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Highlights of ADA Scientific Sessions I – BGC Trial
July 4th, 2011
The American Diabetes Association held its annual Scientific Sessions last week in San Diego. Everybody else in the Islet Sheet research group had work to do so I attended alone. Next time I will summarize all the presentations I found interesting. This week I will fill you in on the poster that made the front page of the Wall Street Journal.
First Clinical Report on BCG Islet Regeneration Study at Harvard
An attempt by Harvard researcher Denise Faustman to cure fully developed autoimmune diabetes in adults has attracted much interest because it is the only immune therapy not focused on newly diagnosed diabetics (who retain significant islet function). BCG vaccine has been in use for decades and is generally regarded as a safe treatment for tuberculosis. I think BGC is a worthwhile clinical study because the risk-reward is so favorable: a safe biologic might revive islet function in autoimmne diabetes. However, based on my understanding of human immune function and diabetes I have regarded this approach is a long-shot very unlikely to work. First clinical results were presented at the American Diabetes Association meeting in late June. After seeing the ADA poster and discussing these interesting new results with Dr. Faustman I think BCG has better odds than before.
The basic idea is that the natural cause of autoimmune diabetes is auto-reactive T cells, the cells ones that actually kill beta cells in the islets. Dr. Faustman hypothesized that the immune modulator TNF will disable these cells permitting islet regeneration in the reduced level of auto-reactive T cells. Animal studies supported the concept. However, clinical administration of TNF presented practical and regulatory difficulties. So she decided to administer a relatively safe drug, BCG, which in known to induce TNF as part of its activity.
This initial Phase I human clinical study was done in 6 people with fully developed autoimmune diabetes (defined a undetectable C-peptide). Three were treated with two injections of BCG and three were controls. The study showed that two out of three of the treated diabetics had an increase in Treg cells, cells that actually (under the influence of TNF) suppress the auto-reactive T cells (think of Tregs as T cell cops). The same two out of three treated diabetics showed an increase in C peptide following BCG injection, suggesting a revived islet function in islets that had previously undetectable insulin secretion. And that is what is so interesting: the usual view is that fully dead beta cells cannot be regenerated.
The study data have some serious difficulties. An unlucky randomization and an unlucky EBV infection in a control mean that the effect might well disappear in a large study now underway. EBV is a virus that affects the immune system and, among other things, causes secretion of THF. This patient seems to have responded to the unlikely EBV infection early in the study period (like two of the three treated with BCG) by increasing islet function. The other problem with the controls is that two of three had functioning islets, so were not fully autoimmune diabetes. It has emerged in the last ten years or so that some people diagnosed with autoimmune diabetes die decades later with small numbers of functioning islets, and these people tend to have fewer diabetes complications. This subpopulation is thought be by around 5% to 10% of all type 1 diabetes. So landing two such imperfect diabetics out of three controls if pretty unlikely! One of three controls had an unusual viral infection and two had small numbers of functioning islet cells, enough to be detected.
The only reason the C peptide was detected is that the study used a new ultra-sensitive C peptide assay, much more sensitive than the assay used to screen diabetic study participants. The assay showed that most of the type 1 diabetics had less than 4 picomolar (pM) C peptide in their blood. The ’spikes’ of C peptide were on the order of 4-5 pM, very low, but probably real (but far too little insulin secretion to make any clinical difference.)
Dr. Fasutman’s plan is the give more and larger doses so that the initial regeneration will serve as a base for further regeneration, fish-ladder style, so that insulin secretion will become clinically useful with repeated dosing of BGC. This might work but my worry is that the auto-reactive T cells will win the war. But congratulations to Dr. Faustman and her research group for intriguing data hinting at a therapy that truly would be a cure.
Given the earlier report on this website of Professor Anne Clark’s demonstration that beta cell regeneration is not possible in diabetics after they reach the age of maturity, it would be interesting to know the ages of the patients in Faustman’s study. If Faustman’s BCG treatment produced any results in mature patients, were these effects correspondingly less according to the increased age of the older subjects?
BCG, while relatively safe and benign, does have some side-effects worth considering, such as flu-like symptoms during the day or two following each injection, as well as occasional joint pain. Since most diabetics have diminished immune function, there might also be more serious side-effects, since BCG is a live bacillis of the tuberculosis family which can cause that disease in patients with weak immunity. It could never be used in the few diabetics with AIDS, or in the many diabetics with a functioning organ transplant.
If BCG does prove to have clinically significant regenerative properties for pancreatic beta cells, this would raise the question of why this effect was not noticed long ago, since the principal indication for the drug, tuberculosis, used to be one of the major complications of diabetes until the early 1950s. BCG has also been extensively used since then as a treatment for bladder cancer, many of whose victims have been diabetics, so again we have to wonder why its effect in reducing insulin dosages in these patients was never reported. Was the impact always too small to attract clinical attention?
Interfering with the human immune system, like intervening in natural ecosystems with large-scale industrial or scientific projects, always produces unanticipated and negative side-effects because of complex interactions with other natural systems which are too intricate to calculate from first principles. The experience up to now with immunosuppression, for example, has always shown surprising and dangerous consequences from interfering with the body’s basic structure for regulating the boundary between the self and the outside world. Even immunomodulatory interventions raise similar concerns, and repeated, life-long administration of BCG may cause more problems than can now be anticipated from the evidence available from its short-term use as a treatment for tuberculosis or bladder cancer.
Enjoy your blog – very imformative and I thank you for the link. Scott, my father was treated with BCG for bladder cancer when he was seventy years old – it worked. He lived to the age of ninety-three and died two years ago and was in great health until the end. I thought that Dad was nuts when he told me about the treatment which was recommended by doctors at Scott and White Clinic in Temple, TX. I do not know whether BCG will work for Juvenile Diabetics, but it sure beats some of the other avenues that JDRF funds.