Delivering chemotherapy directly to the brain of glioblastoma patients might be better than standard chemotherapy if patients receive immunotherapy as well, according to experiments with mice.
The research showed that standard or systemic chemotherapy rids the body of most of the immune cells required for immunotherapy, decreasing its effectiveness. This does not occur with localized chemotherapy to the brain.
The study, “Anti–PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM,” was published in Science Translational Medicine,
“We understand that our research was done in a mouse model and not in humans, but our evidence is strong that systemic chemotherapy alters the immune system in a way that it never fully recovers,” Michael Lim, MD, associate professor of neurosurgery and director of brain tumor immunotherapy at the Johns Hopkins University School of Medicine, said in a press release. He is also a member of the Johns Hopkins Kimmel Cancer Center.
“With aggressive cancers like glioblastoma, it is important that we don’t handicap the defenses we may need to add alternative treatments, such as immunotherapy, to chemotherapy,” he added.
Glioblastoma is one of the most aggressive forms of brain cancer, with patients having only a 10 percent chance of living more than five years after their diagnosis. Currently, these patients are treated with multimodal therapy that includes surgical removal of the tumor, chemotherapy, and radiotherapy. Because the disease has a very poor prognosis, researchers have been investigating whether new immunotherapies could help glioblastoma patients live longer.
Toxic effects of chemotherapy may be weakening the patients’ immune system, however, preventing immunotherapies from succeeding, Lim said. This could impact the way clinical trials that integrate standard chemotherapy with immunotherapy are designed.
Researchers sought to assess if the route of chemotherapy delivery could influence the effectiveness of immunotherapy. They treated mice with an anti-PD-1 antibody, then either injected chemotherapy in the peritoneal cavity or placed chemotherapy-coated polymers directly into the tumors. The two approaches released the drug locally and consistently for two weeks.
Samples from the mice’s lymph nodes, brain, bone marrow, and blood showed that systemic chemotherapy led to a much greater reduction in the immune cells called T-cells than localized chemotherapy. The researchers said their findings align with what doctors have seen in patients receiving chemotherapy, and suggest that giving immunotherapy to these patients is counterproductive.
The team also wanted to know whether the location of the chemotherapy administered would impact the survival of glioblastoma mice models. Localized chemotherapy and immunotherapy led to an 80 percent increase in the survival rate, compared with localized chemotherapy or immunotherapy alone, or a combination of systemic chemotherapy and immunotherapy. One hundred days after completing the therapy, 50 percent of the mice were still alive.
Importantly, only mice treated with a combination of localized chemotherapy and immunotherapy could actually fight off glioblastoma cells when re-challenged, suggesting that this combo could might immunize mice against glioblastoma. The researchers believe this does not happen in mice receiving systemic chemotherapy because their immune system is weakened by the chemotherapy.
Researchers also found that delivering localized chemotherapy before immunotherapy provided similar survival benefits to mice, suggesting that the order of treatment is not important.
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