Mode-of-action of T-cell immunotherapies in focus

26 Jul 2022
Mode-of-action of T-cell immunotherapies in focus

A new 3D imaging technique brings the working mode of T-cell immunotherapies into live view.

T-cell immunotherapy is already leading to promising results in some children with leukaemia.

Researchers plan to use the new imaging technique to improve T-cell therapies for solid tumours.

T-cell therapies, such as CAR-T cells, are a promising type of immunotherapy that is already showing results in treating children with leukaemia.

These kind of therapies use the own immune system.

T-cells, a type of white blood cell, which have been modified in the lab are administered and subsequently attack the tumour in a targeted manner.

Effective T-cell therapies are also being sought for solid tumours, such as neuroblastoma, sarcoma and kidney tumours.

However, to improve their clinical efficacy, we need to better understand the solid tumour-targeting behavior of T-cells.

That’s why the lab of Dr Anne Rios, specialised in 3D imaging at the Princess Máxima Center and Oncode investigator, teamed up with Dr Zsolt Sebestyén and Prof Dr Jürgen Kuball, T-cell therapy experts and group leaders at UMC Utrecht, and the group of Prof Dr Hans Clevers, organoid specialist and visiting researcher at the Máxima and the Hubrecht Institute.

The results of this collaborative research endeavour were published on monday in the leading journal Nature Biotechnology.

Lead authors of the publication dr Florijn Dekkers and dr Maria Alieva from the Rios group developed an imaging and analysis technology, BEHAV3D, that allows to analyse the interaction between T-cell therapies and solid mini tumours, also known as tumour organoids, live and three-dimensionally.

Florijn Dekkers: ‘Unique about this approach is that we are looking at cell therapy efficacy by studying the behaviour of the T-cells. In total, we studied the behaviour of over 150,000 engineered T cells. This revealed a huge variety in behaviour, like very potent behaviours, such as killing of multiple tumour cells in sequence, but also ineffective behaviours, with cells just sitting around and doing nothing. This suggested to us that there is room to improve clinical efficacy by promoting the most potent tumour-targeting behaviours.'

Maria Alieva: 'To be able to stir T-cell therapies towards their most effective behaviours, we need to know the underlying mechanisms that dictate this behaviour. Therefore, I developed a method that for the first time links the behaviour of the cell to the genes that cause this behaviour. With it, we were able to identify the specific gene signature of highly potent T cells that are able to kill many tumour cells in a row. Thanks to BEHAV3D and the use of mini-tumours grown from tumour tissue of children and adults, we can now gather a wealth of fundamental knowledge about the behaviour and ability of T cells to target solid tumours.’

Dr Anne Rios: ’We initially looked at the behaviour of so-called TEG cells, a highly promising therapy based on T-cells that are activated once they notice metabolism changes in tumour cells, developed in the lab of our collaborators; Zsolt Sebestyén and Jürgen Kuball. However, we were able to apply BEHAV3D to different kinds of T cell therapies, as well as cancer subtypes. Therefore, we believe that this platform can be very useful for further improving the targeted attack on solid tumours by the various T-cell therapies currently under development.’

Article: Uncovering the mode of action of engineered T cells in patient cancer organoids

Source: Princess Máxima Center for Pedriatic Oncology