Overview

Advances in biomedical research have resulted in the development of therapies which can boost our immune system by training, re-training and magnifying the efforts of our immune cells and their ability to recognise and destroy cancer cells. Immunotherapy is a rapidly advancing field in healthcare that has seen significant development over the past decade. In essence, immunotherapy uses substances, either naturally occurring in the body or created in a lab, to enhance the body's immune system's ability to target and destroy cancer cells.

Glioblastoma, or Glioblastoma Multiforme (GBM) is the most aggressive form of brain cancer and the most common type of malignant tumour occurring in the brain. The disorder presents with severe neurological dysfunction and extreme headaches, drastically affecting quality of life. Accounting for around 50% of diagnosed brain cancers, the need for advanced and specific treatment methods to address this severe and deadly disease is the need of the hour. Advances being made in research into immunotherapy for the treatment of glioblastomas give us much hope for the future of cancer treatment.

Read on to learn more about immunotherapy and how it is used to treat glioblastomas.

What is a glioblastoma?

Glioblastomas are a type of aggressive, fast-growing brain tumour.¹ They are the most common form of malignant brain tumour, with an incidence of around 5 people per 100,000.² But how does a glioblastoma develop? What cells are affected and why?

Due to external causes like carcinogens, or internal faults in DNA replication or repair mechanisms, a gene in the glial cells may mutate leading to a normal cell turning cancerous.² 

The mutation causes the expression of certain genes that facilitate the formation of tumours. These tend to be genes that promote unrestricted cell replication, immunity to cell death, new blood vessel formation and immune evasion (hallmarks of cancer), which permits the cancerous cells to become basically invisible to the body’s immune system.³

Glioblastomas are most common in individuals above the age of 60 and are more prevalent in men than in women. GBM has a poor prognosis with a survival rate of 26% in the first year and 17% in the second year.³ Five-year survival rates for adults above 40 with GBM is less than 6%.⁴

Symptoms

Glioblastoma is characterised by severe and persistent headaches, issues with speech, hearing and vision issues, and loss of appetite. A progressive rapid decline in cognitive function is accompanied by personality changes and mood swings. Patients may suffer from seizures, muscle weakness or paralysis. The location of the tumour may lead to other symptoms, depending on the function of the affected brain region.^2,4 

Current limitations

Current treatment options are highly restricted due to the nature and location of glioblastomas. The rapid and invasive nature of glioblastomas results in nearby brain tissue quickly turning cancerous. As such, complete removal of the tumour is nearly impossible. The blood-brain barrier also prevents the passage of most drugs into the brain making treatment of GBM very difficult. Lastly, glioma cells differentiate, generating a varied population of tumour cells.⁴

Diagnosis and current treatment options

Several genes and cellular pathways have been implicated in the development of GBM.⁵ By testing for these molecular markers, the tumour can be diagnosed and categorised in order to be appropriately treated. 

• Initial diagnosis is done using brain imaging technology (MRI or CT scans) to determine the size and spread of the tumour. 
• A neurological examination is conducted to evaluate the extent of the impact on the patient’s cognition.¹
• Finally, a biopsy is conducted where a section of the tumour is taken for testing. The testing conducted helps reveal whether chemotherapy would help or not.

A combined approach is the current mode of treatment for GBM, entailing surgical resection, radiation and chemotherapy. These treatments, however, have a debilitating effect on the body, killing normal, healthy cells and severely reducing quality of life, all for a small chance of curing the cancer.

Here, we begin to see the need and benefits of immunotherapy, which we will discuss in the following sections.  

What is immunotherapy?

Developments in cancer treatment research may somewhat alleviate your concerns about the future of cancer in general, including the treatment of glioblastomas. Immunotherapy is a form of cancer treatment in which the patient’s own immune system is augmented so as to enable the body to more effectively detect and destroy cancer cells.⁶

Immune system and cancer

The immune system is composed of several types of cells involved in protecting your body. A type of T-cell, known as killer (or cytotoxic) T-cells, is responsible for recognising signs of cancer or death on the surface of cells. When detected, these T-cells instigate a pathway that leads to apoptosis or programmed cell death.⁷

How does immunotherapy work?

