Denise Faustman, MD, PHd
The Faustman Lab at work

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Questions and Answers about the BCG Human Clinical Trial Program

1. What is the BCG Human Clinical Trial Program?
The BCG Human Clinical Trial Program is testing Bacillus Calmette-Guérin (BCG), an inexpensive generic drug, as a treatment for advanced type 1 diabetes. Please click here to read a brief Fact Sheet about the trials.

2. What is BCG?
BCG (short for bacillus Calmette-Guerin) is a generic drug with an impeccable human safety profile. It is currently approved for use as a vaccine for tuberculosis prevention and as an infusion for the treatment of bladder cancer. BCG has been administered to over four billion people since coming to market over 90 years ago. BCG causes the body to make a natural substance called TNF that helps regulate the immune system. Our FDA-approved Phase I human clinical study successfully demonstrated the safety of BCG vaccination in humans with long-term type 1 diabetes and showed early signs that repeat vaccination may be able to benefit those with this condition.

3. How long will the program take?
The average time frame for a drug to move from the lab to patients is approximately 15 years. We expect that the type 1 diabetes clinical trial will take approximately 8-10 years, but this depends on many factors, such as the requirements of the Food and Drug Administration (FDA) and the availability of funding for the different phases of the trials.

4. What phase are the trials in now?
A Phase I clinical trial has been completed and planning for a Phase II study is underway. For general information on the different phases of a clinical trial, please visit http://www.nlm.nih.gov/services/ctphases.html.

5. What were the results of the Phase I trial?
In the Phase I human study, BCG was administered to adults who had been living with type 1 diabetes for an average of 15 years. This treatment not only helped eliminate the defective T cells that mistakenly attack and destroy the insulin-producing cells of the pancreas, it also temporarily restored the ability of the pancreas to produce small amounts of insulin. The results were published in 2012. The next step, a Phase II study, is currently being underway, with the goal of identifying the drug dose and schedule that will put advanced type 1 diabetes into remission.

6. Are you currently enrolling patients into clinical studies?
We are screening patients for potential eligibility for the Phase II human clinical trial that will test BCG as a possible treatment for long-term type 1 diabetes. As part of this process, we are currently enrolling patients into tissue culture studies to examine their blood for TNF-sensitive immune cells. We are also looking at C-peptide levels (an indicator of insulin production in the pancreas) in patients of different ages and with different durations of type 1 diabetes.

7. What will happen in Phase II? How long will it take?
In Phase II, we will try to identify the best dose of BCG and the optimal timing of BCG administration. This study will cost a total of $25.2 million, with plans to follow enrolled patients over a five-year period to determine any long-term benefits of BCG treatment. Please consider making a donation to support this research.

8. What will the enrollment criteria be for Phase II?
Please see https://clinicaltrials.gov/ct2/show/NCT02081326 for trial details.

9. How do I participate in the clinical trial program?
We are currently collecting blood from diabetic and non-diabetic volunteers to see if they have TNF-sensitive immune cells, which will help us identify potential participants for Phase II and other studies. We are also doing studies using an ultrasensitive C-peptide assay to better understand the decline in insulin production in long-term type 1 diabetes. Interested individuals should fill out a patient information form and email it to diabetestrial@partners.org to be added to our database.

10. Can children also participate?
We are enrolling children 8 years of age and older for the ongoing blood donation studies. We do not yet know if children will be enrolled into Phase II testing.

11. Can I send my blood to your lab instead of going to Boston?
Currently, all blood donations must be made at our lab in Boston, Massachusetts, to ensure that we can rapidly analyze the blood soon after it is drawn.

12. How can I set up an appointment for a blood donation visit?
You can either e-mail us at diabetestrial@partners.org or call the lab at 617-726-4084. Currently, we are booked approximately a year in advance.

13. If I donate blood, will I receive BCG?
If you come for a blood donation visit, you will not receive BCG or placebo. You will receive BCG or placebo only if you are selected to participate in upcoming human clinical trials. 


14. I have been diabetic for many years; can I participate in these trials?
Yes, the BCG Human Clinical Trial Program is focused on individuals that already have type 1 diabetes.

15. How does the selection process for the Phase II trials work? How will I know if I am selected?
When Phase II enrollment begins, we will contact potential participants in our database that fit the enrollment criteria. Those who are contacted will be further screened to determine eligibility for enrollment.

16. If I am enrolled, how often will I have to travel to the lab (in Boston)?
The parameters for Phase II have not been fully determined yet. For the Phase I trial, patients had their blood drawn on a weekly basis at the laboratory over a 20-week period.

