Common antidepressant boosts engineered virus treatment for brain cancer in mice

Repurposing a common antidepressant drug might help a modified measles virus and immunotherapy better fight an aggressive type of brain cancer. In a small animal study, mice that received the antidepressant alongside the viral therapy showed improved immune responses and longer survival times. The research was published in Molecular Therapy: Oncology.

Glioblastoma is the most common and aggressive type of primary brain tumor in adults. The cancer is notoriously difficult to treat because it creates an environment that suppresses the body’s natural immune defenses. One way the tumor protects itself is by trapping white blood cells, specifically lymphocytes, inside the bone marrow. This prevents the immune cells from traveling through the bloodstream to reach the brain and attack the tumor.

This trapping mechanism involves a receptor on the surface of immune cells called S1P1. Under normal conditions, this receptor acts like a chemical passport, allowing the cells to exit the bone marrow and enter the blood. Brain tumors trigger a process that pulls this receptor inside the cell, essentially confiscating the passport. An enzyme known as GRK-2 is primarily responsible for dragging the S1P1 receptor inward.

A team of researchers from the Mayo Clinic set out to find a way to overcome this immune suppression. The team, led by Evanthia Galanis and including Georgios Stergiopoulos, Susanna Concilio, Kim Viker, Susan Clark, and Steven Robinson, had previously developed an experimental treatment using the measles virus. They engineered a safe version of the virus to specifically infect and kill cancer cells.

To make the virus even more effective, the researchers armed it with a bacterial protein designed to wake up the immune system. They combined this viral therapy with immune checkpoint inhibitors, which are drugs that take the chemical brakes off immune cells so they can attack cancer. They suspected that this combination therapy could be enhanced if they could release the trapped immune cells from the bone marrow.

To achieve this, the researchers looked to paroxetine, a widely available antidepressant. Paroxetine belongs to a class of drugs called selective serotonin reuptake inhibitors, or SSRIs. Previous research had shown that paroxetine also happens to block the GRK-2 enzyme. The researchers hypothesized that administering paroxetine would stop the enzyme from hiding the S1P1 receptor, allowing immune cells to leave the bone marrow and join the fight against the brain tumor.

The researchers first tested the interaction between the virus and the antidepressant on laboratory-grown glioblastoma cells. They applied varying concentrations of paroxetine to human and mouse cancer cells in petri dishes. Very high doses of the drug killed the cancer cells directly, but lower doses similar to what humans safely take did not show a major effect. The tests also confirmed that the antidepressant did not interfere with the virus’s ability to infect and kill the cancer cells.

Next, the team established a baseline for how brain tumors affect the immune system in living animals. They injected mouse glioblastoma cells into the brains of healthy mice. Comparing these tumor-bearing mice to healthy control mice, the researchers analyzed blood and bone marrow samples. The mice with brain tumors had lower numbers of circulating immune cells and fewer S1P1 receptors on the surface of the cells inside their bone marrow.

To see if their proposed treatment could reverse this trapping effect, the researchers treated the tumor-bearing mice with the engineered measles virus and the immune checkpoint inhibitors. Half of this treated group also received daily oral doses of paroxetine. The team extracted bone marrow and blood samples from the mice at multiple intervals to measure the immune response.

Mice receiving the full combination that included the antidepressant exhibited higher levels of the S1P1 receptor on the surface of their bone marrow immune cells. This group also had a higher percentage of immune cells circulating in their bloodstream compared to the mice that received the viral and immunotherapy without paroxetine. Adding the antidepressant without the checkpoint inhibitors did not yield the same sustained increase in circulating cells.

Increasing the number of circulating immune cells is only helpful if those cells are ready to attack the cancer. To check the status of these cells, the researchers measured specific protein markers on the surface of white blood cells collected from the blood, spleen, and thymus. These markers indicate whether an immune cell is active or exhausted.

The mice treated with the engineered virus, checkpoint inhibitors, and paroxetine had more active immune cells throughout their bodies. The immune cells in their blood and organs displayed higher levels of activation markers. They also showed lower levels of exhaustion markers, suggesting that the immune system was sustaining a prolonged attack against the tumor cells.

The researchers then monitored the mice to determine if this heightened immune response extended their lives. They tracked the survival rates of the different treatment groups over several months. Mice that received the engineered virus and immunotherapy without the antidepressant lived longer than untreated mice, with a 40 percent long-term survival rate.

The addition of paroxetine improved those outcomes. The mice receiving the full combination of the virus, immunotherapy, and the antidepressant reached a 65 percent long-term survival rate, meaning they lived past the 60-day mark following tumor implantation. The researchers also tested the surviving mice by exposing them to cancer cells a second time, finding that their immune systems successfully fought off the new tumor cells.

Safety is a primary concern when combining multiple treatments that alter the immune system. The researchers monitored the mice closely for side effects, checking their body weight and looking for signs of neurological damage. They also tested the animals’ blood for elevated levels of inflammatory proteins that might indicate a dangerous immune overreaction. They observed no adverse events, and all mice continued to gain weight at a similar rate regardless of their treatment group.

While the results suggest a potential new way to boost brain cancer treatments, the study is limited by its use of an animal model. The immune systems of mice operate differently than those of humans, and treatments that succeed in rodents often do not translate to human patients. The study also relied on a single specific strain of mouse glioblastoma, which might not represent the biological diversity of human brain tumors.

The drug doses used in the study may also not directly map to safe or effective doses in human cancer patients. Paroxetine’s primary function alters serotonin levels in the brain, and its use in cancer treatment would require strict medical monitoring. Future research will need to determine the optimal dosage and test the combination in other animal models before it can be considered for human clinical trials.

The study, “Repurposing the SSRI paroxetine increases lymphocyte mobilization and improves the efficacy of measles virus-based immunovirotherapy,” was authored by Georgios M. Stergiopoulos, Susanna C. Concilio, Kim B. Viker, Susan M. Clark, Steven I. Robinson, and Evanthia Galanis.