This blog post reports on some news that I consider exciting, for at least two different reasons: first because it might be an early milestone on a path that leads to a practical cure of established T1D. The second because it could speed up research into similar cures. However, it is important to understand what is actually new and unique about this news, and how it differs from previous news that sounds similar.
Background: Islet Transplants Without Immunosuppression
At least 50 years ago, it was pretty clear that the beta cells of people with T1D were destroyed, and that gave hope that transplanting in new beta cells might cure T1D in a straightforward way. It did not happen, because the new cells were attacked by the body's immune system for two reasons: (a) they were foreign cells so the immune system attacked them "normally", as part of the healthy attack on foreign cells. And (b) because the immune system is broken, leading to T1D in the first place, it attacked these new cells "abnormally" just as they had attacked the body's own cells to trigger T1D in the first place.
One way to solve both these problems is to modify the new cells so that they are invisible to the immune system. That is, they don't present as foreign cells nor do they present as beta cells. This is the solution that Sana Biotechnology has been researching, and that I'm reporting on here.
What Was Reported
In a very small clinical trial, they reported data on the first person transplanted with beta cells, after one month:
- C-peptide data shows the transplanted beta cells were generating insulin, and were generating it in response to eating carbohydrates.
- MRI images suggest that the new beta cells are surviving.
- No safety issues were seen.
- The new cells appear to have avoided any immune attack ("evaded immune responses").
This is all good news, but notice what was not reported: no specific numbers on C-peptide generation, which means no specific numbers on insulin generation. And similarly, no numbers on insulin usage, A1c, or anything else to show how well the new beta cells were operating.
Also notice the limitations of this reporting: one person and one month, and no scientific journal article, just a press release.
More Study Details
The entire study is a two person, phase-I study lasting a year, so not much bigger. Donated beta cells are modified using Sana’s Hypoimmune (HIP) technology, and then implanted into the forearm of the person with T1D. The procedure took 90 minutes. The HIP technology is the "secret sauce" that Sana hopes will make the cells invisible to the immune system. This protocol is identified as "UP421" and they are using it in another program aimed at cancer.
This study was very much a proof of concept. The researchers are implanting between 2% and 7% of the beta cells that will ultimately be needed, to see if they get any results at all. They are measuring C-peptides, as well as various safety and immune system measurements. But the summary is, even when the whole clinical trial is done, we will have very little information.
Last Minute Update
Just as this blog was going out, Sana released a corporate presentation, which had some additional information. The main updates are as follows, and I think they are all very positive:
- Three months of data are included, and the c-peptide numbers continue to be strong for the entire time.
- They include data (specific numbers) for fasting and mixed meal c-peptide data. Considering how small the transplantation was, the results are very promising.
- They include immunology data that supports their claims that the newly transplanted beta cells are not triggering an autoimmune response.
Discussion
What To Look For In The Future (and When)
To me, this has the potential to be a huge breakthrough, as it could lead to a practical cure in the future. The key words here are "potential" and "future". For many people the next questions is, how likely is it or how long will it take. But those are not my questions. My questions are, what are the next reports we should expect to see, and what data from those reports will signal good news?
Unfortunately, we are not going to get a lot more information any time soon. This data comes from a very small, phase-I clinical trial: only two people in total (both treated, no control group). That means that over the next year, the very best we can hope for is 2 people; no control group; a small dose; all published in a scientific journal. That is not much (although one year is not long to wait).
The next data we should expect, would be the results of a phase-II or maybe a phase-II/III clinical trial. But we should not expect that for 3 or 4 years. And remember, no matter how successful the current study is, and how successful the next study is, approval will still require an additional phase-III study (maybe two phase-III studies), which is more years.
Is it a cure? The immune system is still broken!
One comment I sometimes hear when I talk about transplants is that they are not cures, because the immune system is still broken. They might stop the symptoms, but they do not cure the "real" disease, the flaw with the immune system.
This gets into the very emotional question of what is a cure. After all, if someone's leg is crushed and you install a pin, have you cured them? What if the pin means they can walk but not run? On the other hand, if they crush a leg, and need a wheelchair for the rest of their lives, are they cured? After all, the wheelchair means they can get around. And so on.
My answer to this question is on my web page, just to the right of every blog posting I write:
1. Blood sugar control without testing and with doctor's visits four times a year, or less. Any cure must result in an average lifespan close to normal.
2. Does not require a lifetime of immunsuppressive drugs, so it is not trading one treatment for another. (but a couple of operations, or a short course of drugs is OK)
Obviously, this is my personal definition of a cure; yours may differ.