17. How can I contribute to the research?
You can contribute in many ways. Some people contribute by scheduling a visit to the Faustman Lab to provide blood samples for our research. Please e-mail the lab to schedule a visit. You can also make a gift online to support our work using the Massachusetts General Hospital's online gift giving form. Please note that your gift will be processed by Mass General's web site and that the "Other" field will read "Cure Diabetes Now," indicating that your gift is in support of the Faustman Lab.

Questions and Answers About the Lab’s Type 1 Diabetes Research in the NOD Mouse

1. What were the Faustman Lab’s discoveries in end-stage diabetic mice that led to the current clinical trial program?
In 2001 (1) and in 2003 (2), the results of the Faustman lab's experiments in end-stage diabetic mice were published. The results showed that a brief, 40-day treatment selectively eliminated the disease-causing white blood cells in mice. This treatment killed only the cells that were causing the autoimmune destruction of the pancreas, and not healthy cells. These experiments also uncovered the ability of the pancreatic islets to regenerate on their own once the autoimmune destruction was stopped. In addition, the research team identified a new source of adult stem cells--adult stem cells in the spleen--that could form new islets in the formerly diabetic animals.

The Faustman Lab has also performed research using human blood samples and shown that humans with type 1 diabetes have disease-causing T cells that are similar to those found in diabetic mice (3). Based on this finding, they hypothesized that using a therapeutic approach in humans similar to the approach that reversed diabetes in mice might be effective. The BCG Human Clinical Trial Program is testing one part of this approach.

References:
1. 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.

2. Ryu S, Kodama S, Ryu K, Schoenfeld DA, Faustman DL. Reversal of established autoimmune diabetes by restoration of endogenous beta cell function. J Clin Invest 2001; 108(1): 63-72.

3. Ban L, Zhang J, Wang L, Kuhtreiber W, Burger D, Faustman DL. Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism. Proc Natl Acad Sci USA. 2008; 105 (36): 13644-9.


2. Haven't many treatments had a positive effect on non-obese diabetic (NOD) lab mice?
For those knowledgeable in the field, there are indeed over 200 ways to "cure" mice that are not yet diabetic mice (pre-diabetic). Unfortunately, this does not represent human disease, where the blood sugars are elevated and the disease firmly established. Numerous interventions applied in the pre-diabetic phase can slow or halt progression to hyperglycemia; however, when the immune attack has caused enough beta cell damage to result in severe hyperglycemia, few of these interventions are successful. Our protocols used end-stage NOD mice, rather than pre-diabetic mice, to try to identify treatments that might be successful in humans living with type 1 diabetes. Our work was the first to show that a targeted type 1 disease removal therapy was sufficient to permit impressive islet self regeneration.

3. In March 2006, three labs published their results using the Faustman Lab's protocol for end-stage diabetes reversal in mice. What were the results?
In 2006, Science published three papers from three different Juvenile Diabetes Research Foundation (JDRF)-sponsored laboratories (1-3) that examined the protocol our laboratory published in 2001 and 2003 for end-stage diabetes reversal in the NOD mouse.

All three studies independently verified that our protocol can 'cure' end-stage diabetes in mice. By cure, we mean that the autoimmune attack was sufficiently halted to stop islet destruction and/or promote islet rescue/regeneration and that the autoimmune diabetes did not recur with long-term follow-up. Regeneration of the islets was seen and long-term normal blood sugars were achieved.

The major difference between their results and our earlier findings was their failure to detect evidence that the spleen cells may play a role in islet regeneration. Our research showed that the diabetes cure in end-stage mice could be accelerated by the administration of mouse adult spleen cells. The delivery of a live splenic stem cell was not necessary for cure, but did hasten the return to normal blood sugars. We have never had a clinical protocol where we intended to inject live splenic stem cells into a human.

Independent work by Tran et al.(4) confirms our findings that the spleen can contribute to the regeneration of the pancreas. Tran’s group evaluated our protocol to see if it would be effective in diabetic mice that also had Sjögren’s syndrome, an autoimmune disease affecting the body’s moisture-producing glands. The researchers found that our protocol could be used to reverse both type 1 diabetes and Sjögren’s syndrome in mice, with a success rate of diabetes reversal close to 100%, and that the spleen did contribute in part to regeneration of the pancreas and the salivary glands. Published data from Oxford, England also shows that avian spleens can be coaxed in culture into insulin-secreting cells, thus confirming the spleen as a source of islets. (5) Most researchers working in this field believe that pancreas regeneration after disease removal can occur by many mechanisms.

