Among the hurdles to treating brain cancer is the fact that glioblastoma multiforme (GBM) cells burrow into brain tissue, which makes them difficult to wipe out with conventional treatments like surgery, radiation and chemotherapy. Moreover, they’re “cold” tumors, meaning they don’t contain immune cells that can easily be targeted with immunotherapies.
Now, scientists from City of Hope have found a way to warm up GBM, potentially unveiling a new therapeutic strategy. In a study published Nov. 10 in Nature, the researchers described how they packed two different therapies into a single oncolytic virus—a virus that is used to destroy cancer cells—to hit GBM from multiple angles. The survival time doubled from around 18 days to 40 in half the mice that received the treatment.
“There’s real urgency to come up with novel ways to treat glioblastoma, because decades and decades of chemo, surgery and radiation have failed to move the needle on this disease,” Michael Caligiuri, MD, president of the City of Hope National Medical Center and co-corresponding author, told Fierce Biotech Research. “Looking at immunology, virology and immunotherapy is a very important route to go."
Oncolytic viruses have grown in popularity in recent years as weapons against multiple different cancer types. In 2015, Amgen’s T-Vec became the first oncolytic virus to receive FDA approval—in this case, for melanoma. Other prospects are in clinical trials, including some for pediatric brain cancer.
Like in T-Vec, the City of Hope researchers used a modified herpes simplex 1 virus. Herpes viruses are especially useful against brain cancer because they’re primed to attack the nervous system, Dr. Caligiuri explained.
Oncolytic viruses by themselves kill tumor cells with a one-two punch. The term “oncolytic” stems from their ability to infiltrate the cell and replicate, causing it to explode. On top of that, their presence in the cell triggers the body’s own immune cells to attack the tumor site, potentially leading to long-term remission.
Dr. Caligiuri and fellow corresponding author Jianhua Yu, Ph.D., wanted to see if they could enhance the virus’ efficacy by adding in other anti-tumor tactics. One they were especially eager to try was the release of chemokines, small proteins that healthy cells release to attract T cells, natural killer cells and macrophages as part of the natural immune response. GBM and other “cold” tumors are infamous for silencing chemokines, allowing them to go undetected by the immune system.
"We look to the tumor to tell us what it's doing," Dr. Caligiuri explained. "If chemokines cause trafficking of immune cells to the site of inflammation, Mother Nature is shutting them off because she doesn't want those cells to go there."
The Caligiuri and Yu labs had other ideas, too. GBM cells frequently display mutations in the genes for the epidermal growth factor receptor, or EGFR. EGFR mutations disrupt processes downstream that ultimately keep cancer cells growing. Antibodies against EGFR, such as Eli Lilly’s cetuximab, sold as Erbitux, have been used in glioblastoma with some success.
Looking to outsmart Mother Nature, the City of Hope team packaged CCL5 and cetuximab into a bispecific fusion protein, or type of protein that can bind to two different molecules on two different cells at the same time. They then inserted genes expressing the protein into the backbone of the oncolytic virus and injected it directly into the tumor cells on one side, or hemisphere, of the mouse models’ brains.
Though they had expected the virus to work, they were surprised at just how well it did. Not only did host immune cells attack the tumor on the side of the injection, but they also attacked it in the untreated hemisphere, too—a clear sign that the tumor had been transformed from "cold" to "hot". And cetuximab had an impact on multiple types of EGFR. This was key, Dr. Caligiuri noted, as switching from one type of EGFR to another is a common tactic tumors use to resist treatment.
Overall, half the mice that received the treatment lived for an average of 40 days. Those who received the virus alone lived for 20, while untreated controls only made it to day 18.
The scientists expect that their therapy will be even more effective when combined with others. This is the case for other oncolytic viruses, too. T-vec, for instance, is often used with checkpoint inhibitors.
The viral platform itself can also be customized. Cetuximab and the CCL5 cytokine can be swapped out for other antibodies, fusion proteins or cytokines, the scientists wrote in their paper.
First, though, they want to see how their current formulation performs against GBM in humans. The team is already in the midst of a clinical trial to evaluate the safety and efficacy of the virus by itself. Next, they’ll gear up to submit an application to the FDA to enter clinical trials for the souped-up virus.