Northwestern Medicine scientists have engineered a novel antibody that revitalizes immune cell activity in a deadly brain cancer, according to a study published in Proceedings of the National Academy of the Sciences (PNAS).
This new antibody could make glioblastoma more vulnerable to immunotherapy and help eliminate cancer left behind after surgical resection, according to Irina Balyasnikova, Ph.D., associate professor of Neurological Surgery and senior author of the study.
“It is known that T-cell presence in glioblastoma is limited, and sometimes completely absent,” said Balyasnikova, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “For immunotherapy to be successful, we also need to develop strategies that can attract T-cells in the tumor microenvironment.”
Glioblastoma is a particularly deadly brain cancer, and patients usually have a short life expectancy after diagnosis. The current standard of care is surgical resection, radiation and chemotherapy, but the cancer often quickly returns, Balyasnikova said.
Immunotherapy is an emerging treatment that overcomes immune regulators that normally keep the body’s T-cells in check, unleashing those cells to attack cancer. However, the glioblastoma microenvironment is very immunosuppressive, and T-cells responding to cancer often become non-functional.
To rejuvenate T-cells in the tumor microenvironment, Balyasnikova and her collaborators engineered an antibody that binds to both T-cells and to glioblastoma cells. The antibody bridges the gap between them, facilitating activation through a specific receptor on the T-cells that jump-starts T-cells’ anti-cancer activity.
The antibody is made of genetically linked “building blocks” oriented relative to each other in a specific way to ensure compatibility with functions directed to glioblastoma and T-cells. Furthermore, once individual T-cells are activated, they secrete cytotoxic enzymes and pro-inflammatory cytokines that can recruit additional T-cells to the tumor site, compounding the anti-cancer effect.
When administered to mice with cancer cells derived from human glioblastomas, neural stem cells engineered to secrete the antibody significantly prolonged survival, findings that demonstrate it could help bolster immune activity in human patients, Balyasnikova said. She envisions directly injecting the antibody into the bloodstream to facilitate immunotherapy before or after radiation or chemotherapy. Another strategy could be administering stem cells that produce the engineered antibody into the brain after surgical resection of glioblastoma.
“It’s impossible to remove all the cancer cells with surgery,” Balyasnikova said. “Hopefully, the stem cells can find cancer cells left behind, secrete this antibody and encourage the T-cells to kill those residual cancer cells in the wall of the resection cavity.”
Katarzyna Pituch, PhD, and Markella Zannikou, PhD, both postdoctoral fellows in the Balyasnikova laboratory, were co-lead authors of the study. Co-authors of the study include Maciej Lesniak, MD, chair and the Michael J. Marchese Professor of Neurosurgery, C. David James, PhD, professor emeritus of Neurological Surgery, and Karen Aboody, MD, professor of Developmental and Stem Cell Biology at the City of Hope National Medical Center.
Lesniak and James are both members of the Lurie Cancer Center.
This research was supported by National Institutes of Health Grants R33NS101150, R01NS106379 and P50CA221747.
