Glioblastoma multiforme (GBM) is a highly invasive tumour of the glial tissue that supports and nourishes the brain and the most common primary brain tumour and the most invasive of the glial tumours. Patients usually present with generalised signs of intracranial pressure, behavioural changes and seizures. Although GBM usually occurs in the brain, it can affect the spinal cord and the brainstem (especially in children) and is associated with a poor prognosis, with an average survival of 15 months.
GBM constitutes 15 per cent of all nervous system tumours and commonly occurs in adults aged 45 to 70 years, although it is also seen – albeit much less commonly – in children.
GBM treatment is not curative due to the extent of the tumour on presentation. Goals of palliative treatment include improvement of progression free survival (PFS), overall survival (OS) and quality of life. Current standard of care for newly diagnosed GBM is tumour resection followed by radiotherapy with concomitant systemic temozolomide followed by adjuvant temozolomide. Therapeutic options for patients with recurrent GBM are very limited.
There are many innovative vaccines in development that could offer patients new treatment options
More than a quarter of newly diagnosed patients achieve significantly increased survival with adjuvant chemotherapy; however, none of the currently approved therapies achieves prolonged remission, median time to recurrence after standard therapy being 6.9 months, and chemotherapeutic agents introduced over recent decades have only improved median survival by a few months. Even agents approved within the last decade – a wafer formulation of carmustine (Gliadel) for implantation into the post-surgical tumour cavity and temozolomide (Temodal), an oral imidazotetrazine derivative of the alkylating agent dacarbazine, which readily crosses the blood brain barrier – have only shown modest improvements in overall survival in the majority of patients.
Of the chemotherapeutic agents in development, Adis R&D Insight currently lists 47 drugs in preregistration for regulatory approval or in phase 3 or phase 2 trials for treatment of glioblastoma. Two of these, humanised IgG1 monoclonal antibody bevacizumab, an angiogenesis inhibitor/vascular endothelial growth factor A (VEGF-A) inhibitor, and nimotuzumab, an epidermal growth factor receptor (EGFR) inhibitor, have shown significant improvement in survival and are already marketed in some countries. Bevacizumab is in the preregistration phase in the EU for treatment of glioblastoma as first-line therapy in newly diagnosed patients in combination with radiotherapy and temozolomide following positive results from phase 3 studies.
Novel chemotherapy agents
A major focus in GBM chemotherapy is inhibition of angiogenesis. Following approval of nimotuzumab, many novel EGFR inhibitors are in development including intradermal EGFR inhibitor rindopepimut, which is in phase 3/2 development for first- and second-line combination therapy of newly diagnosed or recurrent GBM in many countries, including fast-track status in the USA. Other EGFR inhibitors include oral erlotinib, lapatinib and gefitinib, all in phase 2 trials in the USA, and oral dacomitinib in phase 2 trials in Spain.
Another angiogenesis inhibitor, cilengitide, is in phase 3 development in Germany and the US in combination with temozolomide and radiation therapy, in newly diagnosed patients, and phase 2 in Germany in combination with temozolomide in adolescents and children. The oral anti-angiogenesis agent lenalidomide is in phase 2 development for GBM in the USA.
Many agents have been unsuccessful. One of these, the pan-VEGF inhibitor cediranib, was discontinued at phase 3 due to disappointing results from pivotal studies.
The immunostimulant polyinosinic-polycytidylic acid with polylysine and carboxy-methylcellulose (poly ICLC) is a biological response modifier acting as a toll-like receptor 3 (TLR3) agonist on dendritic cells, being developed for the treatment of GBM. Phase 2 trial results in patients with newly diagnosed GBM showed that intralymphatic poly ICLC in combination with radiation therapy resulted in modest improvements in PFS rate when used in combination with chemotherapy agents such as temozolomide.
Of the many other agents directed at specific targets, intravenous temsirolimus, a mammalian target of rapamycin (mTOR) protein inhibitor, and oral vismodegib, a hedgehog cell-signalling pathway inhibitor, are both in phase 2 clinical development.
