Battle for the Brain: Glioblastoma’s Invasion and the Immunotherapy Counterattack
Jack Matter
Illustrations by Alexandra Adsit
A silent adversary creeps through the corners of the brain, gathering strength before emerging to wreak havoc. While the body puts up a valiant defense against cancer, it often fails to defeat this enemy, which enlists unsuspecting nervous system cells and evades the body’s immune system defenses [1, 2, 3]. Glioblastoma, often called one of the most lethal brain cancers, is an enemy that comes from within [4, 5, 6]. Conventional treatment options do little to change the outcome of the battle [6, 7, 8]. However, immunotherapies offer hope, aiming to reengineer the body to fight back against the enemy [2, 6, 9]. While substantial challenges complicate the path toward a cure, innovative treatment methods may provide the prospect of a breakthrough in the fight against glioblastoma [1, 2, 9].
Cancer vs. the Immune System
Cancer is a group of diseases typically characterized by several distinct hallmarks, or traits that are crucial to understanding its nature [1, 10]. One of these hallmarks is cancer’s ability to multiply rapidly. While healthy cells contain quality control checkpoints and limits on how often they can replicate themselves, cancerous cells do not; therefore, they can replicate indefinitely. Cancerous cells begin as healthy cells, but genetic misfires transform them into an uncontrollable, aggressive force [1, 10]. Cancer operates like an invading army composed of one’s own rebelling cells that the body’s defense force cannot keep in check [12]. Usually that defense force, the immune system, can effectively prevent the formation of cancerous cells by recognizing unhealthy cells as harmful and sending immune cells to destroy them [12]. Some unhealthy cells, however, can escape immune detection by concealing or shedding the molecules that flag them as harmful [1, 10]. The ability to avoid immune detection — another one of cancer’s hallmarks — makes these cells dangerous and ultimately allows them to become cancerous [1, 2, 10]. After proliferation, cancerous cells often form solid masses called tumors, but it is important to note that not all tumors are cancerous [13, 14, 15]. Tumors are cancerous when they have the ability to send cells, like soldiers, to invade their surroundings and even other parts of the body [13].
What is Glioblastoma?
Glioblastoma is a cancer originating in the brain or spinal cord, which together comprise the central nervous system (CNS) [16, 17]. Glioblastoma is a mass of unhealthy versions of a type of cell called glial cells. But what exactly are healthy glial cells, and what do they have to do with the functions of the nervous system? Glial cells and neurons comprise the brain and spinal cord, working together to perform complex duties. Glial cells regulate a wide range of functions by supervising and modifying the connections between neurons. Neurons create and spread signals throughout the CNS, allowing the brain to communicate with the rest of the body. Think of neurons as the wires that carry electrical signals from one place to another within the CNS. Glial cells are the electricians that help create and maintain the connections between these wires. Without glial cells, the electrical grid fizzles out, and all grid functions are compromised [16, 17].
Glial cells are major players in our brain’s ability to adapt its structure and function in response to new information throughout life, a process called plasticity [18, 19, 20, 21]. One type of glial cell, the astrocyte, plays a critical role in this plasticity [22]. Astrocytes clean up existing connections, remove wires that are no longer used, and form new wiring [22]. Astrocytes also play a key part in creating and regulating blood vessels in the brain, acting as guides for the cells that construct new vessels [23]. When random genetic mutations or DNA modifications alter astrocytes, they can become precursors to glioblastoma cells [24]. Precursor cells that survive long enough to replicate may ultimately turn into glioblastoma tumor cells [24]. As tumor cells, cancerous astrocytes can use existing blood vessels or create new ones that behave like supply lines from other parts of the body [25]. The tumor cells hijack blood supply lines to feed themselves and expand into healthy tissues [25].
Hijacking Plasticity: How Glioblastoma Spreads
While glioblastoma seldom spreads outside the brain, it spreads rapidly and aggressively throughout near and distant neural regions by taking advantage of neuron activity, plasticity, and other healthy cells [26, 27, 28]. Individual neurons can stimulate and connect to other healthy brain cells, forming communication circuits [29]. However, neuronal stimulation is a double-edged sword: two-way signaling between healthy neurons and brain tumor cells increases the activity of tumor cells, unintentionally promoting rapid cancer growth [27, 30]. Since tumor cells can also increase healthy neuronal activity, this can trigger a cycle of neuron-tumor stimulation [30, 31].
