Cell Therapy Takes Aim At Deadly Brain Tumours In Two Clinical Trials

The deadliest form of brain cancer, it rapidly spreads through the brain with limited treatment options. Rounds of chemotherapy temporarily kept the aggressive tumors at bay. This month, two studies genetically engineered the body’s own immune cells to hunt down and wipe out glioblastoma brain tumors.

Therapies using these CAR T cells have been revolutionary in tackling previously untreatable blood cancers, such as leukemia. CAR T therapies have always struggled to battle solid tumors. The cancerous cells form connections with neurons, rewiring neural networks to progressively change how the brain functions and eventually robbing it of cognitive function.

This also makes it nearly impossible to surgically remove the tumors without harming the brain. One, led by Dr. Bryan Choi at Massachusetts General Hospital, found a single infusion of CAR T cells shrank the tumors in three people with recurrent glioblastoma.

Another from the University of Pennsylvania Perelman School of Medicine used a different CAR T formulation to similarly reduce the size of brain tumors in six participants. The tumors reoccurred in several people after six months.

“It lends credence to the potential power of CAR T cells to make a difference in solid tumors, especially the brain,” he told Nature. Our body’s immune system is constantly scouting for them, but the cells rapidly mutate to escape surveillance.

T cells are one of the main immune cell types keeping an eye out for cancer. These gene-edited T cells, used in CAR T therapies, can better hunt down cancerous blood cells.

Physicians isolate a person’s T cells and genetically add extra protein “Hooks” on their surfaces to help them better locate cancer cells. Like all cells, cancerous ones have many protein “Beacons” dotted along their exteriors, some specific to each cancer. After re-infusing the boosted cells back into the body, they can now more effectively seek and destroy cancerous cells.

Unlike leukemia, solid tumors are often made up of a mix of cells, each with a different antigen fingerprint. Reprogramming T cells to target just one antigen often means they miss other cancerous cells, lowering the efficacy of the treatment.

“The challenge with GBM and other solid tumors is tumor heterogeneity, meaning not all cells within a GBM tumor are the same or have the same antigen that a CAR T cell is engineered to attack,” Dr. Stephen Bagley, who led the University of Pennsylvania clinical trial, said in a press release.

Why not add an extra “Hook” to CAR T cells?

As a workaround, the team added an “Engager” protein to tether T cells to their target. In three participants, a single infusion directly into the brain decreased the size of their tumors in a few days.

In one person, a 72-year-old man, the treatment slashed his brain tumor by over 60 percent and lasted more than six months.

The Penn Medicine team also targeted EGFR. In addition, their CAR T cell recipe grabbed onto another protein that’s estimated to mark over 75 percent of glioblastomas.

In the 48 hours after a direct infusion into the brain, the tumors shrank in all six participants, with the effects lasting at least two months in some.

“We are energized by these results, and are eager to continue our trial, which will give us a better understanding of how this dual-target CAR T cell therapy affects a wider range of individuals with recurrent GBM ,” lead study author Dr. Donald O’Rourke said in the press release.

Unlike previous CAR T therapies, which are infused into the bloodstream, both studies require direct injection into the brain.

While potentially more effective because the engineered cells have direct contact with their target, brain surgery is never ideal.

The Penn Medicine team will also map the CAR T cells’ infiltration of brain tumors over time.

The dual targeting method could make it more difficult for cancer cells to evolve resistance to the therapy.

By better understanding these interactions, it’s possible researchers can build better CAR T formulations for glioblastoma and other solid tumors.

For deadly brain tumors, the studies offer a ray of hope.