Despite extensive molecular studies, the outlook for patients diagnosed with the aggressive brain cancer known as glioblastoma (GBM) continues to be poor. This is partly due to the blood-brain barrier (BBB), which blocks most treatments from reaching the brain effectively. For example, modern antibody-based therapies that have been successful in treating many solid tumors fail to cross the BBB. GBM cells tend to spread and invade areas of the brain that appear normal on magnetic resonance imaging (MRI) scans due to the BBB's resistance to many drugs administered systemically. Even after surgical removal of the tumor-visible region, the presence of invasive residual cells often leads to cancer returning, with patients typically facing the inevitable progression of the disease. In a major advancement for the treatment of GBM, researchers have used ultrasound technology to breach the BBB, delivering a small combination of chemotherapy and immunotherapy drugs. This approach has shown potential in enhancing the immune system's ability to recognize and attack cancer cells, leading to a new treatment method.

In this groundbreaking study, researchers at Northwestern Medicine (Chicago, IL, USA) achieved several breakthroughs. For the first time, they used a skull-implantable ultrasound device (SonoCloud-9; Carthera; Lyon, France) that increased the brain's absorption of the chemotherapy drug doxorubicin and immune checkpoint blockade antibodies, a new combination of immunotherapy treatments. This device creates microbubbles that temporarily disrupt the BBB, permitting the entry of immunotherapy into the brain. They also discovered that administering a smaller dose of doxorubicin, compared to traditional chemotherapy regimens, along with the immune checkpoint antibodies, significantly enhances the immune system's ability to identify malignant GBM cells and revitalizes the lymphocytes (immune cells) responsible for attacking the cancer cells.

An immune checkpoint blockade antibody prevents cancer cells from deactivating the immune system. The immune system naturally has checkpoints to prevent excessive damage to the body while fighting cancer and infections. GBM manipulates these checkpoints to prevent attacks from the immune system, specifically the lymphocytes. Moreover, within the GBM tumor environment, there are prevalent cells known as macrophages and microglia. These cells are typically manipulated by GBM to suppress lymphocyte activity. The study indicated that the combination of chemotherapy and antibodies alters these cells, empowering the lymphocytes to detect and destroy the cancer cells effectively.

“This is the first report in humans where an ultrasound device has been used to deliver drugs and antibodies to glioblastoma to change the immune system, so it can recognize and attack the brain cancer,” said Adam Sonabend, MD, associate professor of Neurological Surgery and a Northwestern Medicine neurosurgeon. “This could be a major advance for the treatment of glioblastoma, which has been a frustratingly difficult cancer to treat, in part due to poor penetration of circulating drugs and antibodies into the brain.” 

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