The labyrinth of jumbled blood vessels in the tumor microenvironment remains one of the toughest blockades for cellular therapies to penetrate and treat solid tumors. Now, in a new study published online in Nature Cancer, Penn Medicine researchers found that combining chimeric antigen receptor (CAR) T cell therapy with a PAK4 inhibitor drug allowed the engineered cells to punch their way through and attack the tumor, leading to significantly enhanced survival in an animal model.
The researchers discovered in laboratory experiments that vascularization in solid tumors is driven by the genetic reprogramming of tumor endothelial cells—which line the walls of blood vessels—caused by an enzyme known as PAK4. Knocking out that enzyme reduced abnormal tumor vascularity and improved T cell infiltration and CAR T cell immunotherapies in glioblastoma (GBM), the Penn team found. GBM, the most common and aggressive type of brain cancer diagnosed in more than 22,000 Americans every year, is known for its prominent and abnormal vascularity and being immunologically “cold.”
“The response in GBM patient from CAR T cell therapies is universally poor because the CAR T cells have a problem getting into the tumor,” says senior author Yi Fan, an associate professor of radiation oncology in the Perelman School of Medicine. “Our study shows that turning off this endothelial cell genetic reprogramming with a PAK4 inhibitor may help open the door to let both T cells and engineered T cells reach the tumor to do their job.”
Read more at Penn Medicine News.