Immune cells, specifically killer T-cells, recognise tumours and invade these cells, wreaking havoc against the abnormal cells and working against the survival of the tumour.⁸ When cancer cells are particularly competent, they manage to evade detection by activating proteins that inactivate immune cells. They do so by hiding the signs of cancer from immune cells or by using the neighbouring cells to distract or obstruct the immune cells from the tumour.⁹

In essence, immunotherapy helps to enhance the functioning of the immune system, better enabling the cells to find cancer cells and destroy them. By targeting and boosting immune cells rather than killing fast-growing cells (as in other treatments), immunotherapy serves as a safer and more specific cancer treatment.⁸

Types of immunotherapy

Monoclonal antibodies (mAbs)

Antigens are surface proteins recognised by the body as a sign of damage or of a foreign agent. In response to the detection of antigens, the body releases antibodies which search the system for signs of the antigen and activate the immune system’s killer cells.¹⁰

Monoclonal antibodies are lab-made antibodies which are engineered to specifically target proteins expressed by cancer cells. In essence, they act as biological homing missiles, identifying the presence of cancer indicators and latching on to the suspect cells, leading to their destruction.¹¹

Tumours express excess VEGF (Vascular Endothelial Growth Factor) in order to create new blood vessels to facilitate their uninhibited growth. mAbs targeting VEGF have been designed against glioblastoma survival, and are in clinical trials.¹²

Bevacizumab (Avastin) is one such mAb treatment for GBM. It is administered by means of an intravenous (IV) drip. Treatment is carried out every 2-3 weeks and is administered in cycles, the first drip cycle being 90 minutes, the second of 60 minutes and the third onwards of 30 minutes.¹³

1 in 10 people experience side effects including high blood pressure, fatigue, peripheral neuropathy, fever or tummy issues.

Immune checkpoint inhibitors (ICI)

Immune Checkpoint inhibitors (ICI) are cell surface proteins which immune cells use to check the status of the various cells of the body. Cancer cells activate these checkpoints to disguise themselves from immune cells. Immune checkpoint inhibitors prevent checkpoint activation in cancer cells, as a result of which the immune cells identify it as a threat, killing the cancer cell.^6,13 

Lab-designed mAbs target and switch off such checkpoints in cancer cells, allowing the immune cells to easily detect and destroy them. Common checkpoints that these inhibitors affect are the PD-1/PD-L1 and CTLA-4 pathways. 

Immunotherapies using mAb checkpoint inhibitors are currently in use including Atezolizumab (Tecentriq), Avelumab (Bavencio), Dostarlimab (Jemperli) and more.⁶ Administration and side effects are similar to those seen in monoclonal antibody treatment administration. 

CAR T-cell therapy

T-cells are a type of immune cell characterised by T-cell receptors (TCRs). The body creates millions of possible combinations of such receptors, with each T-cell possessing just one type. These receptors may help the T-cell to recognise various antigens, belonging to bacteria, parasites or even cancer cells.⁷

Chimeric Antigen Receptor (CAR) T-cell therapy involves the extraction of T-cells from the cancer patient. These are then modified in a lab to express TCRs which have specificity to Tumour-Associated Antigens (TAAs) expressed by the tumour. Once these T-cells with chimeric receptors are reintroduced into the body, they target the cancer cells expressing these TAAs.^14,15 

T-cells are collected by leukapheresis in a specialist centre. Genes for the particular CAR are inserted into cultures of these T-cells. Once manufacturing of CAR T-cells is complete, the patient undergoes lymphodepletion, following which CAR T-cell infusion is carried out.^16,17

Side effects commonly include Cytokine Release Syndrome which presents as high fever, fatigue and sometimes low blood pressure or hypoxia. ¹⁶ These are routinely treated as part of the procedure. After 2-4 weeks, no side effects are expected and testing for CAR T-cell persistence is conducted after 3 months. Some examples of CAR T-cell therapies in use include Tisagenlecleucel (Kymriah), Axicabtagene ciloleucel (Yescarta), and Brexucabtagene autoleucel (Tecartus)¹⁷

