Modified T Cells Home to Brain Tumors

Brain cancers, such as glioblastoma and medulloblastoma, are notoriously impervious to T cells, and researchers may now have figured out a reason why: Tumor endothelial cells express high levels of an adhesion molecule that initially links to T cells, but low levels of two other adhesion molecules responsible for fully capturing T cells from the bloodstream and pulling them into the brain. The researchers used this knowledge to reengineer T cells to better penetrate tumors, creating a “homing system” that could improve CAR T-cell therapies for brain cancer.

Nabil Ahmed, MD, of Baylor College of Medicine in Houston, TX, the study's senior author, notes that although CAR T-cell therapies can successfully treat leukemias, they face major limitations in treating solid tumors. “One of these limitations is the homing of T cells to the tumor,” he says. “These cells are able to make it into the tumor in extremely small numbers.”

Ahmed's interest in T-cell homing was sparked by multiple sclerosis (MS), a disease in which the opposite occurs: Too many T cells infiltrate the central nervous system (CNS), creating problematic plaques. Previous research established that in MS there is overexpression of the first wave adhesion molecule ALCAM, which initially engages T cells via their CD6 receptor. Then, a second wave of the adhesion molecules ICAM1 and VCAM1, which are also overexpressed, facilitates the movement of T cells into the CNS. Ahmed and his team decided to investigate that mechanism in glioblastoma and medulloblastoma to see how it differs.

The researchers determined that, as in MS, brain cancer endothelial cells overexpress ALCAM. However, the cells express low levels of ICAM1 and do not express VCAM1, and are thus unable to capture T cells from the bloodstream. “We think that this is a strategy that is employed by the tumor to escape immune recognition, by diverting immune cells that could actually engage the tumor,” explains Heba Samaha of Children's Cancer Hospital of Egypt-57357 in Cairo, the lead author on the study.

The researchers used genetic engineering to enhance the homing part of CD6, the receptor on the surface of T cells that binds to ALCAM. They found that when the modified CD6 receptor anchored T cells to ALCAM, it triggered a series of molecular events that culminated in the unfolding of LFA1, a receptor on T cells that binds to ICAM1. Thus, T cells could engage with low levels of ICAM1 and enter cancer cells. “You've replenished or reconstituted the deficient second wave that cancer is trying to eliminate, so this way you're fighting the escape mechanism,” Ahmed says.

Finally, the researchers equipped the engineered T cells with HER2 CAR molecules, and tested the CAR-equipped homing system on human glioblastoma tumors transplanted into mice. They found that the system improved T-cell homing to the tumor, yielded better tumor shrinkage, and extended survival in the mice compared with HER2 CAR T cells alone, and normal T cells.

Ahmed and his team are now optimizing their homing system, and they plan to eventually test it in the clinic.

Peter Fecci, MD, PhD, of Duke University in Durham, NC, who was not involved in the study, says that it successfully addresses a major obstacle to the success of immunotherapies in brain cancers: getting more T cells into the tumors. “What they've done is find a very clever way to help combat that problem,” he says. However, he notes that increasing T-cell penetration into tumors is “just one part of it, because even once you get T cells there, the tumors do a great job of shutting them down.”

“I think that we probably have to make multiple changes to T cells, reengineer them with a lot of armaments at their behest that can make them work, and avoid the kind of sidestepping that the tumor does,” he says. –Catherine Caruso