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Smart imaging to improve cell therapy

Scientists have expanded their cutting-edge cell imaging tool to visualize how CAR-T and other immunotherapies work in liquid tumors – such as the blood cancer, leukemia – in real time. The work builds on the imaging and analysis platform they developed for solid tumors. By visualizing how cell therapies behave and interact with cancer cells, the scientists aim to better understand and improve how these promising new forms of immunotherapy work.

Immunotherapy is a promising new form of cancer treatment. It harnesses the body’s own defence mechanisms to attack cancer cells. Cell therapies, such as CAR-T cell immunotherapy, are in development for various cancer types. CAR-T is used to treat some children with acute lymphoblastic leukemia (ALL) that has come back after treatment. This therapy has led to a cure for some children, but it doesn’t work for all children with ALL yet.

Immune-tumor interaction

‘To better understand which people with cancer could benefit from cell therapies, it’s essential we learn more about how these engineered immune cells interact with tumor cells,’ says Maria Alieva, guest researcher in the Rios group at the Princess Máxima Center and junior group leader at the Instituto de Investigaciones Biomédicas CSIC-UAM de Madrid. Together with her colleagues in the Rios group, she developed a 3D imaging technique which gives insight into exactly that immune cell-tumor cell interaction – live, and in 3D.

With the imaging pipeline, dubbed BEHAV3D, the scientists were able to pick out those immune cells with more effective tumor killing behaviors. ‘This allowed us to find the immune cells that have the most promise for being developed for therapeutic use,’ explains Alieva. ‘But our imaging tool has much more wide-ranging applications than that. We showed you can use it to study differences in behavior in many different immune cells and forms of cancer. For example, we started looking at breast cancer but we’re now also looking at the aggressive childhood brain tumor DMG.’

Serial killing

The potential of the BEHAV3D imaging platform drew the attention of more colleague scientists who were interested in using it in their own lines of research. This prompted the Rios group to publish their way of working in the journal Nature Protocols last month, making the technology accessible to scientists around the world. Alieva: ‘Importantly, we described how we use BEHAV3D not only to look at solid tumors, but also at liquid tumors. That’s especially relevant since CAR-T cell therapy is increasingly used in children with leukemia. We see notable differences in how T-cells interact with tumor cells in liquid or solid tumors. In blood cancers, we see them moving on from one cell to the next, acting like ‘serial killers’. In solid tumors such as breast and brain cancer on the other hand, the way of serial killing is quite different: the cells strongly hold on to the solid tumor structure and from this point of contact try to reach and kill all the tumour cells. This unique killing mechanism could potentially be exploited in the future to achieve better outcomes of CAR-T therapy in solid tumors, which so far has been less successful compared to blood cancer.’

Different dimension

Dr. Anne Rios, group leader at the Princess Máxima Center and Oncode Investigator, who led the research, says: ‘We believe that cell behavior is an under-studied aspect in cancer. There is an ever increasing knowledge of, for example, which DNA-changes in tumor cells can be targeted with immunotherapy. But this doesn’t fully explain why these treatments work well for one patient and not the other. By visualizing the interactions between tumor and immune cells, our imaging pipeline BEHAV3D offers a different dimension to cancer research, which can offer important clues to improve the effect of cellular therapies.’

Next, the scientists in the Rios group are planning to expand the BEHAV3D imaging pipeline even further, enabling them to look at macrophages, yet another type of immune cell. They are also collaborating with the Den Boer and Nierkens groups to look at a brand new cell therapy developed in the Máxima Center. In this project, the researchers are using the imaging technique to look at how these engineered immune cells interact with ALL cells, with the aim of optimizing them for translation into the clinic.