New glioblastoma therapy targets tumor, aids immune response

Researchers at Northwestern Medicine have achieved a significant milestone in the fight against glioblastoma, a deadly form of brain cancer. By utilizing ultrasound technology, they have effectively penetrated the blood-brain barrier to deliver a combination of chemotherapy and immunotherapy drugs. This innovative approach has demonstrated enhanced recognition of cancer cells by the immune system, potentially paving the way for new treatment methods.

The study, slated for publication in Nature Communications, highlights several groundbreaking discoveries. Scientists successfully employed a skull-implantable ultrasound device to increase the penetration of the chemotherapy drug doxorubicin and immune checkpoint blockade antibodies into human brain tissue. This device generates microbubbles that temporarily open the blood-brain barrier, facilitating the entry of these therapeutic agents.

Notably, this research reveals that even a small dose of doxorubicin, when combined with immune checkpoint blockade antibodies, can significantly improve the immune system’s ability to identify and attack glioblastoma cells. Immune checkpoint blockade antibodies function by preventing cancer cells from deactivating the immune response. Normally, the immune system has regulatory checkpoints to avoid excessive reactions that could harm healthy tissues. Glioblastoma exploits these checkpoints to evade immune attacks.

The tumor microenvironment of glioblastoma includes diverse cell populations, such as macrophages and microglia, which are manipulated by the tumor to suppress lymphocytes (immune cells). The study highlights that the drug and antibody combination modifies these supportive cells, thereby enabling lymphocytes to target and destroy cancer cells effectively.

Dr. Adam Sonabend, co-author and associate professor of neurological surgery at Northwestern University Feinberg School of Medicine, emphasized the novelty of this approach. He stated, "This is the first report in humans where an ultrasound device has been used to deliver drugs and antibodies to glioblastoma, changing the immune system to recognize and attack the brain cancer. This could be a major advancement in treating glioblastoma, which has been notably challenging due to the poor penetration of circulating drugs and antibodies into the brain."

The study was carried out in four patients with advanced glioblastoma who had previously undergone conventional chemotherapy and an experimental treatment but experienced tumor recurrence. Dr. Catalina Lee-Chang, co-author and assistant professor of neurological surgery at Northwestern, described the study as a prime example of translational research. "This sets an exceptional scenario to learn about the immune system's ability to kill brain tumors in real-time upon treatment," she said, adding that these findings could inspire new treatment strategies given the current lack of effective immune responses against these tumors.

Subsequently, these promising results have led to the initiation of a clinical trial at Northwestern. This trial will initially enroll 10 participants to establish the treatment's safety, followed by an additional 15 participants to evaluate the potential for prolonged survival. Unlike previous large-scale clinical trials which showed limited efficacy of this type of immunotherapy for glioblastoma, Dr. Sonabend believes that enhancing drug delivery to the brain might prove beneficial for certain patients, especially when biomarkers indicate susceptibility to immunotherapy.

Dr. Sonabend and Dr. Lee-Chang, both members of the Robert H. Lurie Comprehensive Cancer Center and the Malnati Brain Tumor Institute, underscored the potential impact of their findings. Dr. Sonabend noted, "In a small cohort of patients, we’ve shown that this technology can enhance the delivery of chemotherapy and antibodies, alter the tumor microenvironment, and enable the immune system to recognize the tumor."

The study titled "Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas" could mark a significant step forward in glioblastoma treatment.

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