Whatever the origin of the insulin-secreting beta cells of the islets, the treatment protocol we described enables the permanent restoration of normoglycemia in a percentage of fully treated diabetic NOD mice. Ultimately, the source of the regeneration is less important at this time than the simple fact that regeneration and/or rescue can occur, and that this restores normoglycemia. The final outcome is that the animals in the studies have--from their own pancreata--insulin that regulates the blood sugar, a finding that has also been seen in the human clinical trials.

In the human studies, Dr. Faustman and colleagues hope there is sufficient regeneration and rescue of the islets to not require any transplant, including spleen cell tansplant.

References:
1. Nishio J, Gaglia JL, Turvey SE, Campbell C, Benoist C, Mathis D. Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution. Science 2006; 311(5768): 1775-80.

2. Suri A, Calderon B, Esparza TJ, Frederick K, Bittner P, Unanue ER. Immunological reversal of autoimmune diabetes without hematopoietic replacement of {beta} cells. Science 2006; 311(5768): 1778-80.

3. Chong AS, Shen J, Tao J, et al. Reversal of diabetes in non-obese diabetic mice without spleen cell-derived beta cell regeneration. Science 2006; 311(5768): 1774-5
.
4. Tran SD, Kodama S, Lodde BM, Szalayova I, Key S, Khalili S, Faustman DL, Mezey E. Reversal of Sjogren's-like syndrome in non-obese diabetic mice. Ann Rheum Dis 2007;66(6):812-4.

5. Robertson SA, Rowan-Hull AM, Johnson PR. The spleen--a potential source of new islets for transplantation? J Pediatr Surg 2008;43(2):274-8.

4. The three JDRF-funded groups confirmed Dr. Faustman's cure of some of the NOD mice, but why were their reported success rates lower than those reported in Dr. Faustman's earlier studies?
Success rates in animal and clinical studies are based on numerous variables. The success rates reported by the three Science articles in 2006 ranged from 20-32%. There are probably many reasons why this rate is lower than that reported in other studies using our protocols and in our own papers. In part, disease reversal appears tightly linked to the control of blood sugars during the treatment process. In our 2001 paper (1), the cure rate for end stage mice was only 20% if tight blood sugar control was not achieved during the 40-day treatment interval. In contrast, when tight blood sugars were achieved, the cure rate at 40 days reached over 80%. In a study by Tran et al. (2), our protocol had a success rate close to 100%. In addition, a group of Japanese researchers has also confirmed our approach (disease elimination followed by regeneration) for reversing diabetes in the type 1 diabetic mouse (3), with a 71% response rate.

In addition to blood sugar control, the different success rates may also reflect intervention at different stages in diabetes progression, differences in the age of the mice or differences in application of technique.

References:
1. Ryu S, Kodama S, Ryu K, Schoenfeld DA, Faustman DL. Reversal of established autoimmune diabetes by restoration of endogenous beta cell function. J Clin Invest 2001; 108(1): 63-72.

2. Tran SD, Kodama S, Lodde BM, Szalayova I, Key S, Khalili S, Faustman DL, Mezey E. Reversal of Sjogren's-like syndrome in non-obese diabetic mice. Ann Rheum Dis 2007;66(6):812-4.

3. Okubo Y, Kanazawa Y, Oikawa Y, Miyazaki JI, Shimada A. Islet hypertrophy observed in "reversed" diabetic NOD mouse after pancreatic beta cell line administration (Abstract #1193-P). In: ADA 66th Scientific Sessions; 2006 June 9-13, 2006; Washington, DC: ADA; 2006. p. A281.

5. What are the different cure rates in mice at different institutions?

Cure Rates Using the Faustman Lab Protocol (Kodama et al.) for Type 1 Diabetes Reversal in the NOD Mouse


Author
(Year)

Institution

Cure Rate

Endogenous Islet Regeneration

Exogenous Islet Regeneration 
(Spleen cell contribution)

Kodama, et al. (2003)

Harvard/MGH

85-92%

Yes

Yes

Tran et al. (2007)

McGill/Brigham and
Women's/NIH

100%

Yes

Yes

Okubo et al. (2006)

Keio University/Osaka
University - Japan

75%

Yes

N/A

Nishio et al. (2006)

Harvard/Joslin

42%

Yes

No

Suri et al. (2006)

Washington University
(St. Louis)

20-70%

Yes

No

Chong et al. (2006)

University of Chicago/
University of Illinois

32%

Yes

No



Other Frequently Asked Questions

1. What is an autoimmune disease?
An autoimmune disease is a disease in which the immune system mistakenly attacks the body’s own tissues and cells. Type 1 diabetes is an autoimmune disease in which the insulin-producing cells of the pancreas are the target of the immune attack. Other autoimmune diseases include lupus, Crohn's disease, multiple sclerosis, scleroderma, Sjögren’s syndrome, and rheumatoid arthritis.

