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Beyond the Battle: Illuminating Glioblastoma - Unmasking its challenges and promising horizons

HealthPad

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Cancer

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molecular targeted therapy

nanotechnology

novel therapies

tumor-treating fields

Glioblastoma (GBM) is an aggressive, challenging to treat, and not fully understood form of brain cancer that currently has no cure
Each year ~10,000 Americans and ~2,200 UK older citizens are diagnosed with the disease
The standard of care is surgery followed by radiation and chemotherapy
Prognosis is poor with median survival of ~15 months with treatment and ~3-4 months without treatment
Researchers and medical institutions throughout the world as well as multinational pharmaceutical companies, giant MedTechs and biotech start-ups are exploring novel therapies for the disease
The US leads the world in investment in biomedical research carried out in universities and research institutions, but China is catching up
Promising research avenues include immunotherapy, targeted therapies, gene therapy, nanotechnology, and tumour-treating fields but the current success of multiple clinical trials is not good
Diversified MedTechs might be reluctant to fund research and development (R&D) in GBM due to its complexities, rarity and smaller patient population
As GBM is a public health concern governments might consider increasing their investments and coordination of medical research to find efficacious therapies for the disorder
Agile smaller MedTechs and biotech start-ups with streamlined processes have a presence in GBM R&D, which might be due to the condition’s unique challenges and market dynamics

Beyond the Battle: Illuminating Glioblastoma
Unmasking its challenges and promising horizons

"In the battle against glioblastoma, a relentless and unforgiving adversary, we confront the fragility of our own existence, and the limits of our medical prowess. It is a disease that embodies the epitome of human suffering, where hope and despair dance an eternal waltz, and where the line between life and death blurs into an unsettling haze of uncertainty." Henry Marsh, Do No Harm

This Commentary explores the ever-evolving realm of glioblastoma (GBM) research and suggests that something promising is underway, which needs more support. As the landscape of research and development (R&D) takes shape, a compelling phenomenon emerges: the rising tide of university-based researchers and agile biotech start-ups daring to tackle the unique challenges of this brain cancer. With determination, they delve into niche areas, embarking on ground-breaking endeavours, fueled by scientific curiosity, patient advocacy, and the pursuit of disruptive innovation. Small companies’ streamlined decision-making processes and unwavering focus on GBM research give them a competitive edge, which they share with global pharmaceutical companies, while diversified MedTechs hesitate in the face of the relative rarity and complexities of the disease. GBM’s challenges, which extend from its elusive location to its resistance to conventional treatments pose substantial obstacles that require unconventional approaches. As the stakes rise, smaller MedTechs and start-ups, often fueled by innovative scientific breakthroughs from universities and supported by government research grants, prove their mettle, undeterred by failure or setbacks. Glioblastoma therapies appear to be a world where the underdogs rise, and cutting-edge treatments hold the key to rewriting the fate of the disease.

In this Commentary

This Commentary is in two parts. Part 1 entitled Glioblastoma: Advances and Challenges in Treatment provides an overview of glioblastoma, covering its characteristics, incidence, and standard treatment approaches. It delves into the global efforts of researchers who are exploring novel therapies for GBM, instilling a renewed sense of hope in the battle against this disease. The Commentary describes key innovative treatments such as immunotherapy, targeted therapies, gene therapy, nanotechnology, and tumor-treating fields, and briefly discusses the companies actively pursuing these therapies, highlighting that the current success of multiple clinical trials is lacking. Part 2, entitled Glioblastoma Research: Government Support and the Rise of Innovative Players, acknowledges the research conducted in universities and medical institutions worldwide. American universities and research institutes are particularly well-positioned due to the US’s leadership in biomedical research investment, although China is rapidly catching up. The Commentary suggests that governments should increase their support for novel therapies to treat glioblastoma, as relying solely on private entities to fund research for such a rare and complex disease seems unreasonable. We highlight the Chinese government's commitment to supporting biomedical research and addressing rare diseases like glioblastoma and draw attention to Parag Khanna’s thesis in Technocracy in America, suggesting Chinese state capitalism may have advantages over Western liberal democracies in developing high tech medical technologies. The Commentary ends by noting the significant presence of smaller companies in this field. Many that take risks in pursuing innovative solutions have streamlined decision-making processes and are driven by scientific curiosity, patient advocacy, and potentially disruptive innovation, which gives them a competitive edge.

Part 1

Glioblastoma: Advances and Challenges in Treatment

Glioblastoma (GMB) is an aggressive, common, and malignant form of brain cancer in adults, which is challenging to treat because the tumour is interconnected with healthy tissue, making it almost impossible to excise completely. Also, radiation has the potential to damage peripheral healthy tissue, and the brain’s natural barrier to chemotherapeutics makes GBM one of the most difficult and deadly diseases to deal with.