Glioblastoma tumors further cement the neuron-tumor stimulation cycle and exhibit plasticity, modifying the activity of surrounding healthy neurons and remodeling their connections [3, 30, 31, 32, 33]. In addition to maintaining this growth cycle, glioblastoma can enlist healthy astrocytes to its cause [3]. As unwitting allies, tumor-associated astrocytes release signals that suppress the immune system’s ability to detect and eliminate tumor cells [3]. Glioblastoma can also ‘steal’ mitochondria — the cellular power plants responsible for creating the chemical energy that drives cell processes — from healthy CNS cells [34]. Non-cancerous astrocytes can transfer functional mitochondria to glioblastoma cells through direct cell-to-cell contact, which may help explain how glioblastoma cells proliferate so rapidly and why they are so difficult to eliminate [34].
Hijacking neuron activity, utilizing plasticity, recruiting tumor-associated astrocytes, and stealing mitochondria are characteristics that fuel the aggressiveness of glioblastoma [32, 35, 36]. Glioblastoma is often referred to as the most lethal brain cancer, defined by its nearly unstoppable hostility and current incurability [4, 5, 6, 37]. Despite modern treatment options and periods of remission where glioblastoma is undetectable, around 95% of people do not survive five years post-diagnosis, and 90% of people diagnosed with glioblastoma relapse within two years of diagnosis [6, 7, 8, 38, 39]. Although the outlook for those suffering from glioblastoma remains grim, some hope can be found in new forms of treatment that leverage immunotherapies to target the cancer [6].
The New Frontline: Immunotherapies for Glioblastoma
Current treatments act as a frontline defense against glioblastoma and may prolong a person’s life, but most treatments fall short in some regard due to either intense side effects, minimal success in permanently curing the cancer, or both [40, 41, 42]. Neurosurgery is highly invasive and fails to remove all cancer cells, leading to poor survival outcomes even after surgical intervention, as the surviving cancer cells replicate again [43]. Glioblastoma is also highly resistant to chemotherapies and radiation therapies due to the presence of protective barriers in the brain and the tumor’s ability to repair its damaged DNA [43]. Further, chemotherapies and radiation therapies cannot selectively target tumor cells, so healthy cells inevitably get caught in the crossfire [41, 44]. Damage to healthy cells often has extensive, debilitating side effects, including a severely weakened immune system [41, 44]. Healthy cells that replicate rapidly — such as hair and intestinal cells — are disproportionately damaged or killed by chemotherapies, which cause side effects like loss of hair, appetite, and weight [40, 41, 44, 45, 46].
Despite current treatment limitations and cancer’s methods of evading the immune system, new therapies that boost immune responses show promise [1, 2, 9, 10]. The idea of using the immune system to fight disease has existed for around 2,000 years but has only been consistently applied to fighting cancer since the 1980s [47, 48]. This movement towards harnessing the immune system has led to the development of immunotherapies. These treatments recruit an individual’s immune cells to directly target and kill only cancer cells, avoiding the harmful side effects of more traditional treatments [48]. Immunotherapies retrain immune cells to detect and remember cancerous cells based on identifying molecules called antigens, which are substances that the immune system can typically identify as foreign threats and target with antibodies [12]. Antibodies are molecules produced by some immune cells that bind to specific antigens, activating an immune cell response that can locate and destroy the threat [12, 49]. One type of immune response activates T cells, an umbrella term for a large body of immune cells, including the immune system’s killer cells [12]. To recruit T cells, the immune system must first be able to recognize antigens found on tumors [50]. However, since cancer cells can either hide or shed their antigens, it is difficult for immune cells to detect and destroy the cells [1]. Therefore, by manipulating immune cells, like T cells, immunotherapies could improve their defensive functions against cancerous cells [50].
