Glioblastoma (GBM) is the most common kind of malignant brain tumor in adults. In recent years, the tumor microenvironment (TME) has been recognized as an important player and therapeutic target in GBM. However, the complex GBM TME and difficulty of drug delivery across the blood-brain barrier make it challenging to treat. Now, researchers at the University of Basel and the University Hospital Basel have developed an immunotherapy in mice that not only attacks glioblastoma but also turns its microenvironment against it.
Their findings are published in Nature Communications in an article titled, “Enhancing anti-1 EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker,” and led by Gregor Hutter, PhD, professor of the University of Basel and the University Hospital Basel.
“A significant challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive microenvironment, which is densely populated by protumoral glioma-associated microglia and macrophages (GAMs),” the researchers found. “Myeloid immune checkpoint therapy targeting the CD47-signal regulatory protein alpha (SIRPα) axis induces GAM phagocytic function, but CD47 blockade monotherapy is associated with toxicity and low bioavailability in solid tumors. In this work, we engineer a CAR T cell against epidermal growth factor receptor variant III (EGFRvIII), constitutively secreting a signal regulatory protein gamma-related protein (SGRP) with high affinity to CD47.”
Solid tumors and especially brain tumors present obstacles to the success of CAR T cells. “Especially in the brain, where T cells aren’t normally found, the environment is really hostile to them,” explained Hutter.
Hutter and his team are searching for new ways to fight glioblastoma. A potential approach is injecting the patient’s own T cells into CAR T cells directly into the regrowing tumor to avoid the obstacle of the CAR T cells not being able to get to the cancer. Once inside, the T cells attack all cancer cells that carry the recognized structure.
The CAR T cells developed by Hutter’s team have an extra feature aimed at altering the microenvironment. The researchers also give the therapeutic T cells a blueprint for a molecule. This molecule blocks the signals the tumor uses to hijack the immune cells in its environment for its own purposes. These signals allow the tumor to turn immune cells, or more precisely microglia and macrophages, into traitors to their own body. Instead of attacking the cancer, they prevent the immune system from attacking it.
Once the implanted molecule stops these tumor signals, macrophages and microglia can support the CAR T cells in their attack on the glioblastoma—even on cancer cells that lack the specific recognized structure.
Trials with mice in whom the researchers implanted human glioblastoma cells have already shown that the treatment is very successful. The CAR T cells were able to get rid of all of the cancer cells. The research team also tested the method against lymphoma, which appeared promising in these tests.
As their next step, Hutter and his team want to offer the treatment to patients in a first clinical study to test its effectiveness and safety. “Since we inject the treatment locally and don’t deliver it through the bloodstream, side effects on the rest of the body should be limited,” said Hutter. However, possible side effects on the nervous system—which are already known to occur from other CAR T cell therapies—and how much these can be curbed can only be determined through studies, he added.