What are gliomas? - Mr Ranjeev Bhangoo

Your brain is made up of various types of cells, and GBM specifically affects glial cells, which have supportive roles, such as providing nourishment and protection to the neurons, which are the main cells responsible for transmitting signals in your brain. Glioblastoma develops when there is an abnormal growth of glial cells. However, its exact cause is not fully understood, but researchers believe that it may be influenced by a combination of genetic factors and environmental exposures. When someone is diagnosed with GBM, it means they have a tumour that typically starts in the brain but can spread to other parts of the central nervous system (CNS). The tumour grows rapidly, often infiltrating nearby healthy brain tissue, which makes it difficult to remove entirely through surgery. Because of its invasive nature, GBM can cause various symptoms depending on its location, including headaches, seizures, cognitive changes, weakness, and difficulties with speech or vision.

Incidence

Glioblastoma is relatively rare compared to other cancers and its global incidence rates vary by region. The disease is more common in older adults. While there have been no significant changes in its incidence over time, ongoing research aims to better understand the factors that influence its occurrence. The condition accounts for ~15% of all primary brain tumours and its annual incidence ranges from 0.59 to 3.69 cases per 100,000 people, and these numbers may vary based on factors such as age, genetics, and environmental factors. Each year, ~10,000 individuals in the US will present with the disease, and ~2,200 cases will be diagnosed in England. Advances in diagnostic techniques and increased awareness of the disease may have contributed to improved identification and reporting of cases. Age is a significant factor, with the highest incidence rates occurring in older adults; with the peak observed between 65 and 75, while being relatively uncommon in children and young adults. Researchers continue to study potential risk factors and factors that may influence its occurrence, but because the condition is complex and challenging to study, its causes and risks are still not fully understood. Notwithstanding, some factors that have been associated with GBM include, exposure to ionizing radiation, certain genetic syndromes, and a family history of glioblastoma, but most cases occur without any identifiable risk factors.

Standard of care

Treating glioblastoma is challenging because currently there are no curative therapies for the condition and treatment has remained almost unchanged for >20 years. The standard of care involves surgery, which aims to remove as much of the tumour as possible without causing damage to healthy brain tissue. However, due to the tumour's invasive nature, complete removal is rare. Thus, following surgery, the patient undergoes a combination of temozolomide, a type of chemotherapy medication that can enter the brain through the blood-brain barrier, and radiation therapy, followed by additional temozolomide treatment for six months. The effectiveness of these therapies is limited by high rates of tumour recurrence, treatment-related toxicity, emerging resistance to therapy and ongoing neurological deterioration. GBM has some of the worse outcomes of any cancer: a survival rate of ~15 months after diagnosis makes it a crucial public health issue. Only ~25% of patients survive more than one year, and only ~5% survive >5 years. Despite the first recorded reports of gliomas in British scientific reportswere in the early 19^th century and the first histomorphology was made in 1865, there only have been four drugs and one device approved by the FDA for the condition. Given the disease's poor survival rate with currently approved treatments, new therapeutic strategies for GBM are urgently needed.

Novel therapies

Various researchers, medical institutions, multinational pharmaceutical companies, giant MedTechs and biotech start-ups are exploring novel therapies for GBM, offering renewed hope in the battle against this devastating disease. Promising avenues have emerged and are chronicled here. Part 1 of this Commentary describes the current landscape of these therapies while acknowledging encountered challenges and failures. Despite setbacks in clinical trials, the unwavering commitment to combatting the disease and improving patient outcomes remains evident. Researchers throughout the world strive to unlock the full potential of these therapies, building upon successes and providing new hope for GBM patients, but this could benefit from more centralized support and coordination, which is addressed in Part 2.

Immunotherapy
Immunotherapy utilizes the body’s immune system to treat diseases, including cancer. By stimulating or enhancing the immune response, it strengthens the immune system’s ability to recognise and destroy harmful substances like viruses, bacteria, and cancer cells. For GBM, immunotherapy offers a promising alternative to traditional treatments.

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Is immunotherapy a breakthrough in cancer treatment?

Immune checkpoint inhibitors (ICI) block checkpoints exploited by cancer cells, enabling the immune system to target cancer cells more effectively. Adoptive cell therapy modifies a patient’s own immune cells to specifically attack cancer cells. Immunotherapy for GBM is significant as it potentially improves patient outcomes, increases survival rates, minimizes damage to healthy tissues, and has shown promise in cases where other treatments have failed.

