A new study from researchers at\u00a0Wake Forest University School of Medicine\u00a0has\u00a0identified\u00a0a promising strategy to treat brain metastases,\u00a0one of the most challenging and deadly complications of lung cancer.\u00a0<\/p>\n
The research team developed a highly specialized type of immune cell, called a CAR macrophage, or CARMA, designed to find and attack tumor cells that spread to the brain. These engineered macrophages were able to enter the brain, seek out cancer\u00a0cells\u00a0and slow tumor growth in preclinical models.\u00a0<\/p>\n
The findings\u00a0were\u00a0published online today in\u00a0Nature Biomedical Engineering.\u00a0<\/p>\n
Brain metastases occur in\u00a0nearly\u00a01\u00a0in 3\u00a0patients with lung cancer, and current treatments,\u00a0such as surgery and radiation,\u00a0offer limited options because many drugs cannot cross the blood-brain barrier, the brain’s natural defense system.\u00a0<\/p>\n
“Brain metastases are incredibly difficult to treat because most therapies simply can’t get inside the brain,” said Shih\u2011Ying Wu, Ph.D.,\u00a0assistant\u00a0professor of\u00a0radiation\u00a0oncology\u00a0at Wake Forest University School of Medicine and corresponding author.\u00a0<\/p>\n
“Macrophages, however, naturally know how to cross into the brain. So,\u00a0we asked:\u00a0‘What if we could give them the ability to recognize and destroy cancer cells once they get there?'”\u00a0<\/p>\n
The research team engineered macrophages to express a chimeric antigen<\/a> receptor (CAR) that targets mesothelin, a protein found at\u00a0high levels\u00a0on lung cancer cells that have spread to the brain.\u00a0<\/p>\n To boost the macrophages’ ability to activate and destroy cancer cells, the researchers added a signaling\u00a0component\u00a0called MyD88, which strengthens the cell’s natural “attack” mode.\u00a0<\/p>\n The team then tested these MyD88\u2011CAR macrophages in several laboratory and mouse models\u00a0designed to mimic lung cancer brain metastasis<\/a>.\u00a0They examined:\u00a0<\/p>\n The research team noted these key findings:\u00a0<\/p>\n
CARMA cells not only directly attacked tumor cells, but\u00a0they also released helpful signals, including TNF\u2011\u03b1, that harmed nearby cancer cells even if those cells did not express the target antigen.\u00a0<\/p>\n
<\/p>\n These macrophages didn’t just find the\u00a0tumors;\u00a0they reshaped the entire immune environment in the brain. We were excited to see that they activated other immune cells and helped sustain a long\u2011term anti\u2011tumor response. That combination is something we\u00a0haven’t\u00a0been able to achieve before in brain metastasis\u00a0research.”\u00a0<\/p>\n
Kounosuke\u00a0Watabe, Ph.D., professor of cancer biology at Wake Forest University School of Medicine\u00a0and corresponding author<\/p>\n
<\/p>\n According to Watabe, most existing immunotherapies struggle to reach tumors inside the brain, and treatments that do reach the brain can sometimes cause severe side effects.\u00a0However, this study\u00a0demonstrates\u00a0that\u00a0engineered\u00a0macrophages\u00a0may offer a safer approach\u00a0for patients whose cancer has spread to the brain.\u00a0<\/p>\n The researchers will work to further refine the\u00a0CARMA cell design\u00a0and begin steps toward early-phase clinical testing.\u00a0<\/p>\n “Our ultimate goal is to translate this into a treatment option for patients,”\u00a0Watabe said.\u00a0“There is a tremendous need, and we believe this technology has potential.”\u00a0<\/p>\n This research was supported by the National Institutes of Health grants\u00a0T32CA247819, R01CA185650 and R01CA205067, and by a Department of Defense grant W81XWH2210463.\u00a0<\/p>\n The NCI-designated Comprehensive Cancer Center at Atrium Health Wake Forest Baptist, in partnership with Wake Forest University School of Medicine, the academic core of Advocate Health, advances cancer care through leadership in more than 1,000 clinical trials nationwide.\u00a0<\/p>\n Source:<\/p>\n Wake Forest University School of Medicine<\/a><\/p>\n Journal reference:<\/p>\n
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