This is a very interesting study, which is why I'm giving it, it's own blog posting. The official title of this study says it all, optimistically: "Reversing Type 1 Diabetes After it is Established". It builds on three separate lines of research: Burt's ATG/GCSF/cyclophosphamide trial, a separate line of ATG-only trials, and NOD mice trials on ATG and GCSF (all discussed more below).
The basic idea behind this research is that ATG modulates the body's immune system, while GCSG causes the body to generate more t-cells directly from it's own bone marrow.
ATG is a mixture of different antibodies that target T cells, including the anti-CD3 antibody. The hope is that this multi-faceted approach will be even more successful and have a longer lasting effect than with anti-CD3 alone, and may treat diabetes by several mechanisms. First, it lowers the number of T cells, so there are fewer to attack the beta cells. It also seems to alter the T cells remaining behind, rendering them less likely to be destructive. Following this depletion, the T cells that grow back in the following weeks may be reset and have a healthier balance (meaning that a special type of T cells, called regulatory T cells, will help keep the destructive T cells in check).
GCSG is essentially a growth factor that helps the body repopulate the cells after ATG depletes them. So, if ATG fixes the immune system by getting rid of the destructive cells, and the GCSG can cause the body to generate more t-cells afterwords, and presumably a healthier balance of these cells, then the two together could stop the autoimmune defect that causes type-1 diabetes. (Regrowing new beta cells might still be required for some people.) And, this process has already been used successfully to cure type-1 diabetes in mice, so that is always a good first step.
But the really positive thing about this research is it's relationship to previous research by Burt. You can read my previous blog entries about Burt's research at the URL below, but the quick summary is this: Burt has -- by far -- the best results in people of any researcher. That study used a combination of 3 drugs, ATG, GCSF, and cyclophosphamide. Some patients went into remission (no need for injected insulin) for a period of years, others for months, and all of these people used much less insulin after the trial. Only two patients in the study did not go insulin free for at least a few months. This research also has a serious weakness, which is safety. Although none of the people in Burt's had serious side effects, the process involves "rebooting" the immune system. So while this is happening, the patients are in an isolation ward, because their immune system is highly compromised. Also, there were "hints of toxicity" seen in the trial: a few people had unusual infections, and some of the males had reduced sperm counts afterward. Burt's research was in honeymoon diabetics, only.
A second line of research that has been going for years uses ATG alone to try to preserve beta cell function in honeymoon type-1 diabetics. This research has already completed a phase-I study, and a phase-II study is underway right now. The phase-II study is called START and they hope to finish recruiting patients in 4-6 months. ATG alone is very good in curing mice, but in combination with GCSF the success rate is nearly 90% for the mice, and hopefully that will translate to people.
Oversimplified a little: Burt's research involves using three drugs (ATG, GCSF, and cyclophosphamide), and reinjecting the patient's own precursor bone marrow cells (previously removed). Dosing with just ATG and GCSF can be viewed as a "kinder, gentler" Burt. Especially since the cyclophosphamide is the one that really hammers the immune system and requires the isolation ward.
In the past, I've been asked who was following up Burt's research, and this is a pretty direct follow up. Most phase-I trials are aimed at minimum effect and maximum safety, so minimal doses are used. The follow on research usually involves more drugs. However, in this case the effectiveness is high, while the safety is the issue. So the follow on research involves less drugs. In this case it involves removing the most toxic drug from the treatment.
They are enrolling 25 people who have had type-1 diabetes for more than 4 months, but less than 2 years. Planned completion date is April 2013. They are recruiting at the University of Florida, which is in Gainsville. UCSF (San Francisco, California, USA) and also the Davis Center (Denver, Colorado, USA) will be participating in this study, but they are not listed in the clinical trial record. The coordination is through University of Florida by Dr. Michael Haller (who is running several other clinical trials aimed at type-1 as well). The email contact is listed as email@example.com, so I would start there if you are interested.
Previous blogging on Burt's research: http://cureresearch4type1diabetes.blogspot.com/search/label/Burt
Previous blogging on ATG: http://cureresearch4type1diabetes.blogspot.com/search/label/ATG
Description of study: http://diabetes.ufl.edu/research/clinical-trials-and-studies/established-type-1-diabetes/atggcsf-clinical-trial/
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01106157
Abstract of animal study: http://www.ncbi.nlm.nih.gov/pubmed/19628781?dopt=Abstract
Wikipedia for GCSF: http://en.wikipedia.org/wiki/Neulasta
Wikipedia for ATG: http://en.wikipedia.org/wiki/Anti-thymocyte_globulin
I'd like to thank Dr. Steve Gitelman (who is a Principal Investigator in the ATG START study) for his thoughts on this research. All mistakes here are my own.
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.