Scientists who devised an immunotherapy that can cross the blood-brain barrier in mice hope that the findings may one day translate to humans.
The researchers believe that the new treatment could be the key to improving survival in people with glioblastoma, the most common and aggressive type of brain cancer.
A recent Nature Communications paper describes how they combined advances in nanotechnology and immunotherapy to deliver checkpoint inhibitors across the blood-brain barrier.
Checkpoint inhibitors are drugs that help the immune system fight cancer. In the new immunotherapy, the drugs can remove a mechanism that enables the brain tumor to withstand attack from cancer-killing cells.
The blood-brain barrier is a unique feature of the vessels that supply blood to the brain and the rest of the central nervous system. The barrier stops potentially harmful toxins and pathogens from entering brain tissue from the bloodstream.
To date, promising types of immunotherapy that have passed clinical trials have not been very successful at crossing the blood-brain barrier.
“Although our findings were not made in humans,” says senior study author Julia Y. Ljubimova, a professor of neurosurgery and biomedical sciences at Cedars-Sinai Medical Center in Los Angeles, CA, “they bring us closer to developing a treatment that might effectively attack brain tumors with [systemic] drug administration.”
Using drugs that can treat the brain systemically — that is, by using the bloodstream to deliver them — would be an advantage over treatments that only work when doctors inject them directly into brain tissue.
The new study is also the first to describe an immunotherapy that can stimulate immune systems both throughout the body and local to the tumor in mice.
An aggressive brain cancer
Although they only represent a small percentage of cancer cases, brain cancers account for a disproportionate number of deaths.
According to the National Cancer Institute, which is one of the National Institutes of Health (NIH), an estimated 23,820 people in the United States will find out that they have brain cancer in 2019, and 17,760 will die of the disease in this same year.
These figures show that while brain cancer will only account for 1.4% of cancer cases, it will be responsible for more than double this percentage of cancer deaths (2.9%) in the U.S. in 2019.
Between 2009 and 2015, fewer than one-third of people with brain cancer in the U.S. survived 5 years or more following diagnosis.
About 15% of primary brain tumors are glioblastomas.
Glioblastomas are particularly aggressive and fast growing because a large number of their cells are replicating and dividing at any given time.
These tumors readily invade neighboring regions of the brain.
Removing the shield against immune attack
One of the features that make brain tumors aggressive is their ability to suppress attack from anticancer cells in the local immune system.
Prof. Ljubimova explains that these tumors use immune cells, such as special macrophages and T regulatory cells, as shields against anticancer cells.
So, she and her colleagues decided to pursue a type of immunotherapy that uses checkpoint inhibitors to switch off the macrophages and T regulatory cells and thereby activate the cancer-killing cells.
They developed a nano-immunotherapy that can carry checkpoint inhibitors across the blood-brain barrier. The transporter is a small protein, or peptide, that attaches to the drug by means of a biodegradable polymer.
Without the protection of their shielding cells, the tumor cells are vulnerable to attack by lymphocytes and microglial cells that can eliminate cancer cells.
“The checkpoint inhibitors can then block the [T regulatory cells] and macrophages, allowing the local immune cells to get activated and do their job — fight the tumor,” Prof. Ljubimova explains.
The new immunotherapy has to undergo further tests before it is ready for human trials.
“We hope that by delivering multifunctional new-generation drugs through the blood-brain barrier, we can explore new therapies for many neurological conditions.”
Julia Y. Ljubimova