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PHILADELPHIA – The labyrinth of muddled blood vessels in the tumor microenvironment remains one of the most difficult blocks for cell therapies to penetrate and treat solid tumors. Now, in a new study published online today in Nature Cancer, Penn Medicine The researchers found that combining chimeric antigen receptor (CAR) T cell therapy with a PAK4 inhibitor drug allowed the engineered cells to break through and attack the tumor, leading to significantly longer survival in mice.
The researchers found in laboratory experiments that vascularization in solid tumors is driven by the genetic reprogramming of the tumor’s endothelial cells – which line the walls of blood vessels – caused by an enzyme known as PAK4. The Penn team found that the enzyme reduced abnormal tumor vascularization and improved T cell infiltration and CAR T cell immunotherapies in mouse models of glioblastoma (GBM). GBM, the most common and aggressive type of brain cancer diagnosed in more than 22,000 Americans each year, is known for its prominent and abnormal vascularity and for being immunologically “cold.”
“The response in the GBM patient from CAR T cell therapies is universally poor because CAR T cells have a problem getting into the tumor,” said the senior author. Yi Fan, PhD, associate professor of cancer radiation therapy at the University of Pennsylvania’s Perelman School of Medicine. “Our study shows that deactivating this genetic reprogramming of endothelial cells with a PAK4 inhibitor can help open the door for both T cells and engineered T cells to reach the tumor to do their job.”
First, the team performed a kinome-level screening assay of more than 500 kinases, or enzymes, that regulate the activation of blood vessels in human endothelial cells of GBM patients. They found that the culprit was PAK4, which had previously been shown as a growth factor in solid tumors. By breaking down that enzyme in GBM endothelial cells with a drug, they found, it restored expression of adhesion proteins that are important for immune cell recruitment and stimulated T cell infiltration into tumors. Notably, PAK4 breakdown shifted endothelial cell morphology from a spindle-shaped appearance to a characteristic pebble in GBM, indicating less chaotic blood vessel formation. In other words, it has “normalized” the microenvironment.
Next, in a GBM mouse model, they found that inhibition of PAK4 reduced vascular abnormalities, improved T cell infiltration, and inhibited tumor growth in mice. About 80% of the PAK4 knockout mice survived for at least 60 days after the experiment ended, while all wild-type mice died within 40 days of tumor implantation.
Another experiment with EGFRvIII-directed CAR T cell therapy and a PAK4 inhibitor showed an almost 80% reduction in tumor growth compared to mice that only had CAR T therapy five days after infusion. Notably, nearly 40% of the mice in the combination therapy group survived even when all mice in the other groups had died 33 days after tumor implantation.
Targeting PAK4 may provide a unique opportunity to recondition the tumor microenvironment, as well as provide a much-needed opportunity to improve T-cell-based cancer immunotherapy for solid tumors, the authors said. The findings also support the idea that vessel normalization by inhibiting PAK4 can improve drug delivery and reduce oxygen deprivation known as hypoxia, leading to a better tumor response to targeted therapy, radiation and chemotherapy. .
“To our knowledge, we are the first to show how we can reprogram the entire vascular microenvironment with a PAK4 inhibitor and promote cell therapy,” Fan said. “Importantly, this may not be limited to brain tumors alone; it could potentially be used for all types, including breast, pancreas and others, because vascular abnormality is a common feature for nearly all solid tumors.”
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Penn co-authors of the study include Wenjuan Ma, Yanling Wang, Rongxin Zhang, Fan Yang, Duo Zhang, Menggui Huang, Lin Zhang, Jay F. Dorsey, Zev A. Binder, Donald M. O’Rourke, Joseph A. Fraietta, and Yanqing Gong.
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