2. What is type 1 diabetes?
Type 1 diabetes is a chronic autoimmune disease. In type 1 diabetes, the immune system attacks the healthy insulin-producing beta cells of the pancreas. When this happens, the body is no longer able to produce enough insulin to regulate blood sugar levels which can lead to serious, life-threatening consequences. Approximately 1 million Americans have type 1 diabetes, many of whom are young children.

3. Why are you using BCG?
There is ample data to support the use of BCG in the human diabetes trials. BCG was used many years ago in early-stage diabetic mice and prevented diabetes. Unfortunately, many compounds work in early-stage NOD mice, but do not work in late-stage diabetic mice or in humans with advanced disease. BCG was also tried in the past in humans with new onset diabetes, prior to the knowledge of how BCG actually works in the body. In the human studies, some diabetic patients achieved remission with a single dose of BCG (Shehadeh et al. Lancet 1994), but two subsequent studies with a single dose of BCG showed no benefit.

Compared to when many previous BCG trials were conducted over a decade ago, the way BCG induces one's own TNF to change disease is now mapped in animal models and in some human diseases. This allows for thoughtful translation of this intervention to a human trial. We think these early trials of BCG in humans, although encouraging, could not be advanced until we understood BCG's mechanism of action (what it does) and had a way to monitor the drug's effect in the blood. Think about this: If we did not know that insulin regulated blood sugars, and if we did not know how to measure blood sugar, how could we tell whether insulin actually worked to help diabetics? In many ways, early BCG trials can be seen as similar to injecting insulin without knowing what it really does or how to measure its effects. One of our major laboratory efforts was to create a method to rapidly and precisely count the disease-causing cells in human blood and to use this test to evaluate whether BCG can eliminate these cells, and at what dose.

Only by completing clinical trials will we know if BCG will work to eliminate one population of disease-causing cells in human type 1 diabetes and be an effective treatment for people with long-term disease. We chose to test BCG because the agent is readily available and it works in humans in a similar way as the agent we successfully used in the mouse (CFA): BCG induces TNF, leading to the destruction of disease-causing T cells.

4. I am from outside the US and BCG is a routine vaccine in my country; why do I have type 1 diabetes?
BCG is used in some countries outside of the US as a vaccine to prevent tuberculosis, often given just once. Current evidence suggests that type 1 diabetes prevention or reversal requires repeated vaccination. In our type 1 diabetes reversal trials, we are testing BCG at different doses and schedules to identify the “optimal” regimen.

5. Are embryonic stem cells used in this research?
This research does not use embryonic stem cells.

6. Are adult stem cells or spleen cells being used in the human trials?
The human research does not use adult stem cells or spleen cell transplant. In one version of Dr. Faustman's early experiments in mice, she used live spleen cells to reverse diabetes in mice. It is important to note that live spleen cells are not necessary in the human research and are not being used in the human clinical trial program. One purpose of using the spleen cells in the mouse trials was to show that a subpopulation of these cells could directly regenerate the missing insulin-secreting islets. However, Dr. Faustman's experiments showed that the pancreas could also regenerate without the use of live spleen cells. In other words, it appears that islet regeneration, at least in these end-stage animal experiments, was only dependent upon disease removal- self healing followed.

7. Is islet cell transplantation being used in the human clinical trials?
No, islet cell transplantation will not be used. The concept of the trial is disease reversal followed by spontaneous regeneration of the islets.

8. Are immunosuppressants being used in the human clinical trials?
No immunosuppressant drugs are being used in the human clinical trials.

9. Is this research relevant to autoimmune diseases other than type 1 diabetes?
This research has the potential to impact the treatment of many autoimmune diseases, including multiple sclerosis, Sjögren’s syndrome, rheumatoid arthritis, Crohn's disease and lupus. Worldwide research efforts have discovered evidence of genetic and white blood cell errors in these human autoimmune diseases similar to those seen in type 1 diabetes, and human clinical trials are currently being led by Italian researchers to test BCG vaccination as a treatment for multiple sclerosis.

