Glioblastoma, accounting for more than 60 percent of all brain tumours in adults, poses difficulties in the development of treatments, since most drugs cannot cross the blood-brain barrier. This study, conducted by scientists at Brigham and Women's Hospital and Harvard Medical School, involved the development of a stem cell-based therapy that specifically targets glioblastoma cells, and has proven to have 'profound efficacy' in preclinical mouse models.
'This is the first study to our knowledge that identifies target receptors on tumour cells prior to initiating therapy, and using biodegradable, gel-encapsulated, "off-the-shelf" engineered stem cell based therapy after glioblastoma tumour surgery,' said Dr Khalid Shah, the vice chair of research in the Department of Neurosurgery at the Brigham and faculty member at Harvard Medical School.
The scientists, publishing their results in Nature Communications, used circulating tumour cells, which are cells that enter the bloodstream from the primary glioblastoma, to identify receptor molecules expressed specifically on glioblastoma cells, termed 'death receptors'.
Then, the team used mesenchymal stem cells from healthy donors, and engineered them to express a protein that matches the death receptor on glioblastoma cells. This triggered a cascade of reactions in glioblastoma cells, leading to their death. A safety kill switch was also included that allowed tracking by PET imaging, and when activated, further enhanced cancer cell death.
Finally, the stem cells were packaged into a biodegradable hydrogel capsule, allowing passage through the blood-brain barrier.
Generally, with cell-based therapies, the patient's own cells are harvested, reprogrammed to target diseased cells or tissues, and then reintroduced into the patient's body. In patients with glioblastoma, however, the disease is so fast-moving that surgery must be performed within the first week after diagnosis, leaving no time to develop therapies using the patient's own cells. Hence, the need for pre-made stem cells, or 'off-the-shelf' remedies, developed using cells from healthy donors.
The scientists tested the stem cell-based therapy in a preclinical mouse model of primary or recurrent glioblastoma. The tumours were removed and the stem cell-based therapy was administered. Mice that received the treatment were alive 90 days' post-surgery, whereas those that only had the surgical removal of the tumour survived for an average of 55 days. Various doses of the therapy were administered, and no toxicity to the mice was detected.
These results, the authors believe, will pave the way for clinical trials on patients with glioblastoma to begin in the next two years. They also hypothesise that the stem cell-based therapy could be used to treat other solid tumours.
'This work lays down a foundation to begin building an engineered therapeutic stem cell biobank targeting different receptors on tumour cells and the immune cells in the tumour microenvironment that we will one day be able to use to treat a wide range of difficult-to-treat cancers like glioblastoma,' concluded Dr Shah.