MANAGEMENT, CARE AND PREVENTION Back to the future: investigating new treatments for using old inexpensive drugs

Denise Faustman and Miriam Davis

"Great disappointments in medicine frequently give rise to great More than 20 years ago, we began study- innovation – so the saying goes – but who expected a 20-year ing islet transplants in people with long- detour?" Denise Faustman and her team were disappointed by standing type 1 diabetes. We hoped to their findings from human islet cell transplantation trials and replenish the with healthy islet cells and thereby restore normal blood felt compelled to return to the bench for 20 years to understand glucose. To achieve this, we replaced why the trials had been less successful than had been hoped. people’s islet cells with the same cells They first turned to an animal model of type 1 diabetes, which, modified to shield them from rejection just as in people, features an autoimmune assault on the by their own . In type 1 insulin-producing islet cells in the pancreas. The animal model diabetes and other autoimmune dis- provided an opportunity to tease apart the immune system eases, the immune system regards some that triggers the disease. Over the next 10 years, they turned tissues, such as the insulin-secreting islet to studying the blood of large numbers of people with type cells, as foreign, not part of the self, and 1 diabetes, hoping that the promising mouse data could be it erroneously rejects and destroys them. At first, like many other islet transplant replicated in people. Those years-long and human and mouse researchers worldwide, we thought the studies suggested a new trigger for diabetes and, thus, a new transplanted islet cells could be modi- approach to designing a clinical trial to test a vaccine – a vaccine fied to escape the host's dysfunctional we all hope will be an advance in treatment for people with type immune attack when combined with 1 diabetes, and if successful, a remarkably affordable one. immunosuppressive drugs.

December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 37 MANAGEMENT, CARE AND PREVENTION

But we did not realize that the diseased with a degree of scepticism. We identi- worldwide research had uncovered the immune system was relentless: it con- fied a major culprit as a type of immune mechanism by which TNF usually does tinued to attack the newly transplanted cell known as a CD8 T lymphocytes not harm normal cells. However, the islet cells even decades after diagnosis of (or CD8 T cells) in mice as well as and mutant defective CD8 T cells in humans the original disease. The autoimmunity humans.1 Other immune cells might and mice with diabetes became suscep- once again affected the transplanted participate, but small, potent CD8 T tible to specific killing, much like way insulin-secreting cells, even when the cells were a primary perpetrator. bacteria but not normal cells of the body host received drugs to prevent kidney are vulnerable to antibiotics.2,3 rejection. We decided to take a step Initially, we thought only people with dia- back and turned to studying betes had these disease-provoking CD8 We tested these findings first in tissue how type 1 diabetes occurs T cells since when we studied identical culture with isolated cells from people and how rogue white twins, only the twin with diabetes had with diabetes, and showed, at albeit in blood cells are pro- CD8 T cells. However, there are many culture, evidence that TNF selectively duced in the first different types of CD8 T cells. In type killed only the auto-reactive T cells.4 So place. 1 diabetes, only a particular subset of we hypothesized that TNF also could be CD8 T cells is defective – the subset that used as a treatment to destroy the abnor- targets specific proteins found almost mal CD8 T cells that caused type 1 dia- exclusively on the surface of islet cells. betes, while sparing healthy cells. Simply The quest to find the abnormality in CD8 put, we hoped that TNF would act like a At T cells lasted nearly a decade. In the late laser-guided missile or an ‘antibiotic for first, we 1990s, we published our findings diabetes’. That was the rationale behind used a well- that the educator cell of CD8 T our first experiments in NOD mice, then known rodent cells was defective and thus later in human blood samples and now model of type 1 diabetes the subset of rogue CD8 in clinical trials.5,6 called the non-obese diabet- T cells might also ic (NOD) mouse. We wanted to have similar pro- learn more about the basic science teins with the underlying type 1 diabetes in the hope of defect.1 finding more targeted ways to treat the disease. At that time, little was known The about the kinds of rogue T cells that protein de- caused type 1 diabetes – except that fects enabled the they provoked a self-reactive and au- abnormal CD8 toimmune disease. Laboratory-based to escape the process of ‘T research using rodents does not attract cell education’ – the process the interest that human clinical trials do of learning to be tolerant to cells but it is the surest means to reveal the belonging to one’s own body. complex disease processes. So as they matured, poorly educat- The unusual suspects: CD8 T lym- ed CD8 T cells attacked the body’s phocytes own islet cells. But it turned out that Our first major breakthrough came in one of the dark clouds we had identi- 1991, when we discovered that a new fied also had a silver lining: the CD8 T type of immune cell was in part respon- cells became exquisitely vulnerable to sible for attacking the islet cells in the death by a normal protein of the immune pancreas – and this immune cell was not system known as tumour necrosis fac- the one most scientists pursued. Indeed, tor or TNF. We knew about TNF from other scientists received our finding many basic science studies; previous