Overcome temozolomide-resistance
Response to temozolomide depends on the presence of methylated methylguanine-DNA methyltransferase (MGMT) promoter. Abnormally high MGMT enzyme activity (and subsequent de-methylation of the MGMT promoter) is seen in 40–70 per cent of GBM patients, who have a worse prognosis and reduced response to temozolomide and other alkylating agents due to repair of tumour cell DNA. High-intensity temozolomide regimens are being investigated to see whether they can suppress MGMT activity but this approach is limited by toxicity. In other attempts to overcome temozolomide-resistance, the MGMT enzyme has been identified as a potential therapy target. Although preclinical and early clinical research suggests that inhibition of MGMT and down regulation of MGMT gene expression may improve response and reduce toxicity to high-dose temozolomide, there is no reported clinical development.
Some agents such as VAL 083 (in phase 1/2 development for second-line therapy or greater for recurrent glioblastoma in the USA) show better in vitro efficacy against brain tumour cells than temozolomide, and appear to overcome MGMT-associated drug resistance.
Also of note, the buccal spray nabiximols – an analgesic combination of delta-9-tetrahydrocannabinol and cannabidiol marketed for treatment of cancer and neuropathic pain and muscle spasticity, and the first cannabinoid investigated for GBM treatment – has been shown to improve therapeutic efficacy of temozolomide. Nabiximols inhibits glioma cell growth and viability via apoptosis and is currently in phase 1b/2a development in the UK in combination with dose-intense temozolomide in patients with first recurrence after standard therapy.
Intratumoural formulations
Although adjuvant chemotherapy can prolong survival, many agents are blocked by the blood-brain barrier, and intratumoural formulations are in development to deliver higher concentrations of the chemotherapeutic agent direct to the resected tumour cavity with minimal systemic effects.
An intratumoural formulation of vocimagene amiretrorepvec-flucytosine (VAF) gene therapy is in phase 1/2 development in the USA for recurrent GBM and an oral formulation of this agent is also in phase 1/2 development.
In Germany, parvovirus H1 (H iPV; ParvOryx) – an oncolytic virus product – is under phase 1/2 investigation as an intratumoural agent in patients with progressive primary or recurrent GBM.
Immunotherapy/vaccine therapy
Several immunotherapy vaccines are in development. All use technologies designed to ‘arm’ patient-derived cells to enable the immune system to directly recognise and destroy tumour cells, and as such are patient specific.
AV 0113 is a cytotoxic T lymphocyte stimulant in phase 2 development for GBM as first-line adjuvant therapy in combination with temozolomide and radiotherapy. AV 0113 is administered intralymphatically and is based on the patient’s antigen-presenting interleukin-12 (IL-12) secreting dendritic cells charged with a lipopolysaccharide-stimulated autologous tumour antigen. Another dendritic cell-based vaccine, DCVax-Brain personalised immune therapy, is in the preregistration phase in patients with GBM in Switzerland. DCVax® is manufactured from the patient’s dendritic cells pulsed with tumour cell lysate. ‘Loaded’ dendritic cells are injected intradermally back into the patient. The vaccine is also in phase 3 trials for GBM in the US, the UK and Germany.
A T-cell-based immunotherapy – Immuncell-LC – is in phase 3 development for first-line adjuvant therapy of GBM in South Korea. Another T-cell stimulant, intradermal ICT 107, is in phase 2 development in the USA as an intradermal vaccine for first-line therapy. For the ICT 107 vaccine, dendritic cells are harvested and cultured with antigens known to be expressed in a number of cancers, including GBM.
Subcutaneously administered vaccine ITK 1 has a different mechanism of action from the cell-based vaccines described above. ITK 1 is a personalised immunostimulant vaccine optimised for each patient. Treatment involves selecting high-response peptides for each patient by determining the specific immune response to all the available peptide vaccine candidates. ITK 1 is in phase 3 development in Japan for second-line or greater therapy of GBM.
Moving beyond palliative treatment
Despite some recent advances, treatment of GBM remains palliative and only modest improvements in survival have been achieved in newly diagnosed patients with the latest chemotherapy agents bevacizumab, nimotuzumab and temozolomide, and therapeutic options for recurrent disease remain very limited. Investigational agents include chemotherapy agents targeting a wide range of biological effector molecules and pathways, novel formulations for delivery of chemotherapy with better risk: benefit profiles, gene therapy and immunotherapy (vaccines). Of the latter, there are many innovative vaccines in development that will offer patients new options. This, together with advances in gene therapy and illuminating research into MGMT effects on response to alkylating agents, should lead to increasingly individualised treatment for GBM in the not too distant future.