T-cell therapies are an example of recent antigen-based immunotherapies that have been approved to treat several blood cancers and may be useful in treating glioblastoma [51, 52]. T-cell therapies involve collecting a person’s T cells and re-engineering them in a laboratory so they can bind to distinct cancer cell antigens [53]. Specifically, collected T cells are modified to have chimeric antigen receptors, or CARs, on their cell surface. CARs eliminate middleman cells often involved in T cell activation and allow T cells to bind directly to specific antigens on the surface of cancer cells [53]. Therefore, these receptors give T cells a new capability, combining the specificity of an antibody with the existing lethality of a T cell [54]. Immunotherapies are customized for each person’s specific cancer using their individual T cells [51, 53]. However, even with customization, CAR T-cell therapy is still limited in effectiveness for glioblastoma treatment in particular [55]. Since glioblastoma cells are incredibly diverse in terms of potential target antigens, it is challenging to develop CAR T-cells that can effectively bind to and combat every subtype of glioblastoma cell for extended periods, leading to the potential for relapse [55].
Tumor vaccines are another promising type of immunotherapy in fighting glioblastoma [56, 59]. Tumor vaccines rely on the same principle as traditional vaccines — that viruses have antigens that differentiate them from healthy cells — and adapt that principle to battle cancer [57]. For example, a flu virus has specific foreign antigens not ordinarily present in the body [58]. By injecting a harmless version of a flu virus, the immune system can be trained to remember flu virus antigens and mobilize to neutralize the threat in the future [58]. A tumor vaccine functions similarly, with the knowledge that cancer cells possess antigens that differentiate them from healthy cells [57]. In this case, oncolytic viruses that only target and infect cancer cells are used [57]. Once infected, the cancer cell becomes a host for virus replication and reaches the maximum threshold of virus that it can hold [55, 57]. When a cancer cell reaches this threshold, it bursts like an overfilled water balloon and dies, flooding the environment with its antigens [55, 57]. This phenomenon then stimulates the immune system to activate and kill other cancer cells: popping a cancer cell and releasing its antigens sounds like an emergency alarm urging the immune system to act [56]. Glioblastoma cells are particularly vulnerable to viral infection, and oncolytic virus-based vaccines can simultaneously activate the immune system and train its memory, which is essential in establishing long-term immune resistance to the cancer [56, 59].
Despite the potential success of oncolytic virus-based therapies in treating glioblastoma, there is a difficult challenge to circumvent: the blood-brain barrier (BBB) [56]. The BBB is a selective, tight-knit layer of cells and fluids that prevents harmful substances from entering the brain [60]. Most often, therapies are injected into the veins or taken orally, which can reduce how much of the treatment makes it across this barrier [61]. Substances typically must cross the BBB through the slow process of diffusion, which is the gradual movement of molecules from areas of high concentration to low concentration [56, 60]. However, some virus-based therapies cannot even cross the BBB by diffusion, and these combined obstacles make it challenging to get oncolytic virus therapies to reach a deeply embedded brain tumor [56]. One potential solution to bypass this delivery challenge is convection-enhanced delivery, which allows for direct injection of therapeutics into the brain via the fluid-filled spaces between CNS cells [62, 63]. This method relies on the force of convection — the inherent movement of fluid from high to low pressure — to influence fluid motion at the injection site, creating a high-to-low pressure gradient from the point of injection to the tumor that can overcome the forces of diffusion [62, 63, 64]. A small hole is made in the skull to allow access to the target area of the brain based on the tumor’s location [62, 63]. A syringe containing the immunotherapy is then placed inside the hole; the pressure of the fluid at the syringe tip is greater than the pressure in the brain, which pushes the fluid through the BBB and into the tumor [62, 63].
Glioblastoma, infamous for its relentless aggression, manipulates the brain’s complex circuitry to evade the immune system’s defenses, harnesses the power of plasticity, and subverts healthy astrocytes to fuel its attack [2, 6, 33]. Immunotherapies represent a potential paradigm shift from existing treatments that are often inadequate at completely treating glioblastoma [2, 6, 38]. New treatments, such as T-cell therapies and tumor vaccines, may successfully reprogram the immune system to target cancer cells directly [12, 50, 56]. While the road ahead may contain obstacles, a more effective and less taxing path to victory in the battle against glioblastoma is a goal worth fighting for.
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