Saturday, December 20, 2014

Phase-II Results from Rebooting The Immune System To Cure Type-1

First, a discussion about naming.  In the past, I've referred to this treatment as the "Burt" treatment, because that was the senior (last listed) author of the first paper I saw on it, and because I didn't have a better name for it.  I haven't seen Dr. Burt's name on clinical trial for this treatment in many years, so it's no longer an appropriate name.  But I don't have a better name.  In any case, you can read my previous blogging about this treatment under the label "Burt" on my blog:

Second, a little background. The original clinical trial of this treatment, in Brazil, was one of the very few clinical trials which actually cured people of type-1 diabetes. I know that is a provocative statement, so let me be clear: Some of the people treated in this trial did not need to use external insulin (yet still had reasonable A1C numbers while eating normal diets) for as long as the study ran. Some of these people were followed for years. This was not just a "couple of weeks" or even a "couple of months" event.

Third, some important safety issues. Basically, the treatment is to "reboot" the immune system, hobbling the immune system, and then treating it so that when it comes back, it does not attack the body's own beta cells. There are two serious safety issues here: first, during the time the immune system is down, the patient must stay in an isolation ward in a hospital, and is subject to opportunistic infections, which can cause death. Second, the act of shutting down the immune system is a big deal, and might cause problems "down the road". Cancerous tumors are a particular worry. Neither of these risks is completely unknown. Very similar immune system "reboots" are used today to treat cancer, and some other autoimmune diseases and their safety is understood. Never the less, the level of risk is higher than other possible cures for type-1 diabetes.

The Studies

This paper is not reporting on the results of one study.  Rather, it was reporting on a pool of patients enrolled at three different sites, one in Poland and two in China.  There were a total of 65 people included (24 in Poland, and 13 and 28 in China).  All studies enrolled people as young as 12, while the Polish study limited recruitment to the first 6 weeks after diagnosis, the Chinese studies accepted people for a year after diagnosis, but these are all honeymoon diabetics.  There were a few other differences in experimental procedures, as well.

The Results

The following points are all quotes from the abstract:
  • A total of 59% of individuals with T1D achieved insulin independence within the first 6 months
  • 32% remained insulin independent at the last time point of their follow-up
  • All treated subjects showed a decrease in HbA1c levels and an increase in C-peptide levels compared with pretreatment.
The authors' summary of their own results (also quoted from the abstract) is:
  1. That remission of T1D is possible by combining [bone marrow stem cells] transplantation and immunosuppression; 
  2. That [their procedure] represents an effective treatment for selected individuals with T1D; and,
  3. That safer ... therapeutic options [based on bone marrow stem cells] are required.
And I think that's an excellent summary.

Here are some other points that I'd like to make:
  • Of the 65 people reported on, one died of sepsis; obviously, this is the worst adverse effect possible.
  • 34 people experienced adverse effects (65 events in total).  There was no published data on severity of these events.   As an example, the most common adverse event was fever, but there are no notes on how serious or threatening the fever was.  Alopecia was the second most common adverse effect.
  • The earlier in the honeymoon period that a person was treated, the more successful the treatment.

There are lots of interesting discussion points in here, and I don't have time or space to go into all of them, but here are a couple:

The researchers believe that a specific type of immune cell, called a CD34+, is critical to success of this technique. Remember that the immune system has many different types of cells, which are often named based on proteins on their outside coating which have these "CD" numbers.  CD34+ is not a cell I have seen specifically "called out" in previous research done in people.  However CD34+ cells are found in umbilical cord blood, which has been used in human research, as well as in bone marrow (as in this trial).

The researchers did measure the long term health of the immune system after treatment, and their summary was "Immune system recovery was rapid and complete".  So they found no evidence of long term weakness in the immune system after this treatment.

What is the future direction of this work?  The researchers discuss two paths for future development of a safer cure based on this work.  The first path is to improve the treatment, by using less immunosuppression at the start, and stronger drugs to prevent infections during treatment.  There are many different immunosuppressive drugs in use, and it may be that a safer drug (or drug combination) can be used in the future.  Similarly, there are many drugs designed to prevent infection by bacteria, viruses, etc.  and it may be that there is a better combination of these drugs available. The second path, is to make the treatment more effective, possibly by increasing the number of CD34+ cells infused back into the patient.

Is this treatment a cure?  That depends on your view of safety.  With a death rate of 1 in 65, I think few people would consider this a cure.  However, if you assume that someone with type-1 diabetes lives (on average) 5 years less than someone without, then in an actuarial (purely mathematical) sense, this treatment does extend average life. This is comparing shaving a few years off of many people's lives vs. cutting a few lives very short.  While this might be a mathematically viable comparison, I don't think it's how most people really think, and certainly not in making decisions about their children.  But of course, research is fueled by hope for the future: what it will grow into, not limited to what it is right now.

Previous Blogging:

I want to thank the authors of the paper, who provided me with a copy so that I could blog on it.
Normally, this paper is behind a pay wall.

Joshua Levy 
publicjoshualevy at gmail dot com 
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.