Closing in on the perfect mirror image of a tumor

Alexander is a medical oncologist and currently serves as Chief Scientific Officer at the Prinses Máxima Center for pediatric oncology in Utrecht – one of Oncode Accelerator's coordinating partners. Alexander doesn’t shy away from big promises: “Not only do newly developed organoid models with a stromal compartment have the potential to be an alternative for animal models in drug development, I think bigger. Such organoids are a key feature in the paradigm shift we are witnessing when it comes to treating cancer.”

Let’s start with the basics - what is an organoid model?

Alexander Eggermont explains: "Organoids are best described as mini organs which we can grow out from specific cell types using various combinations of growth factors and other tissue culture conditions. The technology was invented by Hans Clevers and the best-known example may well be the mini guts he created during his tenure at the Hubrecht Institute. Organoid technology also works on tumor cells, allowing us to create mini tumors. At the Princess Máxima Center, the technology was developed further, enabling the generation of childhood tumor organoids. Jarno Drost, Platform lead and Principal Investigator in Oncode Accelerator, is part of our center and one of the pioneers in this field. The Dutch nature of this inventions puts us at the forefront of developments."

Can you explain the potential organoids hold when it comes to modelling tumors?

"To study cancer, whether it is to better understand it or to investigate a new potential drug, you need a model system. When it comes to cancer, it is important to realize that we can’t escape its complexity, we can however mimic it as well as possible. That’s where organoid technology comes in. Widely used model systems based on cell lines lack the complexity a tumor exhibits. They are clonal expansions of specific tumor cells and do not exhibit 3D properties. Moreover, existing animal models are often too slow and, above all, can’t truly capture the role of the immune system in combating cancer. An organoid model comprising tumor cells and the tumor microenvironment – built up of stromal cells, lymphocytes and macrophages – can tackle quite some of these issues. It captures multicellular complexity, it is a truly human model, we can obtain meaningful results within weeks and it’s scalable. We are closing in on a more perfect mirror image of a tumor", Alexander says. 

Why is the microenvironment of the tumor so important?

"What has become apparent in the last years, is that you really need to incorporate the tumor microenvironment in a model. A tumor consists not only of cancer cells, but it also contains many other cell types which influence the clinical outcome of a treatment. These cell types include stromal cells like fibroblasts, which act as a structural scaffold, all kinds of immune cells and blood vessels. Especially the immune cells residing in the tumor are of great influence. One example is the effect of tumor associated macrophages. These immune cells are almost always tumor growth promoting and immune suppressive" - Alexander elaborates. "This severely limits the ability of, for example, T-cells to attack tumor cells. When we try to incorporate these cell types into organoid models, we run the risk that these cells overgrow the tumor cells. Exciting results from a lab at Stanford now show us how to do this. It turns out that under conditions with limited oxygen supply, we can add this layer of complexity in organoid tumor models."

How will the latest organoid models help us to develop new drug candidates?

"Many of our current immune therapies focus on promoting T-cell maturation through targeting CTLA4 or on protecting T-cells through targeting PD1. But what is currently missing in our toolbox, are ways to inhibit tumor associated macrophages. If we can somehow find ways to interfere with these cells, we can actually remove the shield a tumor has and greatly improve the effectiveness of our weapons to attack the tumor cells" - Alexander says.

Do you see more possibilities for the Organoids platform within Oncode Accelerator?

"True acceleration can come if we can couple the power of organoids with clinical practice and clinical research. More and more studies show that you need a properly functioning immune system to increase the odds of beating cancer, especially through immune therapy. After four rounds of chemotherapy, a patient’s immune system is severely compromised. If we then investigate the potential of a new immune therapy regimen, we can predict the outcome. We come in too late and innovative treatments likely do not work in the context of a severely compromised immune system. We need to bring innovative treatments to patients earlier.  I always say that we should bring innovation to the front door, meaning in the first line of therapies, instead of the back door, at the end of multiple prior treatments. In the coming years, these neoadjuvant immunotherapies will dominate drug development and patient management in multiple tumor types with more cures, shorter treatment cycles and less surgery. Early introduction of immunotherapy in cancer treatment is essential to do this. We can increase cure rates and, equally important, we can identify non-responders up front, who can be channeled into various completely different treatment approaches. In the coming years, new immunocompetent organoid models and clever screening set-ups will allow us to match the needs of an individual patient to existing treatment options within weeks. That is not science fiction, we are witnessing this paradigm shift now."