Research published recently in the journal Science Translational Medicine from scientists at the UCLA Jonsson Comprehensive Cancer Center reports on the discovery of a drug that targets melanoma tumors and makes them more susceptible to the immune system. The drug is unique in that it acts like a virus to evade tumors’ immunotherapy resistance.
"Most immunotherapy approaches rely on the ability of T cells to recognize and kill tumor cells," said lead author Dr. Anusha Kalbasi, who is an assistant professor of radiation oncology at the David Geffen School of Medicine at UCLA and member of the Jonsson Cancer Center. "But in some patients, tumors escape the immune system through mutations in genes involved in the interferon signaling pathway. This is a critical pathway because it normally allows tumors to increase their antigen presentation, an intricate machinery that makes tumors visible to T cells."
Interferons refer to proteins in cells that react to viral infection by stopping the virus's ability to replicate while simultaneously flagging the virus’s presence to the immune system. Stimulating such interferon signaling in tumors is helpful because it can limit tumor division while also recruiting immune cells. "This coordinated effort as a result of interferon signaling can help the immune system better identify and kill tumor cells," Kalbasi said.
Kalbasi and his team developed the virus-mimicking drug called BO-112 in order to target virus-sensing pathways in tumors. They showed that by injecting BO-112 into the tumor and activating these pathways, they were able to increase antigen presentation even when interferon signaling was defective. That means that T cells could still detect and destroy tumors despite defective interferon signaling.
"This study helps us understand the interdependence between interferon signaling and antigen presentation, which gives us important insights into how tumor cells are recognized by the immune system," said the study's senior author, Dr. Antoni Ribas, a professor of medicine at the Geffen School of Medicine and director of the tumor immunology program at the Jonsson Cancer Center. "New strategies to promote antigen presentation to make tumors more visible to the immune system will allow immunotherapy to be effective for even more tumor types."
These findings will help pave the path for more effective precision medicine and personalized therapies. Kalbasi is currently launching this idea by heading up a human clinical trial of the combination therapy of nivolumab, an immune checkpoint blockade drug, and BO-112 in people with certain types of sarcoma who are undergoing radiation followed by surgery.