Chimeric antigen receptor T cell (CAR T) therapies have proved remarkably effective against leukemia and lymphoma, but for these therapies to target other types of cancer, there are still hurdles to overcome. Brain cancer is particularly challenging for immunotherapies due to the blood-brain barrier. This semi-permeable barrier tightly regulates the homeostasis of the central nervous system and large compounds, including immune cells, are unable to cross. The blood brain barrier thus beneficially protects the brain from inflammation, but, as a result, it also blocks T cell immunotherapies from reaching brain tumors.
In certain disease conditions, T cells can migrate across the blood-brain barrier. This can be accomplished when T cells bind to endothelial cells that line the bloodstream. First, T cells engage with ALCAM, an adhesion molecule on the surface of the endothelium. Then, subsequent binding of ICAM-1 and VCAM-1 allows T cells to reach a critical adhesion threshold, squeeze between endothelial cells, exit the bloodstream, and enter the brain.
Glioblastoma is an aggressive type of cancer that can occur in the brain or spinal cord. In glioblastoma, endothelial cells produce little or no ICAM-1 and VCAM-1, but do overexpress ALCAM. Researchers at the Baylor College of Medicine reasoned that, by engineering T cells to bind to ALCAM more tightly, they could enhance T cell anchoring in the endothelium to improve T cell passage through the blood-brain barrier and grant immunotherapies access to brain tumors. The authors generated a synthetic ligand for ALCAM, termed homing-system CD6 (HS–CD6), such that individual ligands interacted with one another to produce a multimeric protein. The multimeric HS-CD6 on T cells enhanced adhesiveness between these cells and ALCAM-expressing endothelial cells and, as predicted, enabled transendothelial migration in in vitro models.
Passing the blood-brain barrier is simply the first hurdle. The T cells in the brain must identify and selectively target the tumor cells. The authors engineered their custom T cells to express an antigen receptor to bind to human epidermal growth factor receptor 2 (HER2), an antigen produced by glioblastoma cells. They then introduced these cells into mice with surgically implanted human glioblastomas. T cells that expressed both HS–CD6 and the HER2-specific antigen receptor successfully infiltrated the glioblastomas, leading to complete remission and long-term survival in most of the treated animals.
The article titled “A homing system targets therapeutic T cells to brain cancer” was published in Nature.