Nat Cancer: Combine CAR-T cell therapy with special inhibitor drugs or hopefully treat multiple types of cancer!

4, 2020 // -- The intricate vascular "maze" in the tumor microenvironment remains one of the most difficult obstacles to cell therapy penetration and treatment of solid tumors, and scientists from institutions such as the University of Pennsylvania's Perelman School of Medicine have found that combining CAR-T cell therapy with PAK4 inhibitors can significantly improve survival rates in mice by promoting the breakthrough and attack of tumors by engineered cells.
researchers found in the lab that hemangiogeneization of solid tumors is driven by the genetic reprogramming of tumor endothotres caused by PAK enzymes, which in mouse models of glioblastoma knock out the enzyme or reduce the abnormal distribution of blood vessels in tumors, and improve the leaching of T-cells and immunotherapy of CAR-T cells, the most common malignant brain tumor in the United States, with more than 22,000 cases each year.
Photo Source: CC0 Public Domain researcher Yi Fan says glioblastoma patients are often less responsive to CAR-T cell therapy because CAR-T cells are difficult to get inside the tumor, and the results suggest that gene reprogramming that uses PAK4 inhibitors to shut down tumor endotrative cells may hopefully allow T-cells and engineered T-cells to reach the tumor to kill cancer cells.
First, the researchers screened more than 500 kinases that regulate the activation of blood vessels in the skin cells of glioblastoma patients, and found that PAK4, previously a driver of solid tumor growth, may have been the culprit, using drugs to knock out the enzyme in endodertic cells or to restore stickiness. The expression of adhesive proteins, which are important for recruiting immune cells and stimulating T-cells to immerse themselves in the tumor, is noteworthy that knocking down the expression of PAK4 transforms the form of endoskin cells from a spindle-shaped appearance to a typical cobblestone shape, revealing less chaotic patterns of formation of blood vessels, in other words, which normalizes the tumor microenn environment.
In a mouse model of glioblastoma, the researchers found that inhibiting PAK4 or reducing abnormalities in blood vessels improved the immersion of T-cells and inhibited tumor growth in the mouse body, and at the end of the experiment, about 80 percent of mice with PAK4 being knocked out survived for at least 60 days, while all wild mice died within 40 days of tumor implantation.
In another study using EGFRVIII-guided CAR-T cell therapy and PAK4 inhibitors, the researchers found that tumor growth in the combined mice was nearly 80 percent less than in mice treated with CAR-T cells after five days of infusion, and it was noted that 40 percent of the mice in the combined treatment group survived even though the other groups died within 33 days of tumor implantation.
Targeting PAK4 may provide a new opportunity to modify the tumor micro-environment while also helping to improve T-cell-based cancer immunotherapy to treat solid tumors, and the results support the scientists' previous view that by inhibiting the standardization of blood vessels achieved by PAK4 or improving the transport of drugs, and reducing the hypoxia of tumors, tumors can improve the response rate to targeted therapy, radiotherapy, and chemotherapy.
'According to our results, this study is the first to reveal how the entire angioentic microenvironment can be reprogrammed with PAK3 inhibitors to promote and improve cell therapy for cancer, and importantly, this treatment may not be limited to brain tumors, which can also be used to treat other types of cancer, such as breast and pancreatic cancer, because vascular abnormalities are common to almost every solid tumor,' said Fan, a researcher.
() Original source: Ma, W., Wang, Y., Zhang, R. et al. Targeting PAK4 to reprogram the vascular microenvironment and improve CAR-T immunotherapy for glioblastoma. Nat Cancer (2020). doi:10.1038/s43018-020-00147-8。