Companies conducting immunotherapy R&D
Ongoing clinical studies are actively assessing the effectiveness of immunotherapy in combating GBM. Global pharmaceutical companies such as Merck & Co. and Bristol Myers Squibb, are at the forefront of R&D efforts pioneering immunotherapies for the disease. Additionally, Roche has made investments in novel therapies for GBM and is actively involved in clinical trials evaluating the efficacy of their treatments. Bristol Myers Squibb’s clinical studies investigate the potential of immune checkpoint inhibitors (ICI), which as we explained, is a type of therapy that unleashes the immune system’s full potential by removing the brakes that hinder its ability to identify and eliminate cancer cells effectively. While ICI therapies have achieved substantial success in the broader field of oncology, their impact on GBM has been modest thus far.

Celldex Therapeutics, a clinical stage biotech based in New Jersey, US, is also committed to the development of immunotherapies for glioblastoma. Their research is focussed on innovative therapeutic vaccines and antibody-based treatments that stimulate the immune system’s response against glioblastoma cells. Despite the considerable R&D efforts dedicated to immunotherapy, its efficacy so far in GBM remains limited due to the complex challenges posed by the blood-brain barrier, incomplete understanding of the neuroimmune system, and the multifaceted immunosuppression that accompanies the disease. However, recent advances in treatment strategies offer renewed promise by combining immunotherapy with other complementary approaches.

Targeted therapies
Targeted therapies are a specialized form of treatment that focuses on specific molecules or pathways crucial for the growth and survival of cancer cells. Unlike conventional treatments like chemotherapy and radiation, which can harm healthy cells along with cancerous ones, targeted therapies aim to attack cancer cells while minimizing damage to healthy tissues. In the case of GBM, targeted therapies hold promise as they identify specific abnormalities or mutations driving the growth and survival of cancer cells. These abnormalities can be unique to cancer cells or occur more frequently in them compared to normal cells. Targeted therapies are designed to interfere with these specific abnormalities or mutations in various ways. Some treatments block or inhibit proteins or pathways that are overactive or abnormal in cancer cells, aiming to halt their growth, induce cell death, or hinder their ability to spread.

What are targeted therapies? - Dr. Whitfield Growdon

For instance, tyrosine kinase inhibitors, a group of drugs used in GBM, work by blocking the activity of tyrosine kinases - proteins involved in signaling pathways that promote cancer cell growth. By inhibiting these, the drugs slow down cancer cell growth and potentially shrink tumours. Another targeted therapy approach under investigation for GBM is angiogenesis inhibitors. Glioblastoma tumours, like all tumours, rely on a blood supply to grow and can stimulate the formation of new blood vessels (angio genesis) to sustain their growth. Angiogenesis inhibitors disrupt this process by targeting the molecules involved in blood vessel formation, depriving the tumour of essential nutrients and oxygen.

Targeted therapies are not universally effective, as their success depends on the specific abnormalities present in cancer cells and individual patient characteristics. Ongoing research and clinical trials focus on identifying the most effective targeted therapies and optimal ways to employ them in GBM and other cancer treatments. To enhance the effectiveness of targeted therapy for the condition, several strategies are being explored. These include utilizing nanoparticlesand monoclonal antibodies to transport anticancer drugs directly to the tumour, overcoming the brain's protective barriers. Additionally, introducing genetically modified bacteria into the tumour after surgical removal aims to selectively destroy cancer cells while sparing normal brain tissue. Also, tailoring treatments to individual patients and testing them through clinical trials are crucial steps in maximizing the potential of targeted therapies for GBM and other cancers.

Companies conducting targeted therapy R&D
Several prominent companies, such as Roche and Novartis, are engaged in R&D efforts for targeted therapies in GBM. Bristol Myers Squibb and AbbVie also have ongoing projects focused on targeted therapies for the disease. In January 2023, Cantex Therapeutics’ azeliragon, a targeted therapy developed for glioblastoma, received orphan drug designation from the FDA and commenced a phase II clinical trial. Cantex licensed the drug from vTv Therapeutics, a clinical-stage biotech, which intended the therapy to be for Alzheimer patients. Azeliragon, administered as a once-daily pill has excellent tolerability, and works by blocking the RAGE receptor involved in a specific biological process. By preventing certain substances from interacting with this receptor, the drug has the potential to enhance the effectiveness of GBM treatment. Despite progress in targeted therapy research, multiple phase III clinical studies have failed. This starkly highlights the gap between the urgent need for effective therapies, the expanding scientific understanding of the disease, and the lack of translation into novel treatments. This discrepancy can be attributed to various factors, including the inherent biological and clinical challenges posed by GBM, as previously mentioned.

