Macrophages are a type of white blood cell that are the “first responders” of the immune system, attacking and digesting cellular debris and foreign microbes. In theory, macrophages should also destroy cancerous cells, but in reality cancer cells give off the same chemical signals as healthy ones, essentially going undetected by our “first responders” of the immune system. Sometimes the immune system does detect cancer cells, but the response is not strong enough. In response, researchers have used strategies to boost the immune system via immunotherapy treatments to help the immune system detect cancer cells and bolster its response so that it will eliminate them. Many of these new successful immunotherapy treatments targeting blood cancers, use engineered T-cells. Blood cancers have what is known as “liquid” tumors, but tumors in other tissues are typically more solid, making it difficult for T-cells to penetrate and destroy the cancer cells.
As an alternative approach to go after solid tumors, macrophage-based cancer therapies were started decades ago. However while they were found to be safe in patients, they didn’t do any good either because they couldn’t hone in on the tumors because they received the chemical “I am a good cell, don’t attack me” signal from the cancerous cells. Dennis E. Discher, holding the Robert D. Bent Professorship in Penn Engineering’s Department of Chemical and Bimolecular Engineering, and his research team referred to as Discher Lab, have learned how to re-engineer macrophages, so that they ignore the chemical signals and are additionally programmed only to attack the cancerous cells.
The Discher Lab paper published in the journal Current Biology outlines the approach that starts with selectively extracting young and aggressive macrophages from the bone marrow. The researchers then turn off a key safeguard called SIRPA in the macrophages that cause them to halt when cancer cells emit the chemical “I am a good cell, don’t attack me” signal. With the safeguard off the macrophages are also infused with cancer-specific targeting antibodies so they don’t go after good cells. These engineered macrophages storm into solid human tumors and quickly shrink them with limited collateral damage to healthy cells.
Discher said though that “Safety thus far is likely a consequence of both the relatively small number of engineered macrophages that are injected and their sequestration into the tumors, away from most healthy cells”. Also, the injected macrophages seemed to lose their vigor after a week of attacking a solid tumor, so the first trial required a second injection to finish shrinking the tumors down. The Discher laboratory is overall very pleased with the potency of their engineered macrophages, but further work will continue to maximize the duration of the anti-cancer effects while minimizing side effects, namely attacking healthy cells.