38 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 Finding a fast track to the clinic The successes in killing the rogue T cells monitoring people’s blood, we are able In engaging in clinical trials, our over- and showing pancreas regeneration em- to determine whether the TNF is killing arching aim is to develop only new thera- boldened us to conduct experiments with the disease-provoking cells – like seeing pies that are safe and widely affordable. human blood samples. We studied blood an antibiotic kill bacteria in the blood Clinical development is often very slow samples from 675 people with type 1 of an person with an infection. but a short cut can save time and money diabetes and 512 people without diabetes. and ensure that safety is achieved at earlier Using two different methods to measure Real hope for the future stages. Instead of directly administering cell death in people with diabetes, we As we progress with the testing of BCG, TNF, which is not an existing drug and showed that TNF killed a subpopula- we hope to open up possibilities for treat- would require years of validated manu- tion of CD8 cells but did not kill a dif- ing people with long-standing diabetes facturing processes, or testing it for safety ferent population of T cells. The results using a universally affordable drug. Data on live primates, we chose an indirect applied across all six different doses of from our Phase I trial, using only limited method for TNF exposures that showed TNF.4 Furthermore, TNF was effective doses of BCG and regular blood glucose us faster path to the clinic: we adminis- in selectively killing rogue CD8 T cells monitoring, are encouraging. Our aim is tered an agent that induced internal TNF in several other autoimmune diseases. to carry out these trials quickly and cost- production using an 80-year-old vaccine efficiently in order to develop a cheap called Balcillus-Calmette-Guerin (BCG). TNF was effective in generic drug for type 1 diabetes. selectively killing rogue In 2001 and 2003, we published our results showing that the TNF inducer CD8 T cells in several injected into end-stage diabetic animals autoimmune diseases. Denise Faustman and Miriam Davis was capable of selectively killing the de- Denise Faustman is Director of Immunobiology at fective CD8 T cells responsible for killing By this point, we felt ready to plan for a the Massachusetts General Hospital and Harvard Medical School, Immunbiology Laboratories, 5,6 islet cells. The TNF inducer was an human clinical trial with a TNF-inducer. Boston, USA. ([email protected]) old fashion vaccine that was originally Unlike most other diabetes clinical tri- Miriam Davis is a member of the Department developed for protection from tubercu- als, we focused on advanced type 1 dia- of Medicine at Massachusetts General Hospital and Harvard Medical School, losis and treatment of bladder cancer. It betes. Our rationale was that if mice Immunbiology Laboratories, Boston, USA.

was so successful that after 15 weeks the with advanced type 1 diabetes could be animals with diabetes began to produce cured, we could choose people with the References normal blood glucose levels for sustained greatest need for treatment. Moreover, 1 Faustman D, Li X, Lin HY, et al. Linkage of faulty major histocompatibility complex class I to periods of time. For the first time, killing surmounting the toughest challenge autoimmune diabetes. Science 1991; 254: 1756-61. rogue T cells using TNF was followed by would be the most rigorous way to sup- 2 Hayashi T, Faustman D. Defective function brisk islet regeneration. The concept that port our hypothesis that TNF could of the proteasome in autoimmunity: diabetes might be treated by targeted dis- selectively kill the disease-provoking T Involvement of impaired NF-kB activation. ease removal was surprising and pleasing cells. Our choice of BCG, an established Diabetes Tech Ther 2000; 2: 415-28. news, especially since it worked even in generic drug that was already on the 3 Hayashi T, Kodama S, Faustman DL. Reply advanced disease. market, gave us two advantages: BCG’s to 'LMP2 expression and proteasome activity in NOD mice'. Nat Med 2000; 6: 1065-6. safety is very well established; the drug That additional finding was first met with would be inexpensive. 4 Ban L, Zhang J, Wang L, et al. Selective death widespread scepticism. Now, there is near of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism. Proc uniform acceptance of worldwide data Our 20-year research programme had Natl Acad Sci USA 2008; 105: 13644-9. accumulated over the past eight years that established so many mechanisms about 5 Ryu S, Kodama S, Ryu K, et al. Reversal the pancreas can show growth well into the drug's effects that we were able to of established autoimmune diabetes adulthood. Our results have been repli- monitor those throughout the trial to by restoration of endogenous beta cell cated in other animal models and in other ensure that BCG was working in the function. J Clin Invest 2001; 108: 63-72. autoimmune diseases and there is enor- manner and with the purpose intended. 6 Kodama S, Kuhtreiber W, Fujimura S, et al. Islet mous and growing interest in the many This approach is known as translational regeneration during the reversal of autoimmune diabetes in NOD mice. Science 2003; 302: 1223-7. different ways the pancreas can regenerate. medicine with biomarkers: by closely

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