PanTHERA had an incredible opportunity to chat with Dr. Esme Dijke, Director at the Histocompatibility Laboratory and Assistant Professor for Lab Medicine and Pathology.
Dr. Esmé Dijke is HLA Director of the clinical histocompatibility laboratory at the University of Alberta Hospital and Assistant Professor in the Department of Laboratory Medicine & Pathology at the University of Alberta in Edmonton, Alberta. Her research focuses on the potential of discarded human thymus as a novel source of clinical-grade, stable regulatory T cells (Tregs) for adoptive cell immunotherapy in transplantation and autoimmunity.
Thank you for sitting down with PanTHERA for a chat today Dr. Dijke. Could we ask you to explain your research/work to our readers?
My research at present is about how regulatory T cells, or Tregs, work and affect our immune system, and how we can harness these cells to our advantage. Tregs are basically cells that can suppress an immune response. They are of particular interest for treatment in patients with autoimmune disorders or organ transplantation. Through organ transplantation, an individual gets an organ from another individual to replace their own sick organ. However, the immune system sees the transplanted organ as foreign and will try to get rid of it. We don’t want this to happen because people need the transplanted organ to survive. And so, these patients are treated with a lot of medication to suppress their immune system. However, there are a lot of side effects related to these medications and because everything is suppressed, they contract infections easily and are more susceptible to cancer. That is why there is a lot of interest to look at whether we can use regulatory T cells to suppress immune responses and in doing so, solve the issue of autoimmune disorders and organ rejection after transplantation.
There is at present quite a few clinical trials that are studying this with great success. They obtain Tregs from the blood, either drawing from the patient or a different blood donor. Tregs are then grown, expanded in culture, and returned to the patient. The challenge with this process though, is that these cells are quite rare. They are about 1-2% of your blood make up. If you look at all the immune cells, Tregs are only a small percentage of these immune cells. Hence, you can only obtain a low number of cells, and you will then have to grow and expand them multiple times to get enough cells for the therapy. The cell population you have in your blood is also very mixed, there are different kinds of cells. It is hard to identify Tregs specifically because some other T cells have similar identification markers. Tregs come from your thymus, which is a tissue located in your upper chest. This place is where all the T immune cells grow, develop, and are trained. It is where they learn what is good, and bad for the human body. The cells then exit the thymus where they do their job to make sure we are not getting sick.
Because the thymus is in the upper chest, infants who go for cardiac surgery have a piece of the thymus removed, since it is in the way of the surgeon performing cardiac surgery. The piece of thymus that is removed is then discarded. We have set up a study in which we collect this discarded tissue and try to retrieve the Tregs. The study has been successful in that we can get large numbers of these specific Tregs from these thymus pieces. So, we have found a way to use human tissue that would otherwise be garbage as a source of Tregs for cell therapy. We are working closely with the research team in Vancouver under the supervision of Dr. Megan Levings to bring it from bench to bedside.
To utilize these Tregs for cell therapy, we need to be able to cryopreserve them so we can store them for longer time periods until they are needed. The current freezing protocols are standard in a sense that we use the same protocols that are used for all kinds of cell types.
What we noticed however, is that we lose between 30-40% of the cells, and the process also influences their function. Cell therapies using these cells are very expensive, and we need large quantities of cells, so having recovered only 60-70% of cells means we need to grow much more and that increases the cost even further.
Interesting! Could you share with us if you have tried PanTHERA’s Ice Recrystallization Inhibitors (IRIs) and how has that turned out?
Yes we did – we started with Tregs purified from blood, to set up the project, and we put the cells through different conditions including standard DMSO and a lower concentration of DMSO in the presence of IRIs. It is still in the very initial and infancy stages and the results hence have been preliminary, but we do see improvement compared to the standard protocols.
Is there a difference between Tregs from the blood and Tregs from the thymus?
The Tregs develop in the thymus, and are what we call, naïve. Basically they have not experienced anything else than what is in the thymus, whereas the Tregs from the blood might already have encountered immune responses. In the blood are also other T cells that can start immune responses. Every time they are part of an immune response, they change and basically remember they have seen something that is foreign. These T cells will respond quicker when they see it again because they have been imprinted through responses. These T cells from the blood can look a lot like Tregs because they can have similar identification markers on them but they do not suppress an immune response. It is therefore challenging to isolate the actual Tregs from these other T cells in the blood. Because the cells in the thymus are naïve, these other T cells do not have these similar markers as the Tregs yet and it is therefore easier to separate them from each other.
What do you anticipate will be the timeline for testing the IRIs with these T cells?
We think in the next 1-2 years we will have the data to see how the IRIs can optimize the cryopreservation protocol of Tregs at least from a research point of view. I learned that clinical protocols can take a lot of time mainly because there is a strong administrative element to it. But we feel that within the next two years, we would at least have an understanding of how these IRIs are working on the Tregs, and if it improves the cryopreservation process.
Are there any other similar studies going on now?
As mentioned, we are working with Dr. Megan Levings to set up a trial for the use of these cells in patients who require a bone marrow transplant. There have been other clinical trials using Tregs in the treatment of these patients but the cells are from either the peripheral blood or cord blood. But since the numbers you get from cord blood are very low, our approach is to use thymus to obtain large quantities of Tregs.
Besides working with our colleagues in Vancouver, we have collaborators in Spain who have started a clinical trial in pediatric heart transplant recipients using Tregs isolated from thymuses. At the time of heart transplantation, they have taken out the thymus, isolated and cultured the Tregs, and then returned the cells back to the same patient to use that as an add-on to suppress that immune response to the new heart. The initial results have been optimistic in terms of safety. They are now looking at the other end points including the rejection of the transplant, but the results have been promising so far.
What are some of the industries or areas that you feel the IRIs could potentially be game changing for?
In the field of organ transplantation and in any cell therapy or cell transplants. There are not a whole lot of studies that have really looked at optimizing the cryopreservation protocols in a lot of detail. A lot of time and money is spent on generating these products and then we just take the standard protocols that are out there and use them to store the cells. With PanTHERA, we’re also really looking at the biological properties of the cells, because not every cell is the same. I do think that in the field of cellular therapy and transplantation, these IRIs have potential to be successful for products that are being stored.
And cell therapy is really taking off. It’s not only the regulatory T cell therapies, but also the CAR T cell therapies where T cells are being modified and therapies that use T cells specific to certain viruses. These cells that will likely need to be stored at some point in the process because the timing and logistics of the process are tricky. Having optimized cryopreservation protocols with IRIs would allow us to produce higher quantities of effective T cells to be used for all these various cell therapies.
This conversation has been edited for brevity and clarity.
About PanTHERA CryoSolutions
PanTHERA CryoSolutions is a Canadian corporation that designs and manufactures cryopreservation solutions for cells, tissues and organs for research and clinical markets. Our patented ice recrystallization inhibitor (IRI) technology exceeds other products by providing superior cryopreservation and increasing post-thaw cell recovery and function for our customers. The technology enables the use of significantly less costly storage and transportation systems limiting the need for liquid nitrogen use for some cell therapy applications
