Novel immunotherapy is first-in-human treatment for this brain cancer
In a major advance for the treatment of the deadly brain cancer glioblastoma, Northwestern Medicine scientists used ultrasound technology to penetrate the blood-brain barrier and provide a small dose of a chemotherapy and immunotherapy drug co*cktail. The study, published in Nature Communications, found that this treatment boosted the immune system’s recognition of the cancer cells and could lead to a new treatment approach.
The scientists made several breakthroughs reported in a new study, including showing for the first time that a skull-implantable ultrasound device can enhance the penetration of the chemotherapy drug doxorubicin and immune checkpoint blockade antibodies — a novel immunotherapy treatment combination — into the human brain. The device produces microbubbles that temporarily open the blood-brain barrier, allowing the immunotherapy to enter the brain.
The scientists also showed for the first time that a small dose of doxorubicin (smaller than the dose used for traditional chemotherapy regimens) delivered with the immune checkpoint antibodies can boost the recognition of malignant glioblastoma cells by the immune system and reinvigorate the lymphocytes (immune cells) that are in charge of attacking the cancer cells.
An immune checkpoint blockade antibody blocks the deactivation of the immune system by the cancer cells. The immune system has built-in brakes — called immune checkpoints — so it doesn’t overdo it and injure the body when attacking cancer and infections. Glioblastoma evolves to activate the brakes, and therefore, the immune system (i.e., lymphocytes) won’t attack it.
In addition to the tumor cells, glioblastoma contains other cell populations called macrophages and microglia. These are the most abundant components of the tumor microenvironment and the cells that glioblastoma modulates to inhibit lymphocytes. The study showed that the chemo and antibody co*cktail altered these cells, enabling the lymphocytes to recognize and kill the cancer cells.
“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 co-corresponding author 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.”
The study was conducted in four patients who had advanced progression of their tumors. They had already been treated with conventional chemotherapy for their tumors as well as an experimental treatment in a clinical trial, but both times, the tumors returned.
“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. “Given the lack of effective immune response against these deadly tumors, these findings encourage us to envision a potential new treatment approach.”
Clinical trial launched with new treatment
These new findings are the basis for a novel clinical trial that was just launched at Northwestern using ultrasound to deliver immunotherapy for glioblastoma. The trial will initially 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 might be shown to be effective for some glioblastoma patients.
“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,” Sonabend said.
Sonabend and Lee-Chang are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and the Malnati Brain Tumor Institute. Sonaband is also director of translational neuro-oncology at Feinberg.
Other Northwestern authors include first author Víctor A. Arrieta, PhD; Andrew Gould; Kwang-Soo Kim, PhD; Karl J. Habashy, PhD; Crismita Dmello, PhD, research assistant professor of Neurological Surgery; Gustavo I. Vázquez-Cervantes, PhD; Irina Palacín-Aliana, PhD; Graysen McManus; Christina Amidei, PhD, research assistant professor of Neurological Surgery; Cristal G. Gomez, MS; Silpol Dhiantravan; Li Chen, PhD; Daniel Y. Zhang; Ruth Saganty; Meghan E. Cholak; Surya Pandey, PhD, research assistant professor of Medicine in the Division of Hematology and Oncology; Matthew McCord, PhD; Kathleen McCortney, MS; Rachel Ward, RN; Bin Zhang, MD, PhD; the Johanna Dobe Professor of Cancer Immunology in the Department of Medicine; Jason M. Miska, PhD, assistant professor of Neurological Surgery; Maciej S. Lesniak, MD, the chair and Michael J. Marchese Professor of Neurosurgery; Craig M. Horbinski, MD, PhD, the Director of Neuropathology in the Department of Pathology; Rimas V. Lukas, MD, associate professor of Neurology in the Division of Neuro-oncology; and Roger Stupp, MD, chief of Neuro-oncology in the Department of Neurology and the Paul C. Bucy Professor of Neurological Surgery.
The research was supported in part by the National Cancer Institute grants 1R01NS110703-01A1, 1U19CA264338-01 and 1R01CA245969-01A1 of the National Institutes of Health, grant P50CA221747 SPORE for Translational Approaches to Brain Cancer and the Moceri Family Foundation and the Panattoni family. Sonabend and Stupp have received funding support for research from Agenus, BMS, and Carthera. Sonabend, Arrieta, Kim, Amidei, and Stupp are co-authors of an IP filed by Northwestern University related to the content of this manuscript. (PCT/US2023/034299). Sonabend has served as a consultant for Carthera and EnClear Therapies. Stupp has acted or is acting as a scientific advisor or has served on advisory boards for the following companies: Alpheus Medical, AstraZeneca, Boston Scientific, Carthera, Celularity, GT Medical, Insightec, Lockwood (BlackDiamond), Northwest Biotherapeutics, Novocure, Inc., Syneos Health (Boston Biomedical), TriAct Therapeutics, Varian Medical Systems. Other co-authors C. Desseaux, G. Bouchoux, and M. Canney are employees and hold an ownership interest in Carthera. M. Canney, G. Bouchoux, and A. Carpentier have patents related to the ultrasound technology described herein. Stupp is an advisory member and consultant for Carthera. Carpentier is a consultant for Carthera. Lee-Chang is a co-founder and consultant for Sera BioPharma.
