Immunotherapies have shown little efficacy in brain cancers due to their inability to cross the blood-brain barrier. Now, however, researchers have developed a new nanotechnology approach that allowed immune checkpoint inhibitors to enter the brains of mice with glioblastoma.
The approach increased the amount of immune cells reaching the tumor and improved the survival of the mice, compared with those receiving common immune checkpoint inhibitors, a study found.
The study was published in Nature Communications, titled “Blood–brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy.”
Cancer immunotherapies work by activating the body’s immune system to kill cancer cells. While these therapies have shown exciting results in some kinds of cancer, they haven’t performed any better than standard of care in clinical trials of brain tumors.
One of the reasons for this is the extra layers of protection the brain has that other parts of the body don’t. The blood-brain barrier (BBB) strictly limits what can get into the brain. This can help keep toxins and other dangerous stuff from getting into the delicate brain tissue — but it can keep out medicines like immunotherapies, too.
“Drug delivery is the major obstacle for the treatment of central nervous system diseases, including brain conditions,” Julia Ljubimova, MD, PhD, a professor at Cedars-Sinai and the study’s co-author, said in a press release.
In the new study, researchers sought to overcome this obstacle using nanotechnology, which is the study and application of extremely small things. One nanometer is a billionth of a meter.
They used checkpoint inhibitors — antibodies that block signals — that cancer cells can exploit to help them escape the immune system. In this case, the researchers specifically targeted PD-1 and CTLA-4 proteins. The antibodies were combined with other molecules, including another antibody specific to the mouse transferrin receptor, which can help in crossing the BBB. These were used together to develop nanoscale immunoconjugates (NICs).
Then, the researchers tested these NICs in a mouse model of glioblastoma, the most common kind of brain tumor.
The researchers confirmed that unmodified checkpoint inhibitors could not get into the mice’s brains. As such, they did not improve survival or induce an anti-tumor immune response.
In contrast, the NICs did get into the brains of the mice. Those tumors had higher levels of tumor-killing immune cells — including CD8+ T cells and pro-inflammatory macrophages — and fewer cells that dampen immune responses, such as T regulatory cells. The findings indicate that the treatment did activate an anti-tumor immune response.
Indeed, the NIC-treated mice lived significantly longer than mice treated with a sham or with unmodified checkpoint inhibitors.
The researchers noted that the NICs themselves were actually fairly toxic — so much so that, in initial experiments, nearly all of the mice died from runaway inflammation induced by the treatment. While the NICs are supposed to induce inflammation — that’s what kills the cancer — it’s a double-edged sword because inflammation also can damage healthy parts of the body.
By giving the mice anti-inflammatory medicine, the researchers found they could prevent this toxic effect in 100% of the animals. The anti-inflammatory medications — specifically a combination of triprolidine, an antihistamine, and CV6209, a platelet activating factor antagonist — were given prior to treatment with the NICs.
“This study showed a promising and exciting outcome,” Ljubimova said. “Current clinically proven methods of brain cancer immunotherapy do not ensure that therapeutic drugs cross the blood-brain barrier. Although our findings were not made in humans, they bring us closer to developing a treatment that might effectively attack brain tumors with systematic drug administration.”
“The horizon for treatment of brain cancer is getting clearer,” Ljubimova added. “We hope that by delivering multifunctional new-generation drugs through the blood-brain barrier, we can explore new therapies for many neurological conditions.”
