A novel way of attracting immune cells to fight brain tumors could improve survival rates for one of the deadliest types of cancer
LOS ANGELES — Glioblastoma multiforme (GBM), the most common type of brain cancer, is notoriously difficult to treat. Its tumor cells mutate rapidly, pushing into deep areas of the brain that can be difficult to reach with surgery and other treatments. GBMs are also able to turn off the mechanism that typically brings immune cells to a damaged area of the body, so that immunotherapies don’t work against the disease.
To overcome those challenges, scientists with City of Hope, one of the largest cancer research and treatment organizations in the United States, have developed a new approach to attract immune cells to these tumors. In a paper published recently in the journal Nature Cancer, senior authors Michael A. Caligiuri, M.D., president of City of Hope National Medical Center and the Deana and Steve Campbell Physician-in-Chief Distinguished Chair, and Jianhua Yu, Ph.D., director of City of Hope’s Natural Killer Cell Biology Research Program, explain how the team used an oncolytic virus to release chemokines, which are signaling proteins that help attract immune cells to tumors.
GBMs are known as “cold” tumors for their lack of helpful immune cells. The researchers used chemokines to make GBM tumors “hot,” meaning the chemokines effectively stimulated the migration of immune cells to the tumor microenvironment.
“One of the most exciting signs in immunotherapy is to see a cold tumor turn hot, to see immune cells trafficking to and accumulating around or within a tumor, and we were able to do just that,” Caligiuri said. “And it’s especially hard to do in glioblastoma because the tumors live in this immune sanctuary where there aren't the traditional T cells, NK cells or macrophages. The immune cells have to cross through the blood brain barrier to get to the brain. So, the brain has an extra barrier.”
The team, including the first author Lei Tian, Ph.D., used an oncolytic herpes simplex virus — a virus genetically engineered to kill cancer — in mouse models to both help kill the cells and produce a local and sustained release of a chemokine, called CCL5, which is linked to a molecule, the epidermal growth factor receptor (EGFR) antibody, resulting in binding to tumor cells. Thus, the chemokine linked with the EGFR antibody, produced by the oncolytic virus-infected tumor cells, will be anchored to tumor cells to attract immune cells, such as T cells and macrophages.
This combination of the oncolytic virus, the chemokine function and the antibody worked together to improve GBM therapy and more than doubled the survival time in half the mice that received the treatment.
“Our strategy was to force the tumors to make chemokines, in a nontoxic fashion, and have an anti-tumor effect,” Yu said. “That’s what is novel about this work.”
In addition to effectively eradicating tumor cells at the site of injection, the team was surprised to see that the treatment had an abscopal effect, meaning that tumors at other locations were also killed.
“This was probably the most striking finding,” Caligiuri said. “Not only did it treat a tumor in one side of the brain, but it took away tumors in the other hemisphere, prolonging survival. We could show that the side that didn't get the treatment had bunches of immune cells there. So, what seems to happen is you treat one side, the immune cells flock in, they get sensitized to the tumor and then they themselves go after other tumors.”
While the study’s findings were made in mouse models, they hope to gain approval from the Food and Drug Administration for human clinical trials of the viral platform that includes the chemokines and cetuximab.
Thanks to City of Hope’s on-site Biological and Cellular GMP facility, making the new therapy is less of a challenge than is typical at other institutions, Yu said.
“Because we can make the product at City of Hope, we’ve already cleared a lot of hurdles for moving forward,” Yu said.
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About City of Hope
City of Hope's mission is to deliver the cures of tomorrow to the people who need them today. Founded in 1913, City of Hope has grown into one of the largest cancer research and treatment organizations in the U.S. and one of the leading research centers for diabetes and other life-threatening illnesses. As an independent, National Cancer Institute-designated comprehensive cancer center, City of Hope brings a uniquely integrated model to patients, spanning cancer care, research and development, academics and training, and innovation initiatives. Research and technology developed at City of Hope has been the basis for numerous breakthrough cancer medicines, as well as human synthetic insulin and monoclonal antibodies. A leader in bone marrow transplantation and immunotherapy, such as CAR T-cell therapy, City of Hope’s personalized treatment protocols help advance cancer care throughout the world.
With a goal of expanding access to the latest discoveries and leading-edge care to more patients, families and communities, City of Hope’s growing national system includes its main Los Angeles campus, a network of clinical care locations across Southern California, a new cancer center in Orange County, California, and Cancer Treatment Centers of America. City of Hope’s affiliated family of organizations includes Translational Genomics Research Institute and AccessHope. For more information about City of Hope, follow us on Facebook, Twitter, YouTube, Instagram and LinkedIn.