Selectively adherent T cells target brain cancer

Modified T cells that selectively adhere to brain tumour blood vessels could lead to improved cancer immunotherapy.

T cells need to adhere to molecules on the inner lining of blood vessels, called the endothelium, in order to penetrate the blood–brain barrier and attack tumour cells in brain tissue. But some brain cancers cleverly evade this immune mechanism by reducing the expression of vascular adhesion molecules.

Researchers at the Baylor College of Medicine in the USA, the Children's Cancer Hospital in Egypt, and international colleagues re-engineered T cell receptors to sensitize them to lower levels of adhesion molecules.

Adhesion molecules are expressed in two waves. In the first wave, a molecule, called ALCAM, engages with its receptor on the T cells. In the second wave, two additional molecules, called ICAM1 and VCAM1, mediate the adhesion. The team found that brain cancers reduce the expression of the second wave molecules, leading to insufficient T cell adhesion. ALCAM expression, on the other hand, is increased because it is needed for cancer metastasis.

The team engineered the T cell molecule that triggers their attachment to ALCAM. This also increased their sensitivity to ICAM1. 

When the T cells were injected in the veins of mice with brain tumours, they specifically infiltrated and attacked the cancer cells rather than healthy tissue. Further testing is required before this method can be used clinically.

“Understanding how cancer cells influence the endothelium to divert T cells from the tumour, and engineering a homing system to overcome this impasse, provides a versatile platform for targeted delivery of therapeutic T cells to brain cancers,” says Nabil Ahmed of Baylor College of Medicine, who led the study.

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