LATEST BREAKTHROUGHS IN TREATMENT FOR GLIOBLASTOMA

Glioblastoma (short for Glioblastoma Multiforme) is one of the most common primary adult brain tumors and one of the most fatal cancers diagnosable. Progress in Glioblastoma diagnostics and treatment has been slow until the recent development of cutting-edge genomic sequencing technology.

This article aims to explore the latest breakthroughs in Glioblastoma treatment, covering differences in new Glioblastoma subtypes and precision medicine diagnostics, surgical enhancements, and advancements in chemotherapy, immunotherapy and complementary approaches.

Brief Overview of Glioblastoma

Glioblastoma is currently classified as a grade IV brain tumor due to its high malignancy, predisposition to necrosis and mitotic activity (being able to rapidly divide and grow). The average survival rate for Glioblastoma is currently around 15 months, with as few as 5.5% of patients living past the 5^th year from the date of diagnosis.

There are two main Glioblastoma types: primary and secondary, each of which have unique origins:

• Primary Glioblastomas account for 80-90% of Glioblastomas and currently have no true known origins. They have one of the most aggressive profiles due to being made up of multiple unique cancer cell lines and are viewed by some researchers as a cluster of miniature tumors. As a result, all primary Glioblastomas tend to look radically different from one another (more so than other types of tumors), and this feature often compounds poor treatment outcomes. Recent research over the last decade has suggested that these tumors arise from cancer cell mutations in glial stem cell lines, which has helped scientists to identify new therapeutic targets.^[1]
• Secondary Glioblastomas are thought to develop from lesser types of gliomas (glial cell cancers), such as Astrocytoma or Oligodendrocytoma, and usually take between 2-5 years to develop. These are more prevalent in older adults in their 40s.

There are other further classifications of gliomas, including Glioblastoma, that refer to their physical characteristics, such as small-cell or large-cell gliomas. Over and above these distinctions, Glioblastomas have been further divided into genetic subtypes (see below).

Metastatic or Recurrent Glioblastoma. Recurrence is one of the most frequent complications of Glioblastoma and is often associated with a reduced survival rate. Recurrent Glioblastomas are known to be less uniform in presentation and more difficult to treat with a higher resiliency.

Prevalence. Glioblastoma is known to be the most common primary brain tumor diagnosis, accounting for up to 45% of cases. It is most prevalent in the elderly, men, and individuals of Caucasian ethnicity.

Risk Factors. The greatest risk factors for developing Glioblastoma include ionizing radiation exposure and cell phone use.

Diagnostics. Over the last couple of decades, MRI has been the diagnostic standard for detecting Glioblastoma. Recently, genomic sequencing has allowed for additional diagnostic testing, including IDH mutation, MGMT methylation status and GFAP detection. These are discussed in more detail in the following section.^[2]

Standard Treatment. Surgery, radiotherapy and chemotherapy are the most prescribed treatment options. As full surgery is not always possible depending on the location and size of the tumor, surgeons aim for maximal safe surgical resection, in which only part of the tumor is removed.

This is usually followed by intensive composite chemoradiation therapy with Temozolomide, particularly in the case of Glioblastoma with MGMT methylation. Temozolomide may not be prescribed to those with unmethylated tumors. Prolonged use is associated with bone marrow loss and fatigue. Radiation therapy is typically prescribed for 6 weeks and may be shortened or tailored for individuals over the age of 80, for whom hypofractionation may be a better option. Physically fitter elderly individuals may benefit more from chemo alone, while those unfit may benefit more from radiotherapy alone.

Prognosis. Despite available therapies, diagnosis often occurs late and the prognosis remains poor, even with complete treatment. Treatment has been shown to enhance survival rates by an average of 6-12 months. Metastasis and/or tumor recurrence are the most common outcomes and appear to commonly occur 6 months post-surgery.