Challenges and limitations

Side effects

Immunotherapy is much safer than other cancer treatments like chemotherapy and radiation. Apart from a few low-risk common side effects, severe complications are rare. However, it must be noted that there is a non-zero chance of such complications arising from immunotherapy. Common side effects associated with immunotherapy include fevers, body aches, variations in blood pressure, allergic reactions and gastroenteric issues.^13,17

Very rarely, severe complications may arise, including hypoxia, anaemia, weakened immune systems or neurological issues including confusion or even seizures.^16,18 To a greater extent, however, fine tuning of immunotherapies could lead to treatment programs that do not severely complicate quality of living.

Glioblastoma heterogeneity and resistance

While the therapies described above have shown some positive results in pre-clinical and clinical testing, it is an important point to note that rather than improve overall survival, these therapies improve time to progression. In other words, they successfully delay the progression of the cancer to more advanced stages but do not ensure the elimination of cancer.¹⁹ 

These results however, have yet to be replicated in GBM patients. This is because of a number of reasons that are yet to be addressed:

• Immunotherapy majorly relies on the modified immune cells/substances entering the brain. For this they must cross the blood brain barrier, however, the major role of this membrane is to prevent the entry of blood cells into the brain, thus only few T-cells are able to infiltrate.²⁰
• GBM has a unique immunosuppressive effect, modulating the tumour’s surroundings to restrict entry of the adaptive immune system (such as T-Cells), while using other immune cells to further enhance their immunosuppressive ability.¹⁹
• Heterogeneity of tumour cells in GBM, characterised by inconsistent expression of TAAs makes therapies like CAR T-cell difficult, as the cells must target more than one antigen to be successful.¹⁹ 

GBM is therefore a difficult form of cancer to treat. Clinical trials with successful immunotherapeutics do not replicate their results with this brain cancer, necessitating more research and development to be conducted

Recent advances and clinical trials

While this may make the GBM prognosis seem desolate, this is not in fact the case. It is only current therapies that have not massively broken through in terms of increasing survival rates. However, the principles are known to work and with some additional steps, these therapies can be modified to successfully treat the disorder.

In fact, there are currently several immunotherapies in phase III clinical trials for glioblastoma. Three of these are part of the CheckMate trials for nivolumab. Preclinical trials for the drug showed an increase in both time to progression and overall survival.²¹

Oncolytic viruses such as Vocimagene Amiretrorepvec have a selective specificity to cancer cells, infecting and killing them. Additionally, they are able to turn the immunosuppressive effects of glioblastoma off, potentially allowing their combination with other immunotherapeutics to treat GBM.²² On killing the cancer cells, several TAAs are released, stimulating an immune response. 

SurVaxM is a peptide vaccine with a similar immune-stimulating effect. Combined with the BBB-infiltrating chemotherapeutic temozolomide, this artificial TAA vaccine stimulates an immune response against the glioblastoma. SurVaxM has shown good primary results in phase II trials.²³

GBM therefore, is not against the scope of medical research and we can be sure that with advancements in medical science and sufficient research, current treatment methods will soon be replaced by highly effective and developed immunotherapy.

Summary

Glioblastoma is a severe and rapidly progressing brain cancer which is characterised by painful headaches and neurological complications. Late diagnosis leads to severe decline in both motor and neurological abilities. 

Immunotherapy is a domain of cancer treatment which involves the modulation and enhancement of the patient’s own immune system in order to help the immune cells better detect and destroy cancer cells. However, GBM is a complicated cancer as it has multiple extra protection from the immune system by way of the blood-brain barrier, its own increased immune suppression, immune evasion techniques and the heterogeneity of GBM tumour cells. 

As such, immunotherapy, which has been successful in the treatment of other cancers, struggles with GBM. Advancements in biomedical research have led to Phase III trials for modified immunotherapy and combined immunotherapy regiments which promises a more effective GBM treatment possibility in the future.