Summer 2007

Updatesfrom Dr. Faustman’s Lab at the Massachusetts General Hospital

The Promise of the Future:
A Conversation with Dr. Faustman
Q: Much of this issue of the newsletter talks
about the excitement around the Bacillus
Calmette-Guérin (BCG) Human Clinical Trial.
Can you share, from your perspective, what
is so promising about this trial?
Dr. Faustman: This is truly a unique program
because – first of all – we’re using a generic
drug. If we can introduce this type of drug,
and show that it changes
the lives of diabetes patients
while substantially reducing
costs, it will be a tremendous
achievement.
Also, this is a trial that
may be able to reverse
established disease, rather
than simply introduce new
pumps or other types of
new equipment or drugs
to delay the onset of diabetic complications. Thatis a cause for new hope and a new vision forpeople who already have diabetes.

Q: Can you explain how this approach ties
into “targeted disease removal”?
Dr. Faustman: Previously, it was thought that thehuman immune system was too complex to beable to eliminate individual disease-causing cells.
However, we’re now uncovering novel ways oftargeted disease removal – killing only the “bad”
cells, and sparing the good. This is huge – it’s
the first time in diabetes that we’ve been able
to identify the bad cells and kill only them. It’s atime of unprecedented hope for targeted
disease intervention.

In our BCG trial, we will be counting the numberof bad cells in diabetic blood, via a blood test,
to determine whether we’re able to eliminate
disease, and at what drug dose. It’s like having
the first dose of insulin; we’re at the very
beginning of getting a drug with promise into
the treatment phase.

Q: What do you view as the single mostimportant resource for this trial, and othergroundbreaking advances in diabetes
research?
Dr. Faustman: The worldwide support ofpatients and the public worldwide makes all of
this possible. Support can come in so many ways,
and everyone who steps forward is helping,whether through donations of time, money orother resources.
Blood donors come to us from all over thecountry and the world, every day! You only haveto look at our map (see page 3) to notice that
our research is not merely Boston-based. It’s atruly national and international program.
Of course, financial support makes a huge
difference, but our diabetes research would nothave been able to move to human trials without
the people who have made sacrifices of time,school, travel – just to come here to donate blood.
It’s a unique thing that doesn’t happen often.

Summer 2007

Updatesfrom Dr. Faustman’s Lab at the Massachusetts General Hospital

Taking the Next Steps: Applying Our Research to Human Clinical Trials

Since our research was published, we have been diligently working to apply these findings to human diabetics.
We have been raising money for studies to create the tests and machinery needed to monitor the trials wewill be conducting. As most of you know, our human clinical trial program will begin with an evaluation ofBacillus Calmette-Guérin (BCG), a generic drug that has an impeccable human safety profile and is already usedfor other diseases. This agent will be tested in the first Phase I human trial (see article on page 5). BCG causes thebody to make a natural substance called TNF that helps regulate the immune system, and we hope that this willlead to the selective elimination of one population of disease-causing cells present in diabetics. Dr. David Nathan,director of the MGH Diabetes Center and one of this country’s foremost diabetes experts, will direct the humanclinical trials at MGH.

Only by conducting a clinical trial will we know if BCG will work. We have been hoping to start the human trials
soon, and it looks like they might begin in 2008. Many patients and families ask, “Why can’t these trials beginsooner?” The answer is this: for us to conduct these clinical trials in a way that makes sense, we need to build
and automate the blood tests and machinery first. We have been diligently working to do both of these things,
as you will see on the following page.

Essential New Funding Received
We are pleased to announce that the Iacocca Foundation
has made its second grant of $1.8 million to Massachusetts
General Hospital – crucial funding for the Nathan/Faustman
research program to translate our diabetes ‘cure’ in miceto humans. The three-part program includes additional
studies in mice to refine the therapy, the building andautomation of an important blood test, and the Bacillus
Calmette-Guérin (BCG) Human Clinical Trial, which will be
led by nationally renowned physician-scientist Dr. DavidNathan, director of the MGH Diabetics Center. The BCG
Human Clinical Trial is due to start in 2008.
During the Iacocca Foundation’s most recent site visit to ourlaboratory, we demonstrated that we have successfully
standardized the manual separation of T cells from whole
blood with the desired yield, purity and viability. This process
has been validated in over 266 human blood samples,
amply exceeding our goal of 50 human samples.
In addition, we also were able to demonstrate continued
improvement in our capacity to automate this process,and there is sufficient automation capacity and throughput
in place to support the phase I human clinical trial thatwill commence in 2008. Other research achievements thisyear include progress in the development of a cell death assay
suitable for using in a human clinical trial, and validationof treatment of type 1 diabetes using BCG in the NOD mousemodel. (The NOD mouse is a mouse that spontaneously

gets type 1 diabetes, similar to the onset of the humandisease.)In year two of funding for the Nathan/Faustman research
program, we will continue to translate our diabetes ‘cure’
from mice to humans.
We thank the Iacocca Foundation for their generous support.

