Engineered T cells find a way into the brain to fight glioblastoma
Immunotherapy works amazingly well on some tumours, less on others. Brain cancers are among the hardest, because the blood-brain barrier physically prevents circulating immune cells from reaching the tumour. What is the point in boosting the immune response against cancer, if our soldiers cannot arrive on the spot? Finding a way into the brain is the biggest challenge. In a paper published on Nature, researchers engineered T cells, triggering their infiltration in a brain cancer called glioblastoma.
The blood brain barrier is there for a reason: it actually protects the brain, keeping outside immune cells that can potentially cause life-threatening brain inflammation. In pathologies like encephalitis, the barrier has leaks and T cells can go through, triggering inflammatory reactions in the brain tissues.
Nevertheless, in some cases we might actually want T cells to reach the brain, for example to target a tumour. Glioblastoma is an aggressive brain cancer, particularly resistant to immunotherapy. Unfortunately, as opposed to encephalitis, the blood-brain barrier is impassable and our stimulated T cells remain outside…unless we help them!
How does the migration occur?
How does a lymphocyte decide that it is time to abandon the blood circulation to migrate in an organ or tissues? It does not actually decide: it gets “stuck”. The endothelial cells lining the blood vessels can become very sticky, expressing adhesion molecules that capture the lymphocytes from the bloodstream. These “adhesives” are called ALCAM, ICAM-1 and VCAM-1 and it is no coincidence that they are expressed at higher than normal levels in encephalitis.
All these three molecules are necessary for T cell migration. ALCAM is the first to interact with lymphocytes, halting their progress through the blood vessel. The captured lymphocytes subsequently bind to ICAM-1 and VCAM-1 and, when the binding interactions exceed a certain threshold, the T cells can migrate across the vessel wall.
What happens in glioblastoma?
In glioblastoma the mechanism does not work, because the endothelial cells lining the brain vasculature express only little or no ICAM-1 and VCAM-1. If T cells cannot adhere properly to the vessel wall, they will never be able to reach the brain. Perhaps, we managed to get around the obstacle. In fact, researchers discovered that, despite lacking ICAM-1 and VCAM-1, endothelial cells in glioblastoma express high levels of ALCAM. We said that the three of them were all necessary, but maybe, using a little trick, we can do without the other two.
Engineered T cells find a way into glioblastoma
If the other two are missing, ALCAM must do the entire job. Researchers genetically engineered T cells with a synthetic molecule that bind ALCAM more firmly than the “natural” ligand, enhancing the adhesiveness between endothelial cells and T cells up to the threshold that enables the migration.
And this is not the end of it! T cells must not only enter the brain, but also reach the tumour cells. In fact, the engineered T cells bear not only the ALCAM synthetic ligand, but also a receptor specific for a molecule expressed on the tumour cells (the antigen HER2). In a mouse model, this strategy allowed successful infiltration of engineered T cells in glioblastoma.
Once there, T cells will need to overcome many other obstacles, like the immune suppression in the tumour microenvironment. Reaching the target may not be the end of the story….but at least it is a beginning!
Samaha, H., et al. (2018). A homing system targets therapeutic T cells to brain cancer. Nature 561, 331-337