UCLA researchers found administering a drug that harnesses the body’s immune system to brain cancer patients both before and after surgery could effectively treat recurrent cancer.
In a study published Feb. 11 in Nature Medicine, researchers showed patients who received the immunotherapy drug pembrolizumab before and after surgery lived almost twice as long as patients who only received the drug after surgery. Immunotherapy drugs use the body’s own immune system to attack tumor cells. The study was co-led by Robert Prins, associate professor of neurosurgery and molecular and medical pharmacology, and Timothy Cloughesy, professor of neurology and director of the UCLA Neuro-Oncology Program.
Treatment of glioblastoma, the most aggressive form of brain cancer, typically involves surgery, chemotherapy and radiation treatment. Even if patients undergo all three forms of treatment, those with recurrent glioblastoma have a median survival rate of less than 15 months.
In recent years, researchers have explored using immunotherapy drugs to treat metastatic cancers like melanoma, Prins said. However, glioblastoma has not responded to immunotherapy treatments as well as other types of cancer.
The study, which is the first to observe the effects of also using pembrolizumab before surgery as opposed to just after, offered new and surprising results regarding the effectiveness of the drug in treating glioblastoma, Cloughesy said.
Pembrolizumab works by blocking an immune checkpoint protein called PD-1, which exists on the surface of cells that regulate the body’s immune system and prevent it from attacking the body’s own cells. However, this protein can also prevent T-cells – the body’s immune defense system – from attacking tumors.
In order for the body’s immune system to attack tumor cells, it has to recognize the tumor as a foreign body and develop T-cells that target the specific antigens on the tumor, Cloughesy said.
“When they recognize those, they make these memory T-cells where they can expand those T-cells and kind of develop a small army that will now go against that specific antigen that is on the tumor,” Cloughesy said.
However, the body has checkpoints to prevent the immune system from creating T-cells against itself. When these T-cells begin attacking the tumor and creating inflammation, the body will express PD-1, a protein that interacts with the T-cells to essentially deactivate them, he added.
“Now you have a bunch of soldiers ready to go to work and wage war against the tumor but they’ve been put to sleep, so they’re just kind of sitting there in the field sleeping,” Cloughesy said.
He said this is where the immunotherapy drug becomes useful. The drug unlinks these PD-1 receptors and thus reawakens the T-cells to fight the tumor cells.
In the study, the drug was administered to participants before and after surgery or just after. The study aimed to understand the effect the PD-1 blockade has on tumors, Prins said.
However, the study also showed that the drug unexpectedly increased the life expectancy of patients. Patients in the group administered the drug before and after surgery lived an average of 417 days, compared to an average of 228 days for those who received the drug after surgery.
“When the study was designed, it was really just the main focus to see what happens in the tumor,” said Aaron Mochizuki, co-first author on the study and a fellow in pediatric oncology and hematology at the Ronald Reagan UCLA Medical Center. “At first we didn’t believe it, to be honest.”
Cloughesy added they were not looking to observe a clinical benefit and that he was surprised by the results.
“When we saw there was a clinical benefit my first thought was ‘I don’t believe it, it doesn’t make sense,’” he said.
The researchers hypothesize administering the drug before surgery helps enhance the immune response, as it allows the drug to awaken the T-cells present around the tumor that might otherwise be removed during surgery before they have the chance to wake up, Prins said.
Even when the tumor is removed surgically, microscopic tumor cells are left behind Cloughesy said. By activating T-cells programmed to fight the tumor before they are removed before surgery, the immune system is able to fight the cancer cells that are left after surgery and slow their regrowth.
When the drug is administered only after surgery, many of the T-cells are removed along with the tumor, he said. These T-cells then aren’t present to be awakened by the drugs administered after surgery.
“What we learned was if the patients had T-cells there, then you can enhance their function,” Prins said. “You have to have T-cells … in order for this drug to work.”
These results, although promising, need to be replicated in larger trials to generate more data that could help the treatment gain approval from the Food and Drug Administration, Mochizuki said. He added the researchers hope to expand the group of patients receiving the drug before and after surgery in their next run of the study from 16 patients to around 41.
Mochizuki said the researchers are also planning new studies to explore the effects of combining immunotherapy drugs with other methods of harnessing the body’s immune response. By combining immunotherapy treatments, they hope to bring in more T-cells that will attack cancer cells and would otherwise go unnoticed by the body’s immune system.
Cloughesy said the study’s positive results indicate that immunotherapy drugs could be a viable treatment for glioblastoma. He added if these drugs become more effective in treating glioblastoma, they may eventually be able to treat the cancer by themselves without surgery.
