A Mayo Clinic team has repurposed the antidepressant paroxetine to boost a measles virus–based immunovirotherapy for glioblastoma in mice, producing stronger immune responses and longer survival in the study published in Molecular Therapy: Oncology.
The researchers, led by Evanthia Galanis and including Georgios Stergiopoulos, Susanna Concilio, Kim Viker, Susan Clark, and Steven Robinson, aimed to overcome the brain tumour’s suppression of the body’s immune defences. Glioblastoma is the most common and aggressive primary brain cancer in adults, notorious for creating an environment that traps white blood cells within the bone marrow, preventing them from reaching the tumour in the brain.
A key part of the immune blockade involves the S1P1 receptor on immune cells, which normally acts as a passport permitting exit from the bone marrow into the bloodstream. Brain tumours trigger a process that internalises this receptor, effectively confiscating the passport. An enzyme called GRK-2 is largely responsible for dragging the S1P1 receptor inside the cell.
The Mayo Clinic team had previously developed an experimental therapy using a safe version of the measles virus that selectively infects and kills cancer cells. To enhance its effect, they armed the virus with a bacterial protein designed to wake up the immune system and combined it with immune checkpoint inhibitors, drugs that release the brakes on immune cells.
They hypothesised that releasing trapped immune cells from the bone marrow could further boost the therapy, and turned to paroxetine, a widely available selective serotonin reuptake inhibitor. Paroxetine is known to block GRK-2, which could prevent the S1P1 receptor from being pulled back into the bone marrow, allowing immune cells to mobilise to fight the tumour.
In laboratory tests, the researchers exposed human and mouse glioblastoma cells to varying concentrations of paroxetine. Very high drug doses killed cancer cells directly, but lower doses similar to those safely used in humans did not have a major direct effect. Importantly, paroxetine did not interfere with the virus’s ability to infect and kill the cancer cells in vitro.
For in vivo analysis, the team first established a baseline by injecting mouse glioblastoma cells into the brains of healthy mice and comparing them with tumour-free controls. Tumour-bearing mice showed fewer circulating immune cells and fewer S1P1 receptors on the surface of bone marrow immune cells.
To test their proposed approach, they treated tumour-bearing mice with the engineered measles virus and immune checkpoint inhibitors. Half of this group also received daily oral paroxetine. The researchers collected bone marrow and blood samples at intervals to assess the immune response.
Mice receiving the full combination, including the antidepressant, displayed higher levels of the S1P1 receptor on bone marrow immune cells and a greater proportion of circulating immune cells compared with those given the virus and immunotherapy alone. Adding paroxetine without checkpoint inhibitors did not yield the same sustained rise in circulating cells.
The researchers then assessed the functional state of the immune cells by measuring surface protein markers indicating activation or exhaustion. Mice treated with the virus, checkpoint inhibitors and paroxetine showed more active immune cells throughout the body and lower levels of exhaustion markers, suggesting a more durable anti-tumour response.
Survival analysis showed that mice treated with the engineered virus and immunotherapy alone lived longer than untreated controls, with a 40 per cent long-term survival rate. Adding paroxetine to this regimen improved outcomes to 65 per cent long-term survival, defined as living beyond 60 days after tumour implantation. Surviving mice were later able to resist re-challenge with cancer cells.
Safety monitoring did not reveal adverse events. The mice maintained weight gain across groups, and there were no signs of neurological damage or elevated inflammatory markers in the blood, indicating no obvious safety concerns in this animal model.
The study is limited by its use of a mouse model, with the authors noting that murine immune systems differ from humans and results may not translate directly. They also point out that only a single mouse strain was used and that optimal dosing and applicability to other glioblastoma models remain to be established before considering human 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.
