thousands of patients who had successful organ transplants and their own similar but not identical drug treatments) that there will be some side effects in the long run. These drugs do slightly increase the risks of cancers. They can increase the risks of lymphomas. They can increase the risk of infections. Therefore, in every person that we treat we have to be very cautious to make sure that we do not do any harm.
King: People have said, “Gee I guess I have to get my HbA1c really high so I can get the cure.” Will there be some really tough questions as to who can get this procedure?
Shapiro: We have to balance the risks and benefits in every individual. A type 1 will come to me and I will ask, “What are the risks from your having uncontrolled diabetes? I know your risks of kidney failure will multiply by 25 and your risks of blindness, amputations and heart disease are increased 40 times over. You will also have shortening of your life span by 10 to 15 years.”
I have to weigh those risks against the benefits of the transplant procedure and also the risks of the transplant procedure and the long-term risks of the anti-rejection treatments.
King: You chose people who had hypoglycemia unawareness?
Shapiro: Those were the patients we really concentrated on because those are the patients that have such a devastating quality of life that they are potentially a danger to themselves and to those around them.
King: What about the islets you used? Was there a selection process for you to get some really terrific, healthy islets? Was there any significant improvement in the process you used to select healthy islets?
Shapiro: Absolutely, and the responsibility for that was not mine but Dr. Jonathan Lakey’s. I am a surgeon. I take the pancreas out. And also I work very closely with other surgeons in Canada who supply us with excellent quality pancreases. The process starts with a very high-quality pancreas. I think that if you take a poor quality pancreas it will take a lot to be successful.
King: Is there a better process for harvesting human pancreases in Canada than in the United States?
Shapiro: Well they are heart-beating patients, but they are brain-dead. We’ve carried out successful islet transplants from donors as young as 17 who we previously thought were not suitable for islet isolation and even donors as old as 71. So I think we’ve expanded the potential population.
King: Would it be car accidents for someone dying that young?
Shapiro: Car accidents, strokes and bleeding.
King: I know when you get a kidney transplant, the surgeon tries to match the antigens. You are putting two pancreases together, so is there an issue about matching the pancreas donors?
Shapiro: No. Fortunately, for us, the drugs that we use are more than powerful enough to overcome any effect of the HLA factors. So we don’t have to match for the tissue at all. The only thing we match for is blood group.
King: So do they have to become available about the same time with the same blood group? Can you put them on ice for a few weeks?
Shapiro: No. Part of the ethic of this protocol is to carry out immediate transplants. So when we have sufficient cells of higher quality, we use those immediately. They go into the patient, then we wait, we take the tubes out and we send the patient home within 12 hours.
King: And they’re still on half the insulin dose at that time?
Shapiro: At least half the insulin dose after the first transplant. Then after the second transplant, which occurs as soon as another successful donor and islet isolation happens, the patient is completely off insulin.
King: What was the average time between the first and the second transplant?
Shapiro: Twenty-nine days. However, it varies depending on the availability of the donor. The average is 29 days.
King: They started the anti-rejection medication before the first transplant?
Shapiro: Immediately before the first transplant.
King: And were they cautioned not to let their blood sugar go high? Would the extra glucose load possibly damage the first transplant?
Shapiro: That’s a good question. I think people in the past felt we should keep the sugar control very tight after an islet transplant. I think what we have shown here is that it is possible not to do that and also be successful.
King: Meaning some people did have high blood sugars over 200 during the 29 days?
Shapiro: If they did have values over 200 then we were obviously meaning to put them back on insulin and give them a sliding scale of insulin to keep sugar in a reasonable range.
King: This is between the first and the second?
King: Some people actually went off insulin after the first?
Shapiro: Our very last patient, the 10th patient, is completely off insulin after his first transplant.
King: And didn’t need a second?
Shapiro: And hasn’t needed and probably will not need a second transplant.
King: How do you explain that?
Shapiro: I think that in his particular case he was slightly unique. He was very sensitive to insulin and therefore he was on a small number of units of insulin per day.
King: Like 30 units per day?
Shapiro: He was on less than that.
King: Was he thin?
Shapiro: He was thin and did not weigh very much. So the number of islets we were able to get from one donor was more than enough to fix him.
King: Do pancreases have more islets if they are from a larger donor?
Shapiro: Yes. Generally yes but not always.
King: And Dr. Lakey processed the islets. Would he get the whole pancreas then get to work extracting the islets?
King: Did he do anything different from the other researchers in the past?
Shapiro: He used a new enzyme that has been used before, but Dr. Lakey used it more effectively. He used the Ricordi Chamber developed by Dr. Camillo Ricordi. He also used the Purification System developed by Dr. Bernhard Hering. He also adapted a number of steps along the way.
King: Are you now helping other researchers carry out the same work?
Shapiro: There are a number of steps required to push this forward in the immediate future. First, we have to see if we can reproduce this protocol in many centers across the world and that is a lot of work. It’s being funded by the Immune Tolerance Network in part by the National Institutes of Health and in part by the Juvenile Diabetes Foundation. There will be 10 sites and there will be 40 transplants carried out.
