It left me paralyzed, but every time I met his wife she thanked me for my care and for convincing her not to have an abortion.
My next memorable glioblastoma (GBM) patient was my husband, who showed up after running a marathon. In the examination room, her doctor asked her to lift her right leg, and my husband quickly fell to the side. As a pathologist and oncologist, the diagnosis was obvious and the result could not be denied. With aggressive treatment and clinical trials, we have had 3 years, still not enough. It was clear to me that a lot more research was needed.
We have treated GBM the same for 30 years. Although surgical techniques and radiation therapy have improved, chemotherapy drugs have remained the same. We always use temozolomide with radiation therapy and then continue after radiation therapy.
Currently, GBM has a life expectancy of 14 to 15 months after diagnosis.
The molecular heterogeneity of GBM makes it difficult to treat. Our chemotherapy and immune therapies do not cross the blood brain barrier and the tumor tends to mutate and become resistant to chemotherapy. Additionally, GBM also has the ability to induce immune suppression. This combination makes it extremely difficult to process and test new drugs.
The molecular markers will hopefully show us better ways to treat these tumors. These include methylation of the MGMT promoter, IDH mutations, 1p19q deletion, amplification of variant EGFR III (EGFRvIII), TP53, PTEN, PI3K, PDGF, MAPK, NOT CH1 / 3 and CDK4 / ME T.
In addition, there are several immunotherapies to consider as a potential treatment:
â¢ Checkpoint inhibitors
â¢ Monoclonal antibodies
â¢ Cancer vaccines; dendritic cell vaccines
â¢ Oncolytic viruses
â¢ Adoptive T cell therapy
â¢ Adjuvant immunotherapy
â¢ DV Vax-L
â¢ Electromagnetic fields
â¢ Radiation of the proton beam
Immunotherapies are important therapeutic alternatives in the management of brain tumors because an effective immune response could eliminate neoplastic cells. Crossing the blood-brain barrier is problematic for many therapies, and so is chemotherapy; however, some cells of the immune system have the ability to cross and infiltrate the tumor, which is an advantage over anti-tumor drugs. In glioblastoma, there is no efficient removal of tumor cells due to immunomodulation. This creates a predominantly immunosuppressive microenvironment, which allows tumor proliferation.
Several strategies are being studied to reduce immunosuppression in GBM cells.
Previously, the use of pertussis toxin (PTx) has been studied as an adjuvant therapy.1 Another study evaluated the cytotoxic effect of PTx in combination with temozolomide for the treatment of GMB.2 Survival increased after individual treatments, and this effect was enhanced with the combination of temozolomide plus PTx. PTx could be an adjuvant immunotherapeutic and integral approach against GBM due to its multiple properties, either directly in glioma cells or by modulating immunological subpopulations.
An anti-CD25 + monoclonal antibody daclizumab (Zinbryta) trial and EGFRvIII vaccination in patients previously treated with temozolomide showed responses, investigators said.3 In addition, a greater specific humoral response to EGFRvIII was observed when combined with the monoclonal antibody.
In addition, PD-1 is located on the lymphocyte membrane and is associated with immunosuppression in several tumors, including GBM. Anti-PD-1 immunotherapy was evaluated with stereotaxic radiosurgery in a mouse intracranial GBM model.4 Using combination therapy, patients experienced longer-term survival, an increase in cytotoxic T cells infiltrating the tumor, and a decrease in regulatory T cells. So far, PD-1 inhibitors have not improved survival.
Bevacizumab (Avastin) has been approved for the treatment of GBM.5 It blocks the growth of new blood vessels and is used when the tumor comes back together with chemotherapy.
Promising new drugs are abemaciclib (Verzenio), a cyclin-dependent kinase that may help in tumors with a mutation; veliparib in patients who may have BRCA mutations and DNA repair problems; ivosidenib (Tibsovo), which blocks the abnormal IDH1 and IDH2 proteins; and savolitinib, which works by blocking c-Met.
It is clear that we have a lot of work to do to prevent and treat brain tumors. We need to learn from the hereditary causes of brain tumors. Although most tumors occur sporadically, there are some genetic abnormalities that predispose people to GBM. They include neurofibromatosis, Turcot syndrome, and Li-Fraumeni syndrome. Studying these genetic causes can help find new ways to treat GBM.
In conclusion, we are far from curing GBM, far from early detection and far from new treatments. However, we must continue to try new combinations and bring science and patients closer together in clinical trials.