Major advances in immunotherapy have revolutionizing the way oncologists treat a variety of cancers, however, its success in patients with brain cancer has been extremely limited. One obstacle has been the inability for immunotherapy agents to breach the blood-brain barrier. But now there has been a promising development that has opened up a new pathway to drug delivery.
According to study results published in Science Translational Medicine, human viruses could be used to sneak immunotherapy agents through the barrier and deliver it to brain tumors.
In particular, immune checkpoint inhibitors that target PD-1 have led the forefront, but evidence does suggest that tumor response survival outcomes are determined by PD-L1 expression in tumors.
In a collaboration led by the University of Leeds and the Institute of Cancer Research (ICR) in London, researchers hypothesized that if they preconditioned the tumor immune microenvironment using targeted, virus-mediated interferon stimulation, then it could up-regulate PD-L1 expression in brain tumors. This would, in turn, increase cytotoxic T cell infiltration and improve the efficacy of subsequent checkpoint blockade therapy.
“Our immune systems aren't very good at 'seeing' cancers, partly because cancer cells look like our body's own cells, and partly because cancers are good at telling immune cells to turn a blind eye,” lead author Alan Melcher, professor at ICR, said in a press release. “But the immune system is very good at seeing viruses.”
In particular, oncolytic viruses have represented a promising form of immunotherapy for cancer treatment. To treat brain tumors, most studies have administered these viruses using direct intralesional injection because it is believed that intravenous administration does not effectively deliver the virus to the site in the brain.
In a window-of-opportunity clinical study – partly funded by Cancer Research UK – the researchers injected nine patients that had either high grade gliomas or brain metastases with a virus that seeks out cancer cells, called oncolytic human Orthoreovirus.
The patients then underwent surgery to have their tumors removed, and the researchers analyzed each one.
Ultimately, they found that the Orthoreovirus did in fact reach the target cancer cells, leading to infection of the cells, which increased cytotoxic T cell tumor infiltration. In addition, the researchers demonstrated the virus up-regulated PD-1 and PD-L1 gene expression.
This study was the first to show a treatment virus pass through the blood-brain barrier.
Not only is this an exciting new option, but because the virus was administered into the patients’ bloodstream, it could also be an easier treatment option.
The researchers highlighted that these results support the development of combined systemic immunovirotherapy strategies for the treatment of both primary and secondary tumors in the brain.
“They have proven that the virus penetrates the tumor and does what it is supposed to do: wake up the immune system to see the cancer,” Colin Watts, a brain tumor expert at Cancer Research UK, said in the release. “Now clinical trials are seeing if that wake-up call is sufficient to kill the cancer cells and help to improve survival of patients with brain tumors.”