Scientists have successfully genetically engineered immune cells to hunt down and target brain tumors, thanks to the discovery of a novel molecular target, CSPG4, present on the surface of the cancer cells.
The study was recently published in Science Translational Medicine and is part of program launched at UNC Lineberger which aims to develop personalized immune-based treatments known as CAR-T cell therapies.
The team’s studies, conducted using both murine and cell models of glioblastoma, have shown that immune cells, engineered to recognize CSPG4, are able to control tumor growth. The researchers are now hopeful that their findings could pave the way to the development of a new immunotherapy for glioblastoma.
Senior author of the study Gianpietro Dotti, MD, University of North Carolina Lineberger Comprehensive Cancer Center, commented in a recent press release: "This approach was very potent in vitro and in murine studies. While it didn't cure all of the tumors, we think it is very promising as a single agent, and also could be studied in combination with other investigational approaches."
Glioblastomas are brain tumors that originate from astrocytes and are usually found in the cerebral hemispheres of the brain. This type of tumor is classified as 'grade 4' due to rapid growth of the tumor.
Although other CAR-T cell therapies are currently being developed for glioblastoma, the UNC Lineberger researchers believe that their approach could have the potential to be more potent, due to their ability to specifically target CSPG4.
"...This is a potential new way to treat these tumors using the immune system," explained Dotti. "We know that the CAR-T cells can work in glioblastoma; we have evidence from clinical studies from other people," Dotti explained. "The problem is the target antigens used in trials have been suboptimal. We identified a target that is highly expressed in glioblastoma."
Over half of the team’s brain cell samples expressed CSPG4. Using genetically engineered T cells they were then able to ‘attack’ the samples expressing high levels of CSPG4.
"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." stated Dotti.
The heterogeneity of tumors makes targeting them challenging. A number of glioblastoma cells are able to escape detection by T cells as they do not all express the particular T cell target. "Our hypothesis is that targeting CSPG4 would overcome some of this heterogeneity," Dotti said.
The researchers were also able to upregulate the expression of CSPG4. Increased levels of the cell signaling protein, TNF-alpha, have been shown to lead to increased expression of CSPG4, by manipulating this signaling pathway the researchers believe they may be able to improve the efficacy and potency of the CAR-T cell therapy.
The researchers advised that future studies will likely be aimed at tackling the immunosuppressive response by the cancer cells, something that was observed during the current study – this immunosuppression could unfortunately limit the CAR-T cell response to glioblastoma.
Clinical trials for glioblastoma are planned. "We are working on a potential new way to try to treat this aggressive tumor," Dotti said. "The experiments in vitro and in vivo were promising, but we need to see what happens in patients."
Before future studies commence, the researchers intend to incorporate a ‘safety-switch’ which would enable the rapid removal of the T cells in the event patients experience adverse effects as a result of the therapy.