Diabetes Research in theMGH Immunobiology Lab
Our lab’s experiments in end-stage diabetic mice haveshowed that a brief treatment eliminated disease-causing
white blood cells in these mice. This treatment killed only
the cells that were causing the autoimmune destruction,and not the healthy cells. We also demonstrated that theislet cells of the pancreas – the cells that secrete insulin –could regenerate once the autoimmune destruction wasstopped.
Our lab’s work represents a reversal of diabetes, rather
than just a treatment for the symptoms and complicationsof this disease. These main research findings were publishedin 2001 and 2003.
Ryu S, Kodama S, Ryu K, Schoenfeld DA, Faustman DL. Reversal of establishedautoimmune diabetes by restoration of endogenous beta cell function.
J Clin Invest 2001; 108(1): 63-72.
Kodama S, Kuhtreiber W, Fujimura S, Dale EA, Faustman DL. Islet regeneration during
the reversal of autoimmune diabetes in NOD mice. Science 2003; 302:1223-7.

Laying the Groundwork for Clinical Trials:

New Blood Tests and Machinery
One of the critical steps for upcoming and future clinical
trials has been to create and automate a blood test that
we can use to monitor trial results. This test will quickly
let us know what dose of a drug works best, if at all, byallowing us to precisely count white blood cells before andafter drug treatment. If there are fewer of the “bad” whiteblood cells after treatment, then we know we are onto
something good! For the first human clinical trial, we will
use this method to rapidly and precisely evaluate whether
BCG can eliminate the disease-causing cells in type 1 diabetics,
and at what dose. If we were to proceed without theblood test, it would be like giving insulin without everbeing able to check blood sugar levels.
The test, also known as a blood assay, involves a machinethat separates the white blood cells from the other cells.
Once the cells are isolated by the machine, our blood test
can be used to count the number of disease-causing
white blood cells in the blood sample, therefore allowing
us to see if the drugs we are testing are eliminating or
reducing the number of defective cells. The cell separation
and blood assay machinery is installed at MGH, and includes

robotic arms that will perform cell separation steps on an
assembly line. This robotic automation is going very welland represents four years of our work. Creating andautomating this blood test machinery is a huge researchaccomplishment – an advance that will free up ourresearchers’ time, allowing them to work on other important
projects instead of spending several days working entirelyon cell separation.

Patients Making
Research Possible
The Internet has changed how people
access medical information and care – andthe changes have been amazing. Our current
diabetes research, and our major upcoming
clinical trial, are possible in no small part
because people around the world haveheard about our research through theInternet, and have signed up to participate
by donating blood samples.

Patient recruitment across the U.S.

People have come to our labs in Boston fromacross the U.S., Canada, South Africa, andEurope. The laboratory is using these samples
to fine-tune the cell separation procedureand clinical trial assay. The contribution ofeach and every one of these patients isinvaluable.

Diabetes Findings Translating to Other Diseases
Worldwide research efforts have discovered evidence of genetic and white blood cell errors in several human autoimmune
diseases – such as rheumatoid arthritis, multiple sclerosis, Crohn’s disease and lupus – that are similar to those errors
seen in type 1 diabetes. Our lab has received preliminary funding to begin translating our preclinical diabetes researchso that we can better understand and treat some of these other diseases.
Specifically, we hope to use the blood tests and machinery we have developed for our diabetes research and trials to
help us identify existing generic drugs that will have efficacy in other autoimmune diseases. To date, we have begun
collecting blood samples from patients with Crohn’s disease and lupus who have developed new autoimmune disease
after starting anti-TNF treatment.
We are looking at the disease-causing white blood cells in these patients to see if they have the defect we have previously
identified in type 1 diabetics. We believe that this cellular defect makes these cells susceptible to death in the presenceof elevated levels of TNF ... which is exactly what we are testing in our upcoming diabetes clinical trial, using Bacillus
Calmette-Guérin (BCG), a generic drug.