10. What was the “JoinLeeNow” campaign?
JoinLeeNow was the fundraising campaign created by the Iacocca Foundation to support our Phase I human clinical trial. When the funds were raised for the Phase I trial, the JoinLeeNow campaign was completed. We maintain a strong relationship with the Iacocca Foundation and they continue to provide research support for our lab: http://www.iacoccafoundation.org/diabetes-research/current-research.

11. The lab has published several papers related to the spleen. Why are you interested in the spleen?
Those of you familiar with our research history know that our lab identified the spleen as a potential new source of adult stem cells that could form new islets in mice had their end-stage type 1 diabetes reversed (1). Although these adult stem cells were not required for the pancreas to regenerate after a brief, non-toxic treatment to remove the autoimmune disease, the splenic cells did help speed disease reversal and regeneration when they were used (1). Similarly, data has shown that the spleen also contributes to pancreas regeneration in an animal model of type 2 diabetes (2).

Adult stem cells are not only found in the spleens of mice, but also in the spleens of humans and quails, as documented by new data from world-wide research (3,4). Harvesting and then culturing these adult stem cells allows for the formation of insulin-producing cells, suggesting a potential source of new islets for transplantation (4).

The stem cells of the spleen have the capacity to mature into numerous cell types. We believe this is because the adult stem cells of the human and mouse spleen express the developmental transcription factor Hox11 (5-7), a marker for early embryonic development.

Overall, our lab and others have observed the regenerative ability of the stem cells of the spleen to both directly and indirectly heal a multitude of different tissues, including the pancreas, salivary gland, bone, blood, cranial nerves, inner ear, and, most recently, the heart (1, 2, 8-14). These findings suggest that the spleen may be an important source of stem cells for future cellular therapies for a number of different diseases.

References:
1. Kodama S, Kühtreiber W, Fujimura S, Dale EA, Faustman DL. Islet regeneration during the reversal of autoimmune diabetes in NOD mice.Science. 2003;302(5648):1223-7.

2. Park, S, Hong, SM, Ahn IS. Can splenocytes enhance pancreatic beta cell function and mass in 90% pancreatomized rats fed a high fat diet? Life Sci. 2009;84(11-12):358-63.

3. Dieguez-Acuna FJ, Gygi SP, Davis M, Faustman DL. Splenectomy: a new treatment option for ALL tumors expressing Hox-11 and a means to test the stem cell hypothesis of cancer in humans. Leukemia. 2007;21(10):2192-4.

4. Robertson, SA, Rowan-Hull AM, Johson PR. The spleen—a potential source of new islets for transplantation? J Pediatr Surg. 2008;43(2):274-8.

5. Kodama S, Davis M, Faustman DL. Diabetes and stem cell researchers turn to the lowly spleen. Sci Aging Knowledge Environ. 2005;2005(3):pe2.

6. Lonyai A, Kodama S, Burger D, Faustman DL. Fetal Hox11 expression patterns predict defective target organs: a novel link between developmental biology and autoimmunity. Immunol Cell Biol. 2008;86(4):301-9.

7. Kodama S, Davis M, Faustman DL. Regenerative medicine: a radical reappraisal of the spleen. Trends Mol Med. 2005;11(6):271-6.

8. Faustman DL, Tran SD, Kodama S, et al. Comment on papers by Chong et al., Nishio et al., and Suri et al. on diabetes reversal in NOD mice.Science. 2006;314(5803):1243; author reply 1243.

9. Macias MP, Fitzpatrick LA, Brenneise I, McGarry MP, Lee JJ, Lee NA. Expression of IL-5 alters bone metabolism and induces ossification of the spleen in transgenic mice. J Clin Invest. 2001;107(8):949-59.

10. Derubeis AR, Mastrogiacomo M, Cancedda R, Quarto R. Osteogenic potential of rat spleen stromal cells. Eur J Cell Biol. 2003;82(4):175-81.

11. Tran SD, Kodama S, Lodde BM, et al. Reversal of Sjogren's-like syndrome in non-obese diabetic mice. Ann Rheum Dis. 2007;66(6):812-4.

12. Lonyai A, Kodama S, Burger D, Davis M, Faustman DL. The promise of Hox11+ stem cells of the spleen for treating autoimmune diseases. Horm Metab Res. 2008;40(2):137-46.

13. Yin D, Tao, J, Lee DD, et al. Recovery of islet beta-cell function in streptozotocin-induced diabetic mice: an indirect role for the spleen.Diabetes. 2006:55(12):3256-63.

14. Swirski FK, Nahrendorf M, Etzrodt M, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325(5940):612-6.