One by one, our immune cells march to the frontlines when it gets a whiff of an invader. They are ready to fight and protect our systems from what is about to attack. But what if we can recruit these specialized soldiers for glioblastoma — a malignant brain cancer that struggles to have enough immune cells armed and ready?
To solve this, researchers have harnessed the capabilities of an active virus and genetically modified it to selectively infect and destroy brain cancer cells. As published in Cell, the novel creation builds an army of immune cells that penetrate and persist deep within brain tumors.
“Even though glioblastoma is an aggressive brain cancer, it does not trigger an aggressive immune response,” says co-senior author Kai Wucherpfennig, MD, PhD, chair of Cancer Immunology and Virology at Dana-Farber. “We call this a ‘cold tumor,’ which makes it difficult to treat.”
Building a strong defense
While many physician-scientists have attempted to treat glioblastoma, it remains one of the most difficult human cancer types to manage.
‘Cold tumors’ are associated with a worse prognosis due to what Wucherpfennig describes as “poor infiltration” of the T cells. These T cells are specialized immune cells crucial for targeting and attacking cancerous cells.
“The lack of cancer-fighting immune cells makes glioblastoma resistant to many therapies, so not many patients have benefited from immunotherapies that have transformed patient care in the same way as other cancer types,” Wucherpfennig says.
The immune system is designed to detect intracellular pathogens like viruses. But the challenge is that tumors are not as immunogenic as viruses. They have immunostimulatory signals and many immunosuppressive signals that allow them to be secret attackers on the body.
“Everyone working on glioblastoma now is thinking about how to engage the immune system,” Wucherpfennig says. “This disease is also challenging because it has a shape-shifting capacity that does not respond well to targeted immunotherapies.”
To give glioblastoma patients a boost to fight this cancer, Wucherpfennig and the research team led a recent clinical trial that increases the amount of critical cancer-fighting immune cells that target cancer in the brain. By designing an oncolytic virus, it can identify this ‘cold tumor,’ alert the immune system, and make it a ‘hot tumor.’ This forces the immune system to bring in strong defense and attack unwanted cancer cells.
“We needed a new approach for this very real human problem, so we looked at this complex problem from a new angle,” Wucherpfennig adds.
Making a copy-cat killer
The oncolytic, or cancer-destroying, virus used in the team’s clinical trial – developed by E. Antonio Chiocca, MD, PhD, surgical director of the Center for Neuro-Oncology at Dana-Farber – is made from a herpes simplex virus (HSV). This virus was genetically altered to help deliver the treatment safely.
“These immune cells are targeting the tumor in patients with favorable responses,” says Chiocca. “This expands on our earlier studies where we associated encouraging survival with changes in the number of immune cells infiltrating the tumor.”
Patients are not infected with HSV – rather, the therapy leverages the virus’s natural means of transmission to only make copies of itself in glioblastoma cells and not normal healthy cells.
The virus-based therapy works by spreading to a glioblastoma cell and killing it before making a copy of itself, which spreads to another glioblastoma cell. The cells with the virus can trigger an immune response. The study also found that the treatment successfully introduced more immune T cells into patients’ tumors. This allows more white blood cells to attack cancer over a longer period of time. The therapy not only increased patient survival after treatment but expanded pre-existing T cells in the brain.
In the early phase trial of patients with recurrent glioblastoma, the oncolytic virus treatment extended their survival compared to historically reported survival, especially among those with pre-existing viral antibodies.
“We show that increased infiltration of T cells that are attacking tumor cells translates into a therapeutic benefit for patients with glioblastoma,” says Chiocca, who is also a co-senior author of the study. “Our findings could have important implications for a cancer whose standard of care hasn’t changed for 20 years.”
The team has already begun their next steps for a follow-up clinical trial. Wucherpfennig says the goal is to add a therapeutic antibody — which targets specific cells with less side effects — to the regimen. This will further enhance the immune response initiated by the virus.
“We want to change the trajectory of this disease,” Wucherpfennig says.
Very informative read!
Keep Pushin for a cure!