Immunotherapy offers a promising bet against brain cancer

Abstract

he stars seemed to be aligned for rindopepimut in 2015. A trio of clinical studies had indicated strongly that this peptide-based vaccine elicited an immune response that could meaningfully delay the progression of glioblastoma multiforme (GBM), the most aggressive form of brain cancer. The vaccine's manufacturer, Celldex Therapeutics of Hampton, New Jersey, lobbied the US Food and Drug Administration for accelerated approval on the basis of phase II data but the agency demurred, preferring to wait for the results of a phase III trial. Unfortunately, that trial was a failure. An interim analysis of the data in early 2016 indicated no improvement in the survival of people with GBM who received the vaccine, and Celldex terminated its development. Patients and clinicians were deeply disappointed, but not necessarily surprised. "Neuro-oncologists tend to be nihilistic in a lot of ways, just because we have seen so many treatments come and go, " says E. Antonio Chiocca, neurosurgeonin-chief at Brigham and Women's Hospital in Boston, Massachusetts. GBM is also the most common form of brain cancer, accounting for around 50% of primary malignancies, and these tumours are almost always fatal. Surgery, chemotherapy and radiotherapy offer only short-term respite to those affected. The treatment of other tough-totackle cancers, including melanomas, has been Neurosurgeon John Sampson places a treatment-infusing catheter into the brain of a patient with glioblastoma multiforme.

Molecular Heterogeneity and Immunosuppressive Microenvironment in Glioblastoma

“…A follow-on randomized trial in GBM patients showed significant progression-free and overall survival in patients who received CMV-specific DC vaccination ( 179 ). Another exciting theme involves use of CART-cell therapy (chimeric-antigen receptor T-cell therapy), in which immune receptors are specifically engineered to generate an immune response when they face tumor proteins ( 180 ). A study in recurrent GBM patients, targeting a type of EGF, using CART-cell therapy, was found to kick-start an immune response at the site of the glioma including infiltration by T reg cells ( 181 ).…”

Dual functionalized brain-targeting nanoinhibitors restrain temozolomide-resistant glioma via attenuating EGFR and MET signaling pathways

“…Nanoinhibitors containing cMBP peptides conjugated on the G4 PEGylated dendrimer have been shown to efficiently reduce the proliferation and invasion of human glioblastoma cells by blocking MET signaling with remarkably attenuated levels of phosphorylated MET and its downstream signaling proteins, such as pAKT and pERK1/2 28 . However, with the presence of BBB, glioma patients hardly benefit from immunological therapy 30 . Generally, the BBB formed by tightly packed cells lining the walls of vessels prevents harmful toxins and bacteria in the blood stream from entering the vital organ.…”

“…cMBP, a MET targeting peptide which has been developed for tumor imaging and gene delivery 27 , has a therapeutic efficacy to block MET signaling and provides a potential approach for the treatment of glioma 28 . However, glioma patients hardly benefit from targeting therapy because of the presence of blood-brain-barrier (BBB), a tightly sealed filter formed by blood vessels that prevents unwanted biomolecules and drugs from accessing the brain tissue 29,30 . Encapsulation of poly-2methacryloyloxyethyl phosphorylcholine (PMPC), a zwitterionic polymer plays an important role in delivering small molecular drugs, antibodies or peptides to the central nervous system owing to its excellent biocompatibilities 31 , empowers the nanocarriers with a biomembrane-like structure, providing a biocompatible chemical structure which is the basis for an ability to circulate for a long time in the blood.…”

Generation of Tumor Targeted Dendritic Cell Vaccines with Improved Immunogenic and Migratory Phenotype

“…Moreover, patients randomized to Td showed a statistically significant increase in survival time compared to those receiving the control pre-conditioning. Follow-up data on these patients has revealed nearly a third of this cohort to be long-term survivors without any evidence of tumor recurrence [30,31].…”