Glioblastoma is the most prevalent type of malignant brain tumor found in adults. To date, there has been no successful treatment that can completely eradicate this aggressive tumor. The diversity of tumor cells and the tumor-friendly conditions of the surrounding microenvironment make it particularly challenging. Researchers at the University of Basel and University Hospital Basel have now created an immunotherapy that not only combats the tumor itself but also turns its microenvironment against it.
In recent years, CAR T-cells have revitalized immunotherapy approaches for cancer. The mechanism involves extracting the patient’s T-cells and engineering them in a laboratory to recognize specific markers on cancer cells using a receptor known as the chimeric antigen receptor (CAR). Once these modified T-cells are reintroduced into the body, they seek out and destroy the cancer cells. This strategy has shown considerable effectiveness in certain types of leukemia.
However, solid tumors, particularly those in the brain, pose significant challenges for CAR T-cells. Firstly, it can be hard for these immune cell warriors to penetrate the tumors. Secondly, not every cancer cell contains the identifiable marker that T-cells can target. Lastly, the microenvironment of solid tumors can actively resist immune system attacks. “In the brain, where T-cells are not typically present, the conditions are particularly hostile to them,” explains Professor Gregor Hutter from the University of Basel and University Hospital Basel.
Stubborn tumors
Hutter and his group are exploring strategies to tackle glioblastoma. These brain tumors are notoriously persistent and generally recur after surgery and treatment. However, the interval gained from surgery can be used to genetically modify the patient’s T-cells into CAR T-cells in the lab. By administering these modified T-cells directly into the tumor, they bypass the difficulty of CAR T-cells failing to penetrate the cancer. Once within, the T-cells can launch an attack on all cancer cells displaying the recognized markers.
Transforming from pro- to anti-tumor
The CAR T-cells designed by Hutter’s team possess an additional capability to modify the surrounding microenvironment. The researchers equip these therapeutic T-cells with a framework for creating a molecule that blocks the signals the tumor uses to commandeer immune cells in its vicinity. These signals enable the tumor to convert immune cells, specifically microglia and macrophages, into its own allies, which suppress the immune response rather than attacking the cancer.
Former allies become defenders
Once the introduced molecule disrupts these tumor-favoring signals, macrophages and microglia can assist the CAR T-cells in their assault on glioblastoma — even targeting cancer cells that might not express the specific markers.
The researchers have conducted trials in mice with implanted human glioblastoma cells, demonstrating that the treatment is highly effective. The CAR T-cells succeeded in eliminating all cancer cells. Additionally, the research team has tested this method on lymphoma, another type of cancer affecting the lymphatic system, with similarly promising results.
Upcoming clinical studies
Looking ahead, Hutter and his group aim to initiate a clinical study to evaluate the treatment’s efficacy and safety in human patients. “Since we administer the treatment locally rather than via the bloodstream, we expect reduced side effects on the rest of the body,” notes Gregor Hutter. However, potential adverse effects on the nervous system — which are already known from other CAR T-cell therapies — and the extent to which these can be minimized will need thorough investigation in forthcoming studies, he adds.
