The aggressive brain cancer glioblastoma is infamously “cold” when it comes to immunotherapy, meaning it typically doesn’t respond to immune-boosting therapies because of immune-suppressing molecules in its environment.
A team led by University Hospital Zurich and the University of Zurich tested a protein-based drug that fuses immune-stimulating cytokines with antibodies that specifically target glioblastoma. The drug slowed tumor growth in mouse models of the disease and boosted the ability of immune cells to reach patients' brain tumors in a small, ongoing clinical trial, they reported in Science Translational Medicine.
“Glioblastoma is considered an immunological ‘desert,’” the researchers wrote in the study. “Proinflammatory cytokines are ‘master regulators’ of the immune system that can turn tumors from cold to hot.” But unmodified cytokines are too toxic for patients to tolerate, necessitating new approaches to selecting and engineering them for safety and efficacy, they added.
The Swiss scientists tested three different cytokines in combination with antibodies targeting glioblastoma: IL-2, IL-12 and TNF. They found that antibodies fused to IL-12 or TNF and given to mice intravenously accumulated in glioblastoma tumors, slowing their growth. Two out of five of the animals tested were cured, they reported.
To determine whether the anti-tumor response lasted, the team implanted glioblastoma tumors into the mice 180 days after the initial treatment. Without further treatment, the mice remained protected.
The researchers tested the TNF immunocytokine treatment in three glioblastoma patients. The treatment was safe and resulted in a larger infiltration of immune cells into the tumor environment. Two of the patients remained stable at six months, and the study is currently recruiting additional patients. Italy-based Philogen is developing the treatment, called onkekafusp alpha, with the University of Zurich researchers.
This is one of several new immuno-oncology approaches being tested in glioblastoma, and it’s not the first to focus on pro-inflammatory cytokines. Last year, scientists from Brigham and Women’s Hospital and the Dana-Farber Cancer Institute announced they saw early signs of efficacy in a trial of an IL-12 gene therapy in combination with Ziopharm’s oral drug veledimex in glioblastoma.
Cedars-Sinai researchers are using a polymer-based vehicle to deliver drugs that block the immune checkpoints CTLA-4 and PD-1 into the brain. They showed in mice that the treatment was able to cross the blood-brain barrier and boost the infiltration of cancer-killing immune cells to tumors.
The Swiss team noted that the ongoing clinical trial of their TNF immunocytokine drug only tests one dose, and additional studies will be needed to fully understand the safety and efficacy of the treatment. They are also starting to examine combining the fused drug with other therapies, including medicines that target VEGF, a protein that promotes blood growth to tumors and has been fingered as a major factor in glioblastoma.
Editor's note: This story has been updated to include the involvement of Philogen.