The Cost-Saving (and Life-Saving)
Promise of Generic Drugs
One of the most exciting things about our upcoming
human diabetes trial is that it makes use of an inexpensive
generic drug. This allows us to move fast, in clinical trial
terms, towards human testing – and, if the drug is effective,
we hope it will mean that we can quickly bring an inexpensive
drug to many patients who will benefit tremendously.
Visit Our Website: www.faustmanlab.org
For clinical trial appointments, call:
617-726-4084 or email: DiabetesTrial@partners.org

Summer 2007

Updatesfrom Dr. Faustman’s Lab at the Massachusetts General Hospital

The Importance of Bacillus Calmette-Guérin (BCG)W

hat is BCG? BCG is a relatively risk-free drug that has been around for over 80 years, and has beenused worldwide as a vaccination for preventing tuberculosis (TB). In most countries, this generic drug has
been given as an obligatory vaccination for all citizens for the prevention of TB. It is estimated that four billion
doses have been given worldwide. In the United States, preventative BCG vaccines are not part of the obligatory
childhood vaccination process, since the incidence of TB is lower here than in the rest of the world. However,BCG is approved as a vaccination for TB in the U.S., and, at very high doses, BCG is also approved here as atreatment for bladder cancer.
Albert Calmette and Camille Guérin discovered BCG backin 1908 while they were attempting to find a vaccination
for TB. They developed a way to decrease (attenuate) theinfectious properties of the TB bacteria called Mycobacterium
Bovis, a live bacteria that causes tuberculosis in cattle,
thereby creating BCG. The process took them 12 years.
When they finally obtained the attenuated strain ofbacteria, they ran human clinical trials in 1921 to test
their new vaccination for human tuberculosis. Their trials
were successful, and BCG is now used worldwide. It isconsidered by most to be one of the safest vaccines everdeveloped, and to be effective some of the time inprotecting humans from exposures to TB that mightcause an outbreak of the disease.
Why use BCG for diabetes? In our human clinic trials intype 1 diabetes, we are using BCG because it is known
that BCG induces a patient’s own body to produce more
TNF, also known as tumor necrosis factor. With the helpof your blood donations, we were able find that people
with type 1 diabetes normally produce too little TNF.
Sufficient amounts of TNF help transfer cell signals to theimmune system, which may help it to identify and kill the“bad” T-cells that cause diabetes. The next step is to determine the proper dosage of BCG and begin humanclinical trials, in which we will use BCG to boost diabetics’ TNF levels to kill off their “bad” T cells.
The procedure for administering BCG into the body is relatively painless, with few side effects. BCG as a vaccine
is typically given as a needle injection on the upper arm and causes a slight reaction that will leave a small flat
scar for approximately a week. Side effects may include headache, fever, swollen lymph nodes and skin scalingat the site of injection. However, there are a few people who are allergic to BCG and might develop rashes orinfections. BCG should not be used as a vaccine in people who have AIDS or in those who have a compromised
immune system, such as in hereditary forms of white blood cell deficiencies. Doses of BCG given for TB vaccination
are small compared to those given to cancer patients. The doses that we will start with in our clinical trials also
will be relatively small, but as time passes and we monitor for safety and efficacy, we will be able to increase
the dose and graduate to the next phase of human clinical research.

Summer 2007

Updatesfrom Dr. Faustman’s Lab at the Massachusetts General Hospital

Please Support Our Work
Please support the ongoing research of our lab with a tax-deductibledonation. Every gift makes a difference for patients ... today and tomorrow.
1. To make a secure online donation, please visit:www.mgh.harvard.edu/diabetes/diabetes_support.htm
and click on “Type 1 Research.”
2. You may make a gift by check(payable to “Massachusetts General Hospital”),
and send your check to:
The Massachusetts General Hospital
Development Office
Attn: Jocelyn Hoey
165 Cambridge Street, Suite 600
Boston, MA 02114
On the Memo line of your check, please write:“Type 1 diabetes research” or “Autoimmune research.”Thank you for joining us in the fight against diabetes.
Warmly,Denise L. Faustman, MD, PhD

Massachusetts General Hospital
Development Office
165 Cambridge Street, Suite 600
Boston, MA 02114