A different type of targeted therapy for difficult to treat brain cancers is being developed by C ognos Therapeutics, a MedTech based in Inglewood, California, US. Its lead offering Sinnais, is a novel implantable drug delivery pump designed to overcome the blood-brain barrier (BBB), which is a significant challenge in modern medicine. Although we have mentioned the BBB several times in this Commentary, let us describe it more fully as it is central to Cognos’s Sinnais offering. The BBB protects the brain from potentially harmful substances in the bloodstream. While it serves a protective function, it also restricts the entry of many drugs, including those developed for brain and other central nervous system (CNS) diseases. Numerous medications have been developed by pharmaceutical companies for brain and CNS diseases but cannot be used or have limited efficacy due to their inability to cross the BBB. Sinnais is Cognos’s proposed solution. When implanted the device delivers therapeutics locally and metronomically (at precise intervals) to the desired area in the brain. By potentially providing patient- and tumour-specific targeted chemotherapeutics directly to the tumour site in microlitre resolutions, the device offers a more targeted and effective treatment option for brain cancers, including GBM. A commercial opportunity for the company is to partner with pharmaceutical companies that have developed drugs for brain cancers and other neurological disorders but cannot deliver them across the BBB. In January 2023, Cognos entered into a business combination agreement with Noctune Acquistion Corp, a special purpose acquisition company (SPAC), in a move to become publicly traded on Nasdaq. The deal is expected to help Cognos expedite its R&D of Sinnais, which has the potential to become the world’s first implantable device for local targeted and metronomic delivery of therapeutics for the treatment of neurological diseases.

Gene therapy
Gene therapy is a cutting-edge medical approach that aims to treat genetic disorders and certain diseases by targeting and modifying the genes within your cells. Genes are like the instruction manuals that tell your cells how to function properly. When there is a problem with a gene, it can lead to the development of various diseases.

In gene therapy, scientists use specialized techniques to introduce healthy genes into the cells of a person with a genetic disorder or disease. These healthy genes can replace the faulty ones or provide the cells with the necessary instructions to function correctly. The therapy’s goal is to fix the underlying genetic cause of the disease rather than just treating the symptoms.

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Gene Therapies

Because GBM is known to be aggressive and difficult to treat, gene therapy holds potential for its treatment. One reason is that GBM is believed to be often caused by specific genetic mutations that lead to the uncontrolled growth of brain cells. Gene therapy can target these mutations directly and correct them by introducing healthy genes or inhibiting the effects of the faulty ones. Another advantage is that it can deliver therapeutic genes directly to the tumour site in the brain. This may be achieved by using viral vectors or other delivery systems, with the capability to cross the blood-brain barrier. By doing so, gene therapy can precisely target cancer cells while minimizing damage to healthy brain tissue. The therapy has the potential to enhance the immune system's ability to recognize and attack cancer cells by modifying immune cells or by introducing genes that boost the immune response against the tumour. Gene therapy for GBM is still in its infancy but holds potential for treating the disorder by directly targeting the genetic abnormalities responsible for the tumour's growth. Its ability to deliver therapeutic genes precisely and enhance the immune response against cancer cells makes it a significant avenue to pursue for future treatment options.

Companies conducting gene therapy R&D
Several pharmaceutical and MedTech companies are actively engaged in gene therapy R&D programmes to treat glioblastoma. Novartis is currently conducting ongoing clinical trials, which involve the utilization of modified viruses to deliver therapeutic genes. Genprex, a small clinical-stage biotech traded on Nasdaq and based in Austin, Texas, is developing gene therapies for cancer, including GBM. One of their notable products is GPX1, that employs a non-viral nanoparticle delivery system to introduce a therapeutic gene into tumour cells, inhibiting their growth. Genprex has achieved some early success with advanced non-small cell lung cancer (NSCLC). Mustang Bio, another clinical-stage biotech specializing in gene therapy R&D is focused on developing CAR-T cell therapies. This involves modifying a patient's own immune cells to recognize and selectively attack cancer cells. In May 2019, the company obtained Orphan Drug status from the FDA for an oncolytic virus, licensed from the Nationwide Children’s Hospital, which effectively kills cancer cells and is used in the treatment of GBM.

In April 2019, the FDA granted Ziopharm Oncology Fast Track Designation for its treatment, Ad-RTS-hIL-12 plus veledimex, which targets GBM. The therapy involves delivering a gene that produces a protein to stimulate the immune system's response against the tumour. Initial studies produced promising results in a small number of GBM patients. However, following an activist attack by WaterMill Asset Management Corp, Ziopharm underwent a reorganization, appointed a new CEO, abandoned the clinical study, and rebranded itself as Alaunos Therapeutics, relinquishing its GBM asset.

Tocagen, a clinical-stage, gene therapy company based in San Diego, US, is dedicated to developing treatments for cancer, including GBM. The company developed two drugs, Toca 511 and Toca FC, that can cross the blood-brain barrier and target tumour cells. The drugs work together and involve delivering a therapeutic gene into tumour cells and then activating it with an oral medication to selectively kill the cancer cells. In April 2017 the company listed on Nasdaq and later that year, its lead product received FDA