The joint meeting of the International Pancreas and Islet Transplantation Association (IPITA) and the International Xenotransplantation Association (IXA) has ended in Venice, Italy. This is the first overseas meeting the Cerco Medical team has attended in a long time. We renewed acquaintances with friends and colleagues in the field and learned the latest results.
Camillo Ricordi (Miami) and Scott King at the Ca’ Salvioni reception.
Venice is uniquely beautiful. The visitor is immersed in a thousand years of building history from crumbling Ventian Gothic palazzos to the most beautiful baroque church, San Salute. The food is delicious, especially food from the sea. It was tempting to spend lots of time in the historic city, but I was able to make myself attend most of the five days of scientific sessions, along with my Cerco colleagues Randy Dorian and Rick Storrs.
Medical Association conferences are a mainstay of the science and medical research calendar. They range from intimate gatherings of specialists to huge annual confabs of a whole medical discipline such as the Radiological Society of North America with around 59,000 attendees. (Radiologists spend more than other doctors on expensive equipment because they use things like PET and MRI scanners.) Within diabetes the largest meeting is the annual ADA meeting at 20,600. Our specific field of transplantation therapy for diabetes is a part of the semiannual meeting of the Transplantation Society, which attracted 4,400 participants at the last meeting in Minneapolis. Diabetes can be cured by transplanting the pancreas or just the islets of Langerhans from the pancreas; scientists interested in these two procedures meet together at the biannual IPITA meeting (International Pancreas and Islet Transplantation Association). This year there were about 600 participants from 30 countries, in Venice October 12-16. The latter part of the week included joint sessions with the International Xenotransplantation Association (IXA), a separate medical society.
Pancreas Transplantation
Whole pancreas transplantation is the best-established transplant procedure for type 1 diabetes. Around 1,600 to 1,800 are performed per year, a rate little changed since 1999. A total of 26,660 had been performed through 2006, three-quarters of these transplants in the United States. There was much discussion of immune suppression protocols and technical surgical issues. Performance after transplants is slowly improving. In the crucial measure of performance, insulin independence five years after the procedure, pancreas transplants are 70% successful.
Conventional (pharmaceutical immune suppression) Islet Transplantation
Islet transplantation has been the promising but underperforming little sibling to pancreas transplantation. Since the introduction of the Edmonton Protocol islet transplantation five-year success has been 15% (compared with 70% for pancreas); for this reason islet transplantation has remained a specialized, experimental procedure. A variety of reasons have been identified to explain why isolated islets do not perform as well as islets in a pancreatic matrix. And much progress has been made. At the moment eighty experimental protocols are registered at clinicaltrials.gov.
Using an improved immune suppression protocol, and “T-cell induction” (temporary inactivation of T-cells using antibody) the Minnesota group has produced a small clinical series that has achieved 70% success at five years, matching pancreas transplantation. This is certainly the big news of the meeting with respect to islet transplantation.
The most surprising report (for me) was from Milan. They have developed methods to put islets into a new site, bone marrow, using methods adapted from harvesting bone marrow. The initial result (an autograft) looks promising; they performed their first allograft just before the meeting.
Islet Xenotransplantation (pig islets) with Pharmaceutical Immune Suppression (& “Tolerance”)
Several studies have shown that pig islets can function for months in non-human primates. One of these studies used monolayer cell encapsulation (Belgium), the rest immune suppression (Minnesota, Emory/Alberta, Pittsburgh, Weizman). The immune suppression protocols are very aggressive (e.g., Minnesota used a combination of five drugs) and result in significant morbidity in the animals.
Detailed guidelines for xenograft studies have been drawn up by a committee of IXA (Xenotransplantation 16:4, 2009). The guidelines include a definition of preclinical success in nonhuman primate models (fasting blood sugar of <150 mg/dl in at least 5 of 8 treated monkeys for at least 6 months). Because monkeys are less sensitive to insulin similar doses of islets is thought to be more likely to work in humans; thus old world monkeys are a stringent model.
