With applications in a diverse range of disease areas, including cancer, neurological disorders and autoimmune diseases, cellular therapies have become increasingly more popular in the clinic.
Utilising these naturally occurring cells to improve patient outcomes is something that PolTREG — a clinical-stage biotechnology company specialising in the treatment of autoimmune diseases — is currently working on. It has taken Tregs to clinical trials to treat conditions such as type 1 diabetes and multiple sclerosis, seeing promising results in Phase II trials.
Annabel Kartal-Allen spoke to Piotr Trzonkowski, CEO of PolTREG, to find out more.
Repurposing regulatory mechanisms
Tregs are a highly influential component of the immune system, with their primary purpose being the suppression of other immune cells to maintain self-antigen tolerance and maintain immune-homeostasis. Their application in an autoimmune setting was identified by scientists globally.
The first company that treated patients using autologous Tregs was PolTREG, founded by Prof. Piotr Trzonkowski, Prof. Małgorzata Myśliwiec and Prof. Natalia Marek-Trzonkowska.
Treg cells are unique in autoimmune therapy, as they function through multiple mechanisms. “They act in various ways at the same time,” says Piotr Trzonkowski, CEO of PolTREG. “They can suppress immune responses using various different mechanisms, which means they provide more lines of attack than any standard biologic currently available.”
He continues: “Another important thing, pharmacologically, is the penetration of the drug; its biodistribution is much better than any other form of currently available medicine.
The (infection) occurrences observed in trials were usually very mild, with no consequences for the future health of patients
Safety in application
As well as Tregs being diverse in their ability to suppress autoimmune responses, they have been proven to be safe in clinical trials. “We can confirm that infections do occur, but they are not severe infections and there is no sign of sepsis. The occurrences observed in trials were usually very mild, with no consequences for the future health of our patients.”
Prof. Trzonkowski proposes that the low incidence of severe infections is “likely due to the activity of Tregs.”
“They work in a very precise local way and don’t affect the entire immune system. They only switch off abnormal parts.”
Independence from hospitals
Not only do Tregs have a promising safety profile, they also allow patients some independence from the traditional healthcare environment. Prof. Trzonkowski clarifies: “It is a treatment which doesn’t impose a burden on patients or require them to be constantly connected to a hospital. One dose is usually enough for several months.”
With a less frequent need to visit facilities that can administer treatment, quality of life can be ameliorated for patients who would otherwise be spending a significant amount of time travelling to and from the hospital.
We are currently able to produce approximately 1000 —1500 preparations per year
Manufacturing and distributing Tregs: the challenges
Although there are many benefits to cellular therapy, they come with significant manufacturing issues, including the complexity of the process and the associated price tag. Prof. Trzonkowski comments: “The challenge, which is common for all cell therapies, is scalability. Manufacturing Tregs is complex.”
PolTREG is aiming to scale up its production to provide patients in Europe with Tregs: “We just completed our new manufacturing site, which is scalable. We are currently able to produce approximately 1000 —1500 preparations per year, which is a significant number for our trials.”
When treating patients further afield, the logistics of distributing cells to patients is highly complex — significantly more so than traditional oral treatment modalities. “These are fragile drugs; they are live cells. Making sure they remain undamaged during long-distance transportation is challenging”
However, PolTREG has proposed some solutions to the issue in Europe: "We have built a network that enables us to distribute Tregs to patients, instead of them coming to us. We got the idea to supply hospitals directly, so patients do not need to travel to receive this therapy. They can be treated in any hospital”
“We’re also thinking about distribution throughout Europe. The model is similar to that of CAR-Ts; there would be a principal manufacturing site, with a complementary distribution programme for the whole continent. Our idea is to become that manufacturing site for Tregs.”
Improving patient outcomes with combination therapies
Although Tregs have proven to be efficacious as a monotherapy in clinical trials, it will likely be beneficial to administer combination therapies to patients — both with other immunotherapies and standard biologics that are currently in-clinic.
Prof. Trzonkowski discusses this: “In type 1 diabetes, we have already tested this form of combination therapy. We combined Tregs with available biologics and it works better.
“This is a matter that directly affects patients, so if we can find a combination that offers benefits to patients, we should use it. Currently, our outlook on Tregs in diabetes is that we will be using them in combination with other standard of care products.”
It is highly important, before considering a combination therapy strategy, that the repeated utilisation of Tregs is both efficacious and — most importantly — safe for patients in the long-term. “Right now we see that you need to repeat the treatment every few months. When we demonstrated that one injection was safe, we then progressed to giving at least two Treg injections.”
“When we shared our results with the European Medicines Agency, they said if the results are better with two injections, we should continue with a programme of repeat administration. They subsequently required us to make a treatment protocol recommending the administration of multiple Treg injections.”
“We need to follow these patients closely to be sure that the repeated therapy is safe. So far, it appears that way. I'm sure that treatment will be given every few months for years as a standard of care for patients that have symptoms, for example, of type 1 diabetes.”
Piotr Trzonkowski, CEO of PolTREG
US collaborations
The strong presence of Treg research in the US has also played a role in advancing the clinical understanding of optimising and administering Treg therapy.
Because of this, PolTREG have begun collaborating with US company AZ Therapy, which led to the joint submission of a drug candidate that’s currently in preparation for clinical trials. “We are very much open to make this collaboration wider,” states Prof. Trzonkowski.
Tregs have been in development for the treatment of autoimmune disease for more than 17 years now, with novel moieties in the pipeline for various applications. There are multiple candidates currently in the preclinical stage for PolTREG. “Hopefully, at least one of the novel candidates will reach the clinic at the at the beginning of next year,” Prof. Trzonkowski adds.
“We also need to gain marketing authorisation for the drugs that are currently in clinical trials and get them to the patients that need them.”
Raising awareness about the benefits and applications of Tregs to treat autoimmune diseases is something that Prof. Trzonkowski strongly believes in. He has been involved in the production and testing of these therapies since the beginning and believes that it should be given more attention.
He comments: “We need to generate more interest in using Tregs and make sure that people realise that these therapies are gaining traction in Europe as well as the US."
The use of Tregs has the ability to improve the lives of many people living with debilitating illnesses — although there are still significant hurdles to overcome in terms of manufacturing complexity, and how best to use them in-clinic.
With further dedication from scientists globally, this therapy option can be commercialised and rolled out to patients from all across the spectrum of disease severity.
