Combining CAR-T Cell Therapy with Special Inhibitor Drugs May Hopefully Treat Various Cancers!

The intricate vascular "maze" in the tumor microenvironment is still one of the most difficult obstacles to cell therapy penetration and treatment of solid tumors. Recently, in a study published in Nature Cancer, scientists from the Perelman School of Medicine at the University of Pennsylvania and other institutions found through the study that combining CAR-T cell therapy with PAK4 inhibitor drugs may promote engineered cells to break through and attack tumors, thereby significantly improving the survival rate of mice.

The researchers found in the laboratory that vascularization of solid tumors is driven by genetic reprogramming of tumor endothelial cells caused by PAK enzymes, and knockout of this enzyme may reduce the abnormal vascularity of tumors and improve the infiltration of T cells and the immunotherapy treatment effect of CAR-T cells in a mouse model of glioblastoma, one of the most common malignant brain tumors, with more than 22,000 cases in the United States each year.

Researcher Yi Fan said that glioblastoma patients usually respond poorly to CAR-T cell therapy because it is difficult for CAR-T cells to enter the tumor. The results of this study suggest that the use of PAK4 inhibitors to turn off the genetic reprogramming of tumor endothelial cells may hopefully allow T cells and engineered T cells to reach the tumor to kill cancer cells.

First, the researchers screened and analyzed more than 500 kinases that regulate the activation of blood vessels in endothelial cells of glioblastoma patients. They found that PAK4, which could previously act as a driver of solid tumor growth, may be the culprit. Knockdown of the enzyme in endothelial cells using drugs may restore the expression of adhesion proteins, which are very important for recruiting immune cells and stimulating T cell infiltration into the tumor. Notably, knocking down the expression of PAK4 will transform the morphology of endothelial cells and transform them from a spindle-shaped appearance to a typical cobblestone shape, which reveals the formation pattern of vascular disorders. In other words, this makes the tumor microenvironment standardized.

In a mouse model of glioblastoma, the researchers found that inhibiting PAK4 may reduce vascular abnormalities, thereby improving T cell infiltration and inhibiting tumor growth in mice, and at the end of the experiment, approximately 80% of PAK4 knockout mice survived for at least 60 days, while all wild-type mice died within 40 days after tumor implantation. In another study using EGFRvIII-guided CAR-T cell therapy and PAK4 inhibitors, the researchers found that the growth of tumors in mice treated with the combination was reduced by nearly 80% compared with mice treated with CAR-T cells alone, and it is worth noting that even if mice in other groups died within 33 days after tumor implantation, 40% of mice survived the combination therapy.

Targeting PAK4 may provide a new opportunity to modify the tumor microenvironment, but also help improve T-cell-based cancer immunotherapy to treat solid tumors. The results of this paper support the view that scientists have previously proposed that vascular standardization achieved by inhibiting PAK4 may improve the transport of drugs and reduce the hypoxic condition of tumors, thereby improving the response rate of tumors to targeted therapy, radiotherapy and chemotherapy. Finally, researcher Fan said, "To our knowledge, this study is the first to reveal how to promote and improve cell therapy for cancer by reprogramming the entire vascular microenvironment with PAK4 inhibitors. Importantly, this therapy may not be limited to brain tumors. Since vascular abnormalities are a common feature of almost every solid tumor, they can also be used to treat other types of cancer such as breast cancer and pancreatic cancer."