Current Breakthroughs and Future Directions in Glioblastoma Treatment

Breakthroughs in the treatment of Glioblastoma and other brain tumors have focused on improving surgical techniques, chemo drug delivery, immunotherapy and precision medicine ( incorporating genomics).^[3]

Several recent advancements with key highlights are briefly summarized below.

Glioblastoma Diagnostics and Classification

In recent years, genomics has enabled the identification of four new subtypes of Glioblastoma, as well as the detection of rare astrocytomas that were previously diagnosed as Glioblastoma. Diagnostic centers are beginning to use wider panels that assess for all novel genetic biomarkers in order to enhance current diagnostics, making use of many more genetic markers. In time, treatments can be tailored to account for Glioblastoma subtype differences and response rates.

The Glioblastoma subtypes consist of the following^[4]:

• Classical Glioblastoma is thought to have originated from tumorigenic astrocytes. This is the most common subtype and is believed to be the most responsive toward treatment on average. The survival rate is roughly 14.7 months.
  It is associated with amplification of EGFR (epidermal growth factor receptor) and chromosome 7, a loss of chromosome 10 and CDKN2A/B, as well as a lack of TP53 mutations. Neural stem cell marker NES, alongside Notch and Sonic hedgehog signaling pathways, were upregulated in this subtype.
• Neural Glioblastoma. Neuronal projection, as well as synaptic and axonal transmission, are thought to be features of neural Glioblastoma. It has been argued whether this is a true type of Glioblastoma, as its genetic signature has not been detected across all studies^[5]. It is thought to have arisen from either oligodendrocytes, astrocytes or neurons.
  This type’s discovery has been linked to neuronal markers as opposed to the pro-neuronal growth markers of the pro-neuronal type. These include NEFL, GABRA1, SYT1 and SLC12A5.
• Pro-Neural Glioblastoma. The pro-neural type is likely to have arisen from carcinogenic oligodendrocytes and is found more in children and young adults. This type can convert over time into a mesenchymal Glioblastoma with a high propensity for metastasis.^[6] Pro-neural Glioblastoma survival averages 17 months.
  It carries associations with amplification of CDK4 (cyclin-dependent kinase 4) and PDGFR-a (Platelet Derived Growth Factor Alpha), upregulation of oligodendrocyte growth genes (OLIG2 and NKX2-2), increased pro-neural growth markers (SOX genes, DCX, DLL3, ASCL1 and TCF4) as well as point mutations in the IDH1 gene.
• Mesenchymal Glioblastoma. This type is considered to be the most aggressive subtype, associated with the highest degree of inflammation, necrosis and metastatic activity, as well as a high accumulation of immune-suppressive macrophages and microglial cells. It likely originates from pro-neural Glioblastoma and/or carcinogenic astrocytes. Those with mesenchymal Glioblastoma survive 11.5 months on average and are the most prone to radiotherapy resistance.^[7]
  Precision markers linked to the mesenchymal type of Glioblastoma include loss of NF1 (Neurofibromatosis type 1), metabolic mutations in the PTEN/Akt pathway, upregulation of TNF and NF-kB inflammatory genes as well as associations with the biomarkers CHI3L1 (YKL40), MET, CD44, and MERTK.

IDH: Wildtypes and Mutations. Gliomas presenting with features of Glioblastomas that show isocitrate dehydrogenase (IDH) mutations have been reclassified as grade IV diffuse IDH-mutant astrocytomas. These tumors average better survival rates compared to Glioblastoma. Diffuse gliomas with wildtype IDH can be diagnosed as Glioblastomas if found in adult patients. In children, diffuse gliomas with wildtype IDH may possess the K27 variant, while in adolescents and young adults, they may possess the G34 variant, either of which has been shown to rule out the possibility of Glioblastoma.^[8]

