Immunotherapy strengthens the immune system so that it can recognize and destroy cancer cells. It is a treatment used in children and adults. Some children with B-cell acute lymphatic leukemia (B-ALL) under treatment at the Máxima Center receive immunotherapy with CAR T-cell therapy. These T cells that have been modified in the laboratory “travel” to the bone marrow. This is the place where leukemia cells originate and develop, and so is the place to attack them. However, this journey does not proceed equally well in every child. This may explain why CAR T-cell therapy is not equally successful in all children.
Prof. Dr. Monique den Boer is research group leader at the Máxima and has been researching pediatric cancer for 30 years, specializing in B-ALL. She says: 'If we understand why the treatment works in some children and not in others, we can come up with solutions to adjust the therapy. So that we can make immunotherapy more effective for more children.'
Bone marrow environment on a plate
Leukemia cells, like other cancer cells, do everything they can to protect themselves from immune cells. They modify the bone marrow environment in such a way that immune cells, and thus CAR T cells, cannot simply do their work there. Den Boer: 'To investigate this defense mechanism, I was looking for a research model that imitates the natural situation as closely as possible: a bone marrow environment on a so-called microtiter plate. This turned out not to exist yet.'
Den Boer approached the Dutch biotech company MIMETAS and asked if they could help with their knowledge of making 3D disease models. Thanks to previous research into the composition of bone marrow, Den Boer's team already knew a lot about what the environment should look like. 'Together with the scientists at MIMETAS, we are now working on converting this knowledge into an applicable research model, an organ-on-a-chip platform on a microtiter plate. With this we can examine live under the microscope the 'journey' of immune cells into the bone marrow environment.'
Mapping interactions
Den Boer wants to use the new research model to map the interactions between leukemia cells and cells that support immune cells in the bone marrow.
Immune cells, and thus CAR T cells, receive signals to travel from the blood to the bone marrow. Leukemia cells can affect that journey, causing fewer or different immune cells to arrive in the bone marrow. If immune cells do arrive in the bone marrow, leukemia cells have created another obstacle. The function of immune cells is reduced because supporting cells have been manipulated by leukemia cells. During the interaction between a supporting cell and a leukemia cell, specific substances are released that can be measured with the new research model. With the insights from the interaction process, ways can then be found to ensure that targeted CAR T cells still attack leukemia cells.
Collaboration
With this public-private partnership, knowledge, expertise and production capabilities are coming together. This will allow future researchers worldwide to make use of this research model. For example, scientists at the Princess Máxima Center and MIMETAS are working together to accelerate research into the interaction between leukemia and the immune system. This will make the development of better immunotherapies possible, which will ultimately cure more children and adults with an optimal quality of life.
The collaboration project was co-funded by use of PPP allowance granted by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships.