Tinkering with T-cells aims them at deadly brain cancer

Genetically engineered cancer-killing T-cells can hunt and attack brain tumors that display a new molecular target that is highly prevalent on brain cancer cells, report researchers.

“Glioblastoma is a tumor of the brain that has a very low chance of being cured with current available therapies.”

The engineered T-cells both prolonged survival and controlled tumor growth in experiments with mice and cell models of glioblastoma, the most lethal primary brain tumor.

Based on the findings from their early, preclinical studies, the researchers believe their approach holds promise for a new immunotherapy treatment for glioblastoma.

New treatments are sorely needed for the disease, as patients undergoing conventional treatments, including surgery, radiation, and chemotherapy, typically survive for less than a year and a half. Only about one-third of patients with brain and other nervous system cancers live five years.

“Glioblastoma is a tumor of the brain that has a very low chance of being cured with current available therapies,” says senior author Gianpietro Dotti, a professor in the UNC School of Medicine Department of Microbiology and Immunology and the UNC Lineberger Comprehensive Cancer Center.

“We know from other clinical studies that CAR-T cells can work in glioblastoma. The problem is that the target antigens used in previous trials have been suboptimal. We have identified a target that is highly expressed in glioblastoma.”

Genetically engineering the patient’s cells

The study is part of a research program to develop personalized immune-based treatments called chimeric antigen receptor T cell, or CAR-T, therapies.

“We know it’s very important to target these cells as well because they are probably the cause of tumor recurrence.”

This approach involves removing a patient’s immune cells and genetically engineering them to recognize and attack cancer. Other centers have launched CAR-T clinical trials for glioblastoma, but the UNC Lineberger team designed immune cells that hunt CSPG4, a different target on the surface of glioblastoma cells that they believe could be more potent than other targets.

In this study, CSPG4 was highly expressed in 67 percent of the brain cancer samples, leading the researchers to believe this could be a more effective approach to CAR-T cell therapy for a significant number of patients with glioblastoma.

“The critical point is that the antigen needs to be expressed in a high proportion of tumor cells, and not in normal cells of the brain,” Dotti says. “We found that the CSPG4 antigen is strongly expressed in 67 percent of the tumors that we analyzed. We also found that this target is also expressed in what we call cancer-initiating cells, which are the stem cells of the tumor. We know it’s very important to target these cells as well because they are probably the cause of tumor recurrence. If you don’t target them, they will come back.”

The researchers found that T-cells genetically engineered to target CSPG4 controlled the growth of tumor cells in multiple models of the disease. In cell cultures, the engineered T-cells efficiently eliminated glioblastoma cells displaying CSPG4, while the cancer continued to grow in the presence of regular T-cells. The engineered T-cells also prolonged survival and controlled tumor growth in glioblastoma models in mice.

Adding a ‘safety switch’

Doctors plan to launch clinical trials for glioblastoma. As envisioned, the trials would focus on patients with advanced disease that has recurred and requires additional surgery.

To further ensure the safety of patients participating in the future study, researchers plan to incorporate a “safety switch” into the therapy that would allow for the rapid elimination of the T cells in case toxic effects are observed.

T-cells more actively sniff out cancer cells than we thought

“We will continue working on a potential new way to try to treat this aggressive tumor,” Dotti says. “These experiments in vitro and in vivo for mice were promising, now we need to see what happens in patients.”

The findings appear in Science Translation Medicine. Coauthors are from Fondazione Istituto di Ricerca e Cura a Carattere Scientifico in Milan, Italy.

Source: UNC Chapel Hill