In a study involving four human patients with recurrent glioblastoma, Northwestern Medicine scientists for the first time demonstrated the use of ultrasound technology to penetrate the blood-brain barrier (BBB) and aid delivery of a cocktail of chemotherapy and immune checkpoint blockade immunotherapy into the brain.
The approach applies low-intensity pulsed ultrasound (LIPU), produced using a skull-implantable ultrasound device, and intravenously administered microbubbles (MB) to temporarily open the BBB and allow therapeutic agents to enter the brain. In their reported study, which also evaluated the technique in mouse models of glioblastoma, the researchers showed that their system enabled delivery of increased concentrations of liposomal doxorubicin and anti-PD-1 (aPD-1) immunotherapy.
The study showed that using the LIPU/MB system delivery of a small dose of doxorubicin (DOX)—an amount that is less than the dose used for traditional chemotherapy regimens—together with anti-PD-1 immunotherapy effectively boosted recognition of malignant glioblastoma cells by the immune system and reinvigorated lymphocytes that attack cancer cells. In preclinical testing, most glioma-bearing mice treated using the new approach achieved long-term survival.
“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 at Northwestern University Feinberg School of Medicine 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.” A new clinical trial has been established to further investigate the approach.
Sonabend is co-corresponding author of the team’s published paper in Nature Communications, titled, “Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas.” In their report, the authors concluded: “Overall, this translational study supports the utility of LIPU/MB to potentiate the antitumoral activities of doxorubicin and aPD-1 for GBM.”
The immune system has built-in brakes—called immune checkpoints—to stop overactivity that might injure the body when attacking cancer and infections. Glioblastoma evolves to activate the brakes, and this stops the immune system’s lymphocytes from attacking the tumor. Immune checkpoint blockade (ICB) antibodies are designed to block deactivation of the immune system by cancer cells.
The prognosis for glioblastoma patients “remains dismal despite extensive molecular characterization,” the authors wrote. The failure of some drug-based treatment approaches may be in part the BBB acting to prevent sufficient penetration of therapeutic agents into the brain. “For instance, modern antibody-based treatments that have improved the outcomes of many solid tumors do not cross the BBB,” the team commented.
“The failures of recent large randomized clinical trials that evaluated anti-PD-1 immunotherapy (aPD-1) to improve the outcome of patients with newly diagnosed or recurrent GBM20–22 highlight the importance of developing treatment combinations that reach the tumor cells and elicit effective anti-tumoral immunity.”
“Penetration of different drugs and biologicals in the brain can be achieved through the opening of the BBB with low-intensity pulsed ultrasound (LIPU) in combination with intravenous injection of microbubbles (MB), i.e., LIPU/MB,” the authors further wrote. “This technology works by using a skull-implantable device or MRI-guided transcranial focused ultrasound (FUS) that sends ultrasound waves that induce the vibration of MB to open the BBB.” Prior studies have found that the technology can enable increased brain concentrations of therapeutic agents in preclinical glioma models and patients with either GBM or brain metastases, the investigators also pointed out. “Clinical studies have shown that this technique is safe and effective, with ongoing studies further exploring its therapeutic applications.”
For their reported work the authors evaluated pharmacokinetics and immune responses following the use of LIPU/MB as a technology for enhancing the brain penetration and therapeutic effects of both DOX and aPD-1 in mouse GBM models, as well as in a cohort of 4 recurrent GBM patients. The patients had advanced progression of their tumors and had previously been treated using conventional chemotherapy as well as the experimental treatment in a clinical trial, but both times, the tumors had returned. “Four patients with GBM, who failed two lines of therapy including standard of care (radiation and temozolomide) and LIPU/MB-based opening of the BBB with concomitant albumin-bound paclitaxel, were treated with LIPU/MB with intravenous administration of DOX and aPD-1 at recurrence,” the authors continued.
In addition to tumor cells, glioblastoma contains populations of macrophages and microglia. These are the most abundant components of the tumor microenvironment and the cells that glioblastoma modulates to inhibit lymphocytes. The newly reported study showed that using the LIPU/MB technology allowed delivery of a combination of the chemotherapeutic agent doxorubicin and the anti-PD1 antibody across the BBB to alter these cells, enabling the lymphocytes to recognize and kill the cancer cells.
“Doxorubicin and aPD-1 delivered with LIPU/MB upregulate major histocompatibility complex (MHC) class I and II in tumor cells,” the scientists stated. “Increased brain concentrations of doxorubicin achieved by LIPU/MB elicit IFN-γ and MHC class I expression in microglia and macrophages.” In sum, they said, the integration of these preclinical and clinical results shows the ability of LIPU/MB to enhance the penetration of therapeutic antibodies into the human and murine brains.
“This is a great example of translational bench-to-bedside-back-to-bench research, which sets an exceptional scenario to learn about the ability of the immune system to kill brain tumors in real-time upon treatment,” said co-corresponding author Catalina Lee-Chang, PhD, assistant professor of neurological surgery at Northwestern University Feinberg School of Medicine. “Given the lack of effective immune response against these deadly tumors, these findings encourage us to envision a potential new treatment approach.”
Sonabend said, “Here we show in a small cohort of patients that when you use this technology, you can enhance the delivery of the chemotherapy and the antibodies, and change the tumor’s microenvironment, so the immune system can recognize the tumor,”
Based on the reported findings a Phase IIa clinical trial was recently initiated at Northwestern, using the ultrasound system to deliver immunotherapy for glioblastoma. The trial will initially aim to enroll 10 participants to determine the safety of the treatment, followed by 15 additional to measure whether the treatment can prolong survival.
Previous large clinical trials have failed to show that this type of immunotherapy can prolong survival in glioblastoma patients. Sonabend, however, believes that by enhancing the delivery of these antibodies and drugs into the brain and relying on biomarkers that indicate which tumors are most susceptible to immunotherapy, this treatment may prove effective for some glioblastoma patients.