By that definition, this would be a cure, if it works. The fact that the immune system is still broken does not change the fact that the person no longer needs to take insulin, count carbs, or wear a pump 24x7.
History and Complexities of Islet Transplants
You don't need to read this section to understand the research, or why it is important. I'm putting it here for people who find it interesting.
The history and complexities of islet transplant research is a huge topic, far to big to fit in one blog posting, much less one section of a blog posting. However, I will try to summarize both the history of transplant-based cures and the complexities that have prevented the research from succeeding:
Transplant History
In the 1970s and 1980s, it was commonly thought that type-1 diabetic's beta cells had been destroyed, and if they could just be replaced, their diabetes would be cured. This led to several attempts at transplants to cure T1D, especially whole pancreas transplants, beta cell transplants, and drug treatments designed to get beta cells to regrow (such as human growth hormone).
These did not work because the new beta cells were destroyed by the broken immune system just as the old ones had been, and also because the properly working immune system attacked transplants as foreign cells.
Starting in the 1980s, researchers tried encapsulating beta cells: they put beta cells inside a wrapper and then implanted the bundle in a person. The wrapper would need to be a very high-tech material that would allow nutrients and oxygen to flow in, wastes to flow out, insulin to flow out, and the chemicals which triggered insulin production to flow in. But if they succeeded, it would be like having a natural pancreas inside you, but protected from the immune system.
Many different companies and many different researchers tried to use encapsulated beta cells to cure T1D. There were a lot of different options to try. Every researcher needs to choose a source of beta cells, and an encapsulation technology. Optionally, they might also add an unusual transplant location or a new drug protocol for the transplant itself. Since there are many different sources of beta cells, and an almost unlimited number of encapsulation technologies, you can see how this would keep many researchers busy for many decades.
At different times, beta cells have been sourced from: pigs, genetically modified pigs, human cadavers, or live humans. Plus, they have been grown from stem cells sourced from: the person with T1D themselves, other people's skin cells, placenta cells, or embryos. Plus, I'm probably forgetting a few, since this research has been going on for 40 years!
As for encapsulation technologies, there are dozens of them, and I'm not even going to try to list them, but all kinds of modern material science has been applied to the problem.
However, to date nothing has worked. I believe that there are several problems and solving one tends to make the others worse, and it is very hard (so far, impossible) to solve all of them at once. The problems include:
- Allowing nutrients to pass from the body into the new beta cells, and waste products to pass from the beta cells back out to the body.
- Not allowing immune cells to move from the body to the beta cells.
- Allowing sugar to pass in and insulin to pass out.
- Not having the body build up scar tissue around the beta cells, which blocks access to them.
You'll notice that solutions to problems 1 and 3 tend to make problem 2 worse, while solutions to problems 2 and 4, tend to make problems 1 and 3 worse. Of course, all problems must be solved at the same time, for this to work.
Sana's Approach Is Different
Sana Biotechnology is not trying to encapsulate beta cells. Instead, Sana is trying to alter them so that the immune system can not detect them. This would solve both major transplant problems at once. The "natural" attack on any foreign cells would not even see the new cells, and the "broken" attack on beta cells would not even see the beta cells to attack them.
The immune system identifies cells by identifying specific structures on the outside of cells. MHC Class I and II are two such structures and the CD-numbers refer to other such structures. So Sana is trying to remove these structures from the outside of their beta cells. The hope is that then the immune system will not see the cells at all.
I'm not a researcher, so I have a lot of trouble evaluating the science behind Sana’s Hypoimmune (HIP) technology. However, here are two summaries of HIP that I could find:
Sana's approach seeks to modify cells to evade both innate and adaptive immune responses by knocking out MHC Class I and II expression and over-expression of CD47.
The goal of Sana’s hypoimmune (HIP) platform is to eliminate the need for immunosuppression by cloaking cells from immune recognition while at the same time generating the manufacturing scale and reproductibility of allogeneic cells. The challenge for the field to date in generating immune cloaked cells has been turning off both the adaptive and innate immune system concurrently. Sana’s platform includes disruption of major histocompatibility (MHC) class I and MHC class II expression to hide cells from the adaptive immune system, which includes antibody and T cell responses, as well as overexpression of CD47 to inhibit activation of the innate immune cell system, in particular macrophages and natural killer (NK) cells.
As with all research approaches, it doesn't matter if it sound good or if it makes sense. It only matters if it works in clinical trials.
Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official BreakthroughT1D or JDCA news, views, policies or opinions. My kid has type-1 diabetes and has participated in clinical trials, which might be discussed here. I am obese and right on the boarder of T2D and therefore may be taking drugs for those conditions. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog!
