Stronger Together

Anti-fibrotic drug Setanaxib may have found a new use by boosting immunotherapy response rates, according to research published by scientists at the University of Southampton, UK (1).  Despite exciting results in recent years, approximately 80 percent of cancer patients still fail to respond to immunotherapy (1). 

The research group, led by Gareth Thomas, demonstrated that the drug helped improve immunotherapy response rates in mice by targeting cancer-associated fibroblasts (CAFs) –  cells that Thomas’ previous work had shown help tumors evade immune recognition, increasing the risk of a poor response to immunotherapy.

“We found that several cancer types were rich in CAFs but also contained low levels of T-cells. By targeting NOX4 – an enzyme on CAFs, we realized that we could eradicate them from tumors,” explains Thomas.

The group’s findings led to a collaboration with Genkyotex in Geneva, who had developed Setanaxib, a NOX4/1 inhibitor, for the treatment of organ fibrosis and taken it through phase II trials. The drug was shown to prevent and reverse CAF formation, allowing anti-PD1 and vaccine-based immunotherapies to work more effectively in resistant tumors. Setanaxib has already undergone phase II clinical testing and is safe in humans. “Setanaxib’s excellent safety profile means that we can begin to plan clinical trials in humans,” Thomas explains.

And though clinical trials may be an immediate goal, the British team still intends to further investigate the regulation of CAF differentiation and function to develop new cancer therapies. “CAF remains a relatively poorly characterized cell population, and so we have adopted new technologies, including single-cell gene sequencing, to identify novel CAF subgroups in cancers,” says Thomas. “Intriguingly, we have discovered several different types of CAF that likely have different functions. We have been investigating the mechanisms regulating their accumulation and distribution in tumors, and how they interact with other cell types. In this way we hope to get a better understanding of how the tumor microenvironment makes cancers more aggressive.”

The project was funded by Cancer Research UK. The charity is also funding the group’s ongoing study examining strategies for combining anti-cancer vaccinations with CAF-targeting in triple-negative breast cancer.