Improved CAR-T therapy

C&I Issue 11, 2020

Anthony King

Novel approved cancer therapy CAR-T involves taking immune cells out of a patient, altering them to target a protein called CD19, and reinfusing them into the patient. CD19 is a distinguishing marker of some blood cancers.

The CAR-T cells will kill healthy antibody-producing B cells, but also leukaemia cells with CD19 on their surface. The results have been outstanding. In a recent study of over 100 patients with B cell lymphoma resistant to all other available therapies, 40% showed no disease 15 months after treatment with the CAR-T cells (New Engl. J. Med., 2017, 377, 2531).

Unfortunately, 64% of these patients experienced neurotoxicity. CAR-T side effects include seizures, confusion and even brain swelling hours after the cell therapy is infused. ‘It wasn’t really well understood how that happened and what was the mechanism,’ says Denis Migliorini, neuro-oncologist at the University of Pennsylvania and now at the University of Geneva in Switzerland.

His research showed that ‘mural cells’ in the brain that surround blood vessels – crucial for the protection of the blood brain barrier – express CD19. The same protein targeted by the cancer therapy.

Migliorini and his colleagues looked at single cell RNA sequencing datasets from brain cells and immuno-histochemistry stains in human brain samples (Cell, doi: 10.1016/j.cell.2020.08.022). ‘We observed CD19 expression on mural cells within the human brain,’ says Migliorini, explaining that these cells are ‘like a wall protecting the brain from aggressions from bacteria, viruses, compounds, and basically protect the brain.’ Because they are studded with CD19, this suggests they will likely become targets themselves for the CAR-T cells.

The researchers believe that their discovery opens up two possibilities to reduce CAR-T therapy side effects. First, it might be possible to develop tools to predict which cancer patients are prone to neurotoxic side effects.

‘The second would be to further engineer CD19 CARS,’ says Migliorini. ‘This would be [transformed into] a T cell endowed with two different CAR molecules that would be specific for either leukaemic cells or mural cells in the brain,’ he explains. ‘These cells will still be able to kill leukaemic cells, but whenever they encounter a mural cell, T cell activation would be shut down.’

‘By having a better understanding of the distribution of molecules that CAR T cells recognise, we are in a better position to be able to design CAR T cells, which perhaps only recognise the high levels of CD19 present on leukaemia cells, rather than the levels present on these blood-vessel lining cells in the brain.’ says Sara Ghorashian, CAR-T scientist at UCL Great Ormond Street Institute of Child Health, London.


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