MGMT (O6-methylguanine-DNA methyltransferase) Methylation and Prognosis. MGMT is a novel biomarker that is currently being used to distinguish outcomes in patients with Glioblastomas. Its presence suggests under-methylation of the tumor, which is associated with improved tumor regeneration and growth as well as a worse prognosis. Methylated tumors possess less MGMT, which indicates that the tumor has a reduced ability for DNA repair and is more susceptible to the effects of chemo drugs.^[9] Approximately 40% of Glioblastoma patients have methylated tumors with little to no MGMT, suggesting better treatment responses, a 50% increase in survival and a longer time till tumor recurrence post-surgery. In those with unmethylated tumors displaying higher MGMT levels, it has been shown that current chemotherapy, including Temozolomide, is entirely ineffective and ought to be avoided. ^[10]

Surgical Techniques

Standard surgical resection for Glioblastoma is similar to other types of Glioma surgery. The outcomes of patients with Glioblastoma that opt for surgery depend upon the quality and safety of the surgery administered.^[11] Surgical advancements have progressed towards better tumor imaging techniques and less invasive surgical options:

Intraoperative MRI has allowed for better tumor mapping and has improved the success rates of total resection across brain tumor patients by more than double.^[12]

Fluorescent Tumor Definition. 5-ALA (5-Aminolevulinic Acid) is a substance administered to cause fluorescence in the tumor that allows for the tumor to be seen and accurately removed by a surgeon. The success of 5-ALA is on par with intraoperative MRI.^[13]

Wider Resection Scope. Some studies suggest that recurrence often occurs within a 2 cm radius around the original tumor site and that prognosis may be improved if surgical resection is slightly extended into this area.

Laser Interstitial Thermal Surgery is a new surgical technique that involves heating the tumor with a fiber optic laser. It is currently used to remove small tumors that have been well mapped out and that reside in deeper brain compartments. Studies reveal that in these applications, laser interstitial thermal therapy works better than ordinary surgical resection, with comparable survival outcomes that can be additionally improved upon with chemoradiotherapy.^[14]

Frequency-Based Modalities

Electromagnetic stimulation has been gaining popularity in recent years due to being entirely non-invasive and offering a wide range of therapeutic actions. The most prominent frequency-based therapies include ultrasound and tumor-treating fields:

Ultrasound. Ultrasound may be used as a diagnostic tool, a treatment option as well as a chemo-enhancing agent. Focused ultrasound has been shown to increase blood-brain barrier permeability, allowing for higher saturation of the tumor with chemotherapeutics. One study revealed that Temozolomide concentrations increased by as much as 15-50% in Glioblastomas after ultrasound therapy. This application is currently undergoing phase I/II clinical trials.

Tumor-Treating Fields are devices that can be worn on the head which deliver an alternating electrical current to the brain at a low intensity, averaging 100-300kHz. They have been approved by the FDA for use since 2015 to treat glioma, including Glioblastoma. Their benefits extend to promoting tumor cell death, reducing tumor repair capabilities, inhibiting metastasis, increasing tumor permeability (allowing for better drug penetration), as well as boosting immune function and anti-tumor activity.^[15] Tumor-treating fields have the potential to extend the treatment-free progression and overall survival rates of other treatment options by 20-30%.^[16] 

Radiotherapy

Radiotherapy has yielded mixed results for patients with Glioblastoma, before and after surgery. In many cases, radiotherapy can increase the size of the tumor, which is attributed to underestimating the required radiation dose.

Adaptive radiotherapy is an attractive option for limiting radiotoxicity to surrounding brain structures. This is achieved through real-time imaging of the brain during therapy. Studies are currently underway that are testing the efficacy of an MRI-assisted linac radiotherapy system for this purpose.^[17]

Proton therapy may be a better option than current intensity-modulated radiotherapy due to its higher selectivity for target tissues and lower toxicity rates. A promising avenue for preventing metastasis of Glioblastoma post-surgery, Proton radiotherapy is associated with reducing the risk for cancers of the head, neck and spinal column.