King: Is the Immune Tolerance Network a wealthy group?
Shapiro: They have $144 million funded by the NIH and JDF. Five million dollars of those funds have been allocated to reproduce the Edmonton Protocol across the world.
King: It sounds like there is a lot of money available if there is something that looks successful.
Shapiro: Yes, so that is step one. Step two will be to see if we can then carry out the transplants without needing such powerful drugs. And that is where the Immune Tolerance Network comes in because they will be carrying out the transplants but using hardly any drugs or no drugs at all.
King: Are you going to try encapsulating?
Shapiro: That’s not on our agenda right now. Encapsulation technology has been very exciting previously and I think what has recently become clear is that the steps that are used to encapsulate also cause difficulties. They have to have sufficient holes to let the insulin come out. If they cannot come out then the damaging chemicals can get in and destroy the cells.
King: Are there any risks in your procedure?
Shapiro: Very few.
King: Just a little incision?
Shapiro: No incision. It’s a very simple treatment. It’s an injection in the side under some local freezing antiseptic. A needle is guided through the skin into the liver. A very fine catheter tube is placed into the vein going up toward the liver through the portal vein. And then we simply infuse the islets upward.
King: A fine catheter tube? How does that get in there?
Shapiro: They pass the needle, over the needle they pass a wire, over the wire they pass a little plastic tube.
King: It goes in behind the needle? Is it another incision?
Shapiro: Over the needle. No incisions.
King: How long is the needle to get to the liver?
Shapiro: It has to be long enough to get from the skin. It is going to be about that long. (spreads hands apart about 4 inches)
King: Okay, so you stick that in and then you pass a catheter tube?
Shapiro: No, and then you pass a wire down the needle. From the wire they look at an x-ray and they make sure it’s in the right place. Then down over the wire they thread a little plastic tube.
King: And then the islets go inside the plastic tube?
Shapiro: You could be a transplant surgeon. You just literally connect the syringe to the tube, press and then they go.
King: So you’re not leaving the catheter in there?
Shapiro: Just while we do the infusion. It takes five minutes to do.
King: So you’re just trying to get them into the portal vein?
King: There are so few islets available, so only a few people can get the procedure. How are we going to resolve that?
Shapiro: That challenge is for the future.
King: Do the islets become vasularized? Will they reproduce? What is the life span of an islet?
Shapiro: I don’t know in this situation. I don’t think anyone knows. Certainly the islets are functioning well over time and the function is not falling off so that is very promising information. But do the islets reproduce? Possibly. We do not have a very easy way of measuring that right now.
King: Do you expect that these people are going to need more islets in a couple of years?
Shapiro: I would hope not. I would hope that this islet infusion is more than enough to fix their problems in the long run. Honestly, I do not know. We have to do the experiment and wait and see.
King: Obviously you would be tracking these people closely. Do they get a C-Peptide reading? Is that one of the standards?
Shapiro: Yes, and after their procedure they have very high C-Peptide levels. Higher than has ever been seen before in other transplantations.
King: Does their insulin output approach what a normal person, a non-diabetic, would have?
Shapiro: Almost, but not quite.
King: Do they get any spike in blood sugar after eating carbohydrates?
Shapiro: The best that someone can achieve on insulin from moment to moment, day to day, is huge swings despite being on insulin. If we give the islet transplant the control is almost flat, very tight.
King: Are there any restrictions on what they can eat?
Shapiro: We advise them to stay on a healthy diet.
King: But they can eat sugar?
Shapiro: Potentially they could. However, we prefer they don’t because that would put additional stress on the islets.
King: What could that do?
Shapiro: We don’t know. Maybe excess of stress in the long run could make the islets burn out. We wouldn’t want that to happen. That’s one of the reasons for advising a healthy diet.
King: Do these people test their blood sugar?
Shapiro: Initially they have to test because it’s a research study. They have to test quite intensively. They use a meter that keeps a record. However, in the longer term we have patients now testing two or three times per week. Instead of up to 15 times per day.
King: I guess you would want to spot if there was a spike after a meal? That is something you would want to catch early on.
King: To the parents out there who want it for their children, could you guess how many years away that would be?
Shapiro: I think we would be ready to do another transplant in a child very soon, provided that the child is already on the anti-rejection drugs. I think we have to wait now and see.
King: But that would be unlikely.
Shapiro: No, there are patients that I can think of now who have had full organ transplants who I have done liver transplants on, for example, that have diabetes.
King: So they would be eligible?
Shapiro: Yes, they would b
very ideal candidates. However, in the future, before this is ready to use in children, we have to crack mainly the drug problem to make sure we can minimize those risks.
King: Thanks for coming down to talk with us. This has been a pleasure for me.
Shapiro: You’re very welcome
Editor’s Note: An extension of the Edmonton Protocol will take place at 10 centers throughout North America and Europe. Each center will conduct four transplant procedures. Dr. Shapiro understands several islet-transplant centers will wish to reproduce the Edmonton Protocol and says his team will cooperate with them, provide the protocols and help them. However, they will have to receive their own funding.