At the IXA meeting, the general issue of prevention of xenograft rejection was addressed by Dr. Sachs (Harvard) and others. The classic distinction of central tolerance (site of thymic ‘education’) and peripheral tolerance is getting fuzzy; they are not distinct. The most successful protocol in animals to date is the thymokidney, where donor thymus tissue is co-transplanted. To summarize a lot of observations, true tolerance has not been achieved, and even then, in the animals, at a high cost of recipient morbidity and mortality.
Islet Encapsulation
Some interesting new data using various encapsulation methods was presented. The only new clinical data was from LCT using neonatal pig islets in alginate microcapsules. Apparently, because they are not following rules developed by IXA, LCT’s Bob Elliot was asked not to present his clinical results but rather his experience of regulatory approval. Fortunately some of their clinical data was presented in poster form. What they have found is a reduction in the need for injected insulin coupled with improved HbA1c, strongly suggesting significant islet function for at least six months. No immune suppression was used. One patient became insulin independent after her third implant (and remains so).
In his review of encapsulation research, Ricardo Calafiore (Perugia) mentioned three clinical encapsulation studies from the early 2000’s, New South Wales Sydney (Diabetes Care 32:1887, 2009) and Novocell and Amcyte (acquired by ReNeuron), both unpublished. None achieved insulin independence. His conclusions:
1. Early pilot clinical trials ongoing with ‘conventional’ [Alginate]-based capsules with no recipient’s immunosuppression;
2. Safety demonstrated in human recipients;
3. Efficacy not achieved in full yet.
Beta O2, an Israeli company, had a poster showing results from their oxygen charged encapsulation device. Their former design using algae as an O2 source has been modified to use a reservoir of O2 gas instead. They demonstrated success for 75 days in diabetic rats.
We presented some of our preliminary results in poster form.
(L to R) Scott King, Robert Elliott (LCT), Ricardo Calafiore (Perugia), Shimon Efrat (Tel Aviv), Jonathan Lakey
Reception at Ca’ Salvioni
A maggiore highlight for Cerco Medical was a reception hosted by the Hanuman Medical Foundation (thank you, Edgar Brenninkmeyer for making it possible). The venue was Ca’ Salvioni a 16th century palazzo designed by Jacopo Sansovino. Ca’ Salvioni features its original piano nobile with 17th and 18th century art and a view down the Rio de la Pieta of Palladio’s San Georgia Maggiore. In addition to our ‘official’ scientific advisors from Perugia and Louven, other friends and potential collaborators came. Drs. Basta and Calafiore (Perugia) attended; they have the most experience in islet encapsulation in the world. Denis Dufrane and the rest of Dr. Gianello’s group (Louven) attended; he is the inventor of a monolayer islet encapsulation device soon to enter clinical studies. We were pleased to see Bob Elliott and two colleagues from LCT. Shimon Efrat (Tel Aviv), Paul Johnson (Oxford) and Camillo Ricordi (Miami) were also there.
Summary
The most recent data from researchers across the world support our belief that the most likely functional cure for type 1 diabetes in the near term is implantation of encapsulated islets. We believe the Islet Sheet will offer advantages in safety and efficacy over all the devices presented at IPITA ‘09.
Mr. King,
Quick question. Do you do any collaboration with LCT? Seems to me that you are both researching the same technology (encapsulating) but I don’t see any interaction between the two companies. Also, it seems they are much further along on trails. Does this stem from US laws hindering efforts within the US?
Omar Perez
Omar–
You can see proto-interaction between LCT and Cerco above: the second photo shows Bob Elliott and me talking at our reception at the IPITA conference. Bob and I have always gotten along well; last year he invited me to speak at the LCT Science Advisory Board meeting in Auckland.
You are quite right; it makes sense for LCT and Cerco to cooperate. The time is not yet ripe. We expect that the Islet Sheet will (1) be retrievable and replaceable, making the Sheet safer than microcapsules, and (2) will support greater functionality from each islet. The latter means that a smaller number of islets would be required using the Islet Sheet capsule. Clearly LCT would benefit if we are right.
The Hanuman Medical Foundation grant means we have the funds to determine the safety and efficacy of the Islet Sheet at UC Irvine using the best characterized models of islet transplantation. Once we have solid results from those studies we would want to begin collaborative studies using LCT’s pig islets in our sheets. LCT is aware of this.
Scott King