Chemotherapy Advancements

There are several hundred trials currently underway testing the efficacy of chemotherapeutic drugs specifically designed to treat markers of Glioblastoma. Of these, a few ground-breaking discoveries are explored below:

Mutation-Specific Therapeutics. TERT promoter mutations are common in up to 80% of all Glioblastomas. TERT inhibitors are currently being investigated for their actions against tumor-specific telomerase, which directly targets cancer cell growth and division. While preliminary studies have been promising, more research is required before human trials can be commissioned. Other Glioblastoma mutations that have recently been of interest in test-tube studies include BRAF V6ooE, FGFR TACC1/TACC3 and EGFRvIII, for which mutation-specific chemo drugs and therapies are currently being investigated. NTRK may be a novel target for treating pediatric Glioblastoma.

Chronotherapy. Studies assessing the circadian rhythm of tumors have highlighted new approaches for treating Glioblastoma. Conventional Temozolomide treatment may be better implemented in the morning than in the evening as it appears to have a much greater efficacy with fewer side effects that align with Glioblastoma circadian signaling.^[18] Chronotherapy may not pose benefits with respect to the timing of surgery or radiotherapy on Glioblastoma, despite having positive effects with these therapies on other cancer types.

Improved Chemodrug Delivery Methods. Most drug delivery methods have focused on even distribution when administering directly into the brain during biopsy or surgery, or through enhancing uptake by the blood-brain barrier via intravenous or oral means. Nanoparticles and cell-mediated delivery methods are also being investigated. CAR T Cell therapy, genetically modified neutrophils, macrophages, other immune cells and stem cell lines may all make for ideal drug delivery candidates, as well as vehicles for tumor-infecting viruses.

Other Chemotherapeutics. Many other novel therapeutic targets have been identified for treating patients with Glioblastoma, including enzyme inhibitors (especially tyrosine kinase inhibitors), small tumor protein inhibitors, gene silencing agents and many combinations of all the above.^[19] These are expected to play a role in enhancing future treatment through precision targeting of patient-specific Glioblastoma.

Immunotherapy

Glioblastoma is known to effectively evade and suppress the immune system through secreting various anti-inflammatory compounds (cytokines) which prevent a wide variety of immune cells from detecting it or attempting to remove it.^[20]

Several immunotherapies are currently being developed with the aim of enhancing the immune system’s ability to destroy the tumor. Some of the main treatment problems that are being explored as therapeutic targets pertain to antigen detection, the impermeability of the blood-brain barrier, “exhausted” (suppressed) T lymphocytes and a higher proportion of anti-inflammatory regulatory T lymphocytes.

Recent advances in Glioblastoma immunotherapy have only shown little to no benefit in the overall survival rate of patients. Some of these developments are discussed briefly below.^[21]

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors are immunotherapeutic drugs used in oncology to improve tumor detection and the immune system’s ability to destroy the tumor. They target proteins called immune checkpoints which are produced by both immune and cancer cells. Checkpoints lower immune reactivity toward tumors, often helping the tumor to evade detection.

There are two main immune checkpoints that are being investigated in Glioblastoma treatment: programmed cell death protein 1 (PD-1) and its receptor (PD-Ligand 1), as well as CTLA-4 (Cytotoxic T-Lymphocyte-associated antigen 4). Hypermutated Glioblastomas with larger volumes of CD8+ T lymphocytes may be more responsive to this type of immunotherapy.

Bevacizumab inhibits VEGF, reduces tumor vascular abnormalities, and is known to inhibit PD-1. Across trials, its use is associated with delaying tumor progression in those with recurrent Glioblastoma. Lower doses administered at further times apart nearly doubled this improvement from 3.22 months to 5.89 months^[22]. More studies are required to assess the optimal dose and application for bevacizumab. It also proved to have a better or similar efficacy to other PD-1 inhibitors, such as nivolumab, which has far more severe side effects.^{[23] [24]}

Ipilimumab is a CTLA-4 inhibitor currently being investigated. It has been shown in animal studies to reduce immune tolerance towards tumors and greatly improve their detection, resulting in tumor regression and prolonged survival.^[25] The combination of ipilimumab with nivolumab delivered intravenously to patients with Glioblastoma yielded very poor results^[26]. Future trials with ipilimumab alone will reveal whether it can help promote survival and slow disease progression when paired with bevacizumab or not.

