Zsolt Sebestyén

Research with animals complements non-animal methods

2 weeks ago

Zsolt Sebestyén is an associate professor of Translational Immunology at the UMC Utrecht. He currently works on the development of living medicines to fight against cancers with cell-based immunotherapies. In this interview, he explains to us the importance of animal models and the place of the transition towards animal-free innovations in his research field.

What is the most relevant model that you use for your research?
"We use different models depending on the part of the research process we are in. Part of our group uses in vitro models to select the most interesting candidate therapies. Then, the second step concerns the preclinical loop where we want to show that the candidates with the greatest promise for clinical development are effective, safe against cancer and not harmful for healthy tissues. For that we use a combination of preclinical models: 3D models as well as mouse models. Finally, when we know all the ins and outs of a certain new medication, we can bring it to patients by carrying out clinical human trials."

How do you choose between using animals and other models?
"In our field, we often develop totally new types of immune therapies and the ultimate way of testing them includes patients, which is not an easy step to get to. We choose animal models when we would like to understand a complex system in a whole organism, such as immune cells expansion. In a body, immune cells expand in a homeostatic way, which phenomenon cannot really be reproduced in a 3D model. Moreover, every cellular immunotherapy may have a different capacity to expand. This aspect is a good example showing that some tests can only be done with mice models. Another aspect is persistence, namely how long the immune cells remain circulating in the system. And the third one concerns how the immune cells can then attach to the tumor. Now we can make more and more complex in vitro models with non-tumor tissues for example. We can even mimic some of the blood vessels around, but still, some complexities such as how we can interfere with an embedded tumor growing in an organism are very difficult to do in vitro."

Is there any other model apart from mice that you can use to get strong evidence?
"For example, in one of our clinical trials we used a combination of in vitro and in vivo models. We had to use some efficient in vivo models for various tumor types, at least to show that our new therapy worked against various tumors. However, toxicity was very difficult to test in mice, because the mechanism we were studying doesn't exist in them. We had therefore to come up with a new system: we transplanted human stem cells in mice. It was actually a very beautiful model, because we had a fully engrafted human immune system in mice that we could treat with our new immune therapy. We also built a 3D bone marrow system that we also treated with our new immune therapy. These were short-term tests, but we could show that in such low complexity systems we did not see any toxicity while we saw efficacy. Therefore, we used two very important systems next to each other: one of them is purely in vitro, including primary patient materials, and the other one is an in vivo model, namely a mouse model. In vitro models are practical because they are small, relatively quick and easy to follow up. They are also less expensive and cause less animal suffering. On the other hand, the advantage of in vivo models is that they provide a more established and complex system, which is something that you will never be able to reach in an in vitro model. I don't think we could have been able to convince the regulatory authorities with only one of the two models. And I must say that combining the two gave us a lot of opportunities to even develop new models."

How do you reduce and refine the use of laboratories animals in your research field? 
"Refinement is an ongoing process in discussion with the Animal Welfare Body. In our field, almost every model that we set up to develop new immune therapies can be a new challenge. As for reduction, I think everybody is reducing the number of animals in experiments for sure. In vivo models are expensive, cause suffering, and ask for huge infrastructures and very well-trained personnel. Nevertheless, the number of animals we use is increasing lately, because of a growing number of pre-clinical leads that we would like to move towards a clinical trial. We have to be able to make the decision of the most promising lead that will go to the patient, and for some of these new leads we have to choose an animal model. However, instead of testing various leads in separate animal experiments, we would rather conduct big experiments where we can compare various immune therapies against tumor in the very same model."

What do you think about the transition towards animal free innovations?
"I know that Utrecht University and UMC Utrecht have a strong ambition to accelerate this transition. From my point of view, it is almost impossible to reduce animal use any further. I think that our work is going to be very difficult if we can’t use animal models anymore because we want to develop new medicines. So, to me it is a kind of scary movement. On one hand I'm supporting it, because part of my work is to develop in vitro pre-clinical models, and it gives more space to my science. But on the other hand, if the transition is not discussed in a dynamic way, and if it's just a black and white or a number decision, it can compromise the number of new opportunities and new medicines that we develop."

Where would you draw the line between using lab animals and using animal-free innovations?
"Once you move on with the development of a pre-clinical lead, but you have made slight changes or you just want to improve certain medicines, extensive animal studies may not be necessary. Then, you can probably answer many of your questions in an animal-free model. But I think that in certain cases when you develop something substantially new or you change a property of certain medicines that would affect criteria such as persistence, expansion, and penetration to the tumor, these are questions that are very difficult to answer in vitro. Here I would absolutely go for animal models in combination with in vitro models."

What could be a possible avenue for animal-free innovations in your field?
"I think that animal-free innovations are already broadly used even in my field, so it has been a great breakthrough. I don't know whether we still can encourage it more. That’s why I think that ethical organizations should sit more often with scientists to really understand each other’s limitations. The biggest danger to me is that we start seeing animal-free innovations as a replacement for all animal work, because to me, they are complementary."