About 3,400 people receive the devastating diagnosis “glioblastoma multiforme” each year. Despite therapy, their remaining lifetime is only a half year on average. The current standard treatment can only slow the progression of the disease, because glioblastoma is still considered to be incurable.
The search for new treatment approaches
Yet why is this particular tumour so vicious? The reason for this, according to experts, is the enzyme IDH1, which is thought to be characteristically altered in some glioblastomas in association with tumour specificity. Together with the company Bayer, the researchers developed a substance that blocks a particular variant of IDH1, thus inhibiting tumour growth. It is said to be in line for a trial in near future.
Elsewhere scientists led by Dr. Maria Stella Carro from the University Hospital Freiburg (Germany) discovered “a central control mechanism” in mesenchymal glioblastomas. The protein molecule ANXA2, predominantly created in mesenchymal glioblastoma, plays a role in blood loss, cell growth and cell movement. If it is blocked, the cancer cells no longer multiply. Results were published in the freely available journal EbioMedicine.
A slightly different approach is being pursued by one senior physician in the Department of Neurosurgery at University Hospital Ulm (Germany), Professor Dr. Marc-Eric Halatsch. In his opinion, a mixture of long proven drugs and substances, in combination with the chemotherapeutic agent temozolomide, leads to the death of glioblastoma cells.
This clinical concept, targeted at recurrent forms of glioblastoma, was given the name CUSP9v3 (Coordinated Undermining of Survival Paths by 9 repurposed drugs – Version 3). Preclinical studies and so-called individual therapeutic trials were positive; a clinical study was initiated at the end of 2016. The primary endpoint of this study was safety, secondary endpoints were progression-free survival period and overall survival period.
Using “reprogrammed” immune cells against the tumour
We also hear all the more often about cancer therapies in which T-cells are genetically altered in such a way that they attack the tumour. This so-called CAR-T-cell therapy has already been able in part to achieve very good results with lymphomas and forms of leukaemia. However, their use on solid tumours is more complicated because the T-cells need to first get to the cancer cells in sufficient volumes. Behnam Badie, from the Beckman Research Institute at the City of Hope Hospital, however indicates that CAR T-cell therapy may be an option even with highly malignant glioblastoma. The results were published in The New England Journal of Medicine.
Behnam Badie’s phase I trial took in, along with six other affected patients, one 50-year-old patient. He was suffering from a glioblastoma in the right temporal lobe and had already endured surgery as well as radiation therapy and chemotherapy. Six months after surgery, however, the glioblastoma recurred. Behnam Badie and her team took blood from this patient and focused on T-cells. Working with harmless lentiviruses they then programmed the T-cells they had obtained: the virus loaded the immune cells with a gene containing information for a chimeric antigen receptor (CAR).
For each type of cancer a different CAR-expressing T-cell needs to be constructed. The immune cells created by the scientists led by Badie, for example, aimed at the tumour-associated gene IL13Rα2 (interleukin-13 receptor alpha2). Following “reprogramming” the T-cells were propagated in culture. The entire process took about 60 days to complete. When these cells are then infused into the patient they attack any cancer cells that carry the antigen.
Video: Behnam Badie
Remission in relapsed, multifocal glioblastoma
While Badie and her team were constructing CAR expressing T-cells for the 50 year old patient, the disease progressed rapidly. A multifocal glioblastoma ultimately developed (with involvement of the leptomeninx). The prognosis was very bad.
Before the patient received immunotherapy, he was operated on once again. The doctors were able to remove three of the five tumours. Then the doctors applied the “reprogrammed” T-cells once a week directly into the cavity produced by the removal of one of the tumours in the patient. Although tumour growth was indeed able to be brought to a halt for more than 45 days at this location, the two unremoved tumours continued to grow.
Moreover two new metastases were formed in other brain regions. Therefore the physicians decided to administer the “reprogrammed” T-cells via a second catheter into the right lateral ventricle. The reason for this was that the immune cells would be best able to reach the metastases via the CSF pathways. The result was impressive: after another five infusions (day 190), all tumours had decreased by 77 to 100%. This remission lasted for about seven months.
Video: CAR T-cell therapy
Only mild side effects
It was stated that the patient tolerated the immunotherapy well, and that within 72 hours following the infusion only mild side effects such as fatigue, headache, anxiety disorder or myalgia occurred. Serious or even life-threatening adverse effects were not noted by the team led by Badie. In addition, the quality of life of the study participant undertaking the CAR T-cell therapy significantly improved according to the authors – systemic glucocorticoid therapy was no longer needed and he was able to return to everyday activities.
“Unfortunately, the patient’s disease eventually returned after 16 cycles (228 days after the first CAR-T cells treatment) in four new locations […]”, the authors say in their study. Why these tumours occurred is something being currently investigated. The preliminary results indicate that the expression of the tumour-associated gene IL23Rα2 had decreased.
Nevertheless, the study participant would hardly have survived without the treatment for so long. Whether CAR T-cell therapy will achieve such positive results with the other patients, or whether the 50 year-old is an isolated case, will probably only be established by the end of the study in two years.