Anti-Glioblastoma Vaccines

Several types of vaccines are being continuously tested for treating Glioblastoma in the hopes that they will increase the immune system’s responsiveness toward the tumor and its proteins. Despite some progress, most vaccine studies have not been very successful in terms of improving patient survival or health-related quality of life. They have averaged enhancing overall survival rates by 8-12 months as well as inhibiting tumor progression for roughly 3-4 months.

Anti-Tumor Vaccine Mechanisms. The vaccines typically target tumor proteins by making direct use of tumor proteins, heat shock proteins, viral proteins or through modifying immune cells before re-injecting them back into the patient. Of all these methods, pre-conditioning immune cells appears to be one of the better-tolerated approaches with the best results. Immune cells can better pass through the blood-brain barrier and, if pre-conditioned, tend to have a higher selectivity for Glioblastoma. While other vaccine methods can theoretically increase the permeability of the blood-brain barrier due to eliciting an immune reaction, they are likely to provoke non-selective systemic reactions that reduce the chances of success.

DCVax-L Vaccine. One vaccine that has a proven higher efficacy than the rest would be DCVax-L, in which dendritic cells are pre-conditioned with proteins from the tumor before being injected back into the patients. Dendritic cells detect tumor antigens and signal to the rest of the immune system. Recent developments in this type of vaccine have been used to target Glioblastoma stem cell lines, which have been found to be resistant to chemoradiotherapy. Trials revealed that this vaccine extended average overall survival rates for primary Glioblastomas by 22.4 months after surgery, methylated (MGMT) Glioblastoma by 33 months post-surgery and recurrent Glioblastoma patients by 13.2 months. Just under 21% of patients with recurrent Glioblastoma lived for 2 years (vs 9.6%) and about 11% lived for 3 years (vs 5.1%) after receiving the injection.^[27] Genomic studies suggest that those with classical Glioblastoma will respond the best to dendritic cell vaccines, which supports these results as the classical type is the most common in adults.

CAR T Cell Therapy

Chimeric Antigen Receptor (CAR) T cell therapy is an immunotherapy that has been slowly gaining popularity in the treatment of various types of cancers. It works by modifying lymphocytes in such a way that allows them to detect specific tumor antigens (foreign proteins) prior to being injected into the patient. The signals from the injected CAR T cells promote an immune response against their specific antigens that engages other immune cells from the patient, theoretically strengthening the immune system’s ability to detect the tumor through homing in on its antigens.

Glioblastoma CAR T Cell Therapy Targets Stem Cells. One benefit of CAR T cell therapy over other new treatments is that it can target Glioblastoma stem cell lines, making it potentially complementary to surgical resection to avoid recurrence or disease progression. Several Glioblastoma stem cell antigens have recently been tested in small CAR T Cell Therapy trials. These include EGFR-vIII (Epidermal Growth Factor Receptor Variant III), HER2 (Human Epidermal Growth Receptor 2) and IL-13 Ra2 (Interleukin-13 receptor alpha 2). Most of them were able to extend survival by an average of 8-11 months without recurrence near the original tumor site, yet recurrence occurred in some participants at distant brain and spinal areas. A small number of patients across studies showed improved survival and disease-free progression for 24-33 months after the trials ended. The CAR T cells largely disappeared in the weeks after treatment stopped, with low numbers remaining present in circulation.^[28]

Trivalent CAR T Cells May Be Able to Eradicate Glioblastoma. One study managed to eradicate up to 100% of Glioblastoma tumor cells across 15 patients using trivalent CAR T Cells. Using viral DNA, these T cells were modified in such a way that they targeted three different antigens which were found evenly dispersed inside all the patient’s Glioblastoma tissues. Survival rates and tolerability of the treatment were not recorded, and neither was the rate of tumor recurrence post-treatment. In the future, this discovery is expected to revolutionize treatment options, highlighting the importance of a multimodal approach in Glioblastoma therapy.^[29]

Other

There are several other types of immunotherapies currently being researched and developed, some of which make use of cytokines or “suicide genes”. Both cytokines and suicide gene therapy may be able to enhance the efficacy of chemotherapy by increasing their toxicity to tumor cells. Many combinations of these and all the above immunotherapies are also currently being followed up in early human trials. Immunotherapy can expect to see more rapid advancements over the next decade or two.

Oncolytic Viral Therapy

Viruses have the ability to infect any cell and change its genetic code in a way that can be either beneficial or detrimental. Many viral strains have been tested for their effects against brain tumors over the last couple of decades. Genetic modification has made several improvements to this type of treatment, however, progress is still slow, even after 20+ years of testing. A handful of patients from every study appear to achieve partial to full remission in response to viral therapy, while the rest show slowed tumor progression. Most viral therapies do not yet improve survival rates.^[30]

A couple of oncolytic viral therapy highlights are reviewed below:

• DNX-2401 (Delta-24-RGD; tasadenoturev) is a modified adenovirus variant that has anti-Glioblastoma activity. The way in which it has been genetically altered prohibits it from infecting ordinary brain cells while allowing it to specifically infect malignant glioma cells. In vitro studies reveal that it promotes tumor cell death and enhances immune reactivity towards the tumor’s antigens, promoting sustained immune detection and clearance of the tumor. In a recently completed trial where tumors of the patients were injected with the virus, overall survival was not greatly enhanced by comparison to other novel treatment options, being extended by 9.5 months on average. However, the size of the tumors decreased in 18 of the 25 participants, with three of them seeing a greater than 95% reduction. 20% of the cohort survived for longer than 3 years post-treatment.^[31]
• Newcastle Disease Virus MTH-68/H. In a very small pilot study on four participants with high-grade gliomas, recurrent administration of MTH-68/H allowed participants to survive long after receiving their diagnosis (5-9 years) and resume ordinary lives. ^[32]

Complementary Treatment Considerations

Despite a lack of human trials, complementary treatments may be able to enhance the prognosis for those with Glioblastoma. These include lifestyle, dietary and supplemental interventions that aim to protect the brain from inflammation, boost immune function and counteract potential side effects of conventional therapies, including chemo drug resistance.

In the context of Glioblastoma treatment, antioxidants can help to protect the brain from toxicity arising from both treatment and the tumor itself. In animal and test-tube studies, several dietary and supplemental antioxidants lowered brain inflammation and, in some cases, helped to shrink the size of the tumor by promoting cancer cell death. These include melatonin, curcumin and piperine, alpha-lipoic acid^[33], quercetin, resveratrol, gingerol, berberine and many other phytochemical compounds. Studies on some of these agents, such as quercetin, highlight their usefulness in Glioblastoma prevention^[34], which suggests they may help to lower the risk of post-surgical recurrence.

Extracts of these natural compounds may prove more effective than dietary sources. Consuming a nutrient-dense diet is likely to also improve health outcomes and quality of life in Glioblastoma patients. Due to their limited bioavailability, researchers are developing methods for enhancing the uptake of these antioxidant compounds into the brain in order to enhance the efficacy of treatment.^[35]

Conclusion

Due to recent breakthroughs in genomics, the treatment and diagnosis of Glioblastoma is expected to change dramatically and for the better. With the discovery of three new Glioblastoma subtypes and other subtle genetic distinctions, therapeutics can be accurately tailored to adequately treat each patient. Strategies for precision treatment include Glioblastoma vaccines, oncolytic viral therapy and carcinogenic inhibitors. These enhancements, coupled with optimal timing and enhanced drug delivery methods, have been shown to improve patient survival in preliminary trials by 50-100% on average. Developments in imaging techniques have begun to improve upon both surgery and radiotherapy, with laser surgery and proton therapy both contributing towards better outcomes, respectively.

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