A combination strategy may overcome two major obstacles that have historically limited the effectiveness of immunotherapy against glioblastoma. In a study published in Neuro-Oncology, researchers found that simultaneously reprogramming immune cells that suppress the immune response and strengthening T cells can make glioblastoma tumors shrink in preclinical models and produce a lasting immune memory that prevents tumors from returning.
“Immunotherapy works in many different cancer types, but the same approach has yielded only a 10% success rate in glioblastoma,” said Filippo Veglia, PhD, assistant professor at The Wistar Institute and senior author of the study. “Our study shows that combination therapy is paramount to making immunotherapy work for glioblastoma patients. We need to target two different populations of cells.”
One key barrier for immunotherapy in glioblastoma is the tumor’s unusual immune environment, which is dominated by myeloid cells that glioblastoma take advantage of to suppress nearby T cells. Another major obstacle concerns T cells entering an exhausted state that leaves them progressively less capable of killing tumor cells.
Veglia’s team first investigated why myeloid cells become immunosuppressive inside glioblastoma tumors. Using single-cell RNA sequencing, they found that monocyte-derived macrophages and neutrophils were among the most abundant and suppressive myeloid populations in the tumors. Conditions of hypoxia were found to act as a driver of immune suppression by reprogramming myeloid cells to suppress T-cell activity.
The researchers then tested low-dose axitinib, a drug already used with immunotherapy in advanced kidney cancer, in mouse models of glioblastoma. Although the drug reduced tumor hypoxia and interfered with the immunosuppressive reprogramming of myeloid cells, it was only able to produce a modest benefit on its own.
“By reducing hypoxia, we can impair the immunosuppressive activity of myeloid cells, and this results in the accumulation of more T cells in the tumor microenvironment,” said Veglia. “But this is not enough, because when T cells go into the tumor, they become exhausted.”
Many of the T cells accumulating after axitinib treatment were beginning to show signs of exhaustion but still retained the capacity to attack cancer. They also expressed CD137, a receptor associated with recognition and activation of tumor-reactive T cells.
Combining axitinib with an agonist targeting CD137 proved substantially more effective than either treatment alone, extending median survival from 23 to 42 days in mice. When researchers later re-exposed surviving animals to glioblastoma cells, the tumors failed to grow, suggesting that the treatment had generated durable immune memory.
Veglia said the next step is to explore the approach in a clinical trial. His team also plans to test whether reducing tumor hypoxia could improve CAR T-cell therapy, an approach that has shown promise in blood cancers but has so far struggled against solid tumors. Because low-oxygen tumor environments are common in other treatment-resistant cancers, including pancreatic cancer, the strategy could eventually have applications beyond glioblastoma.
“There are no cures for glioblastoma, so this is an opportunity to make a real difference for patients,” Veglia said. “We are also excited to see if our findings extend to other types of recalcitrant cancer and ultimately improve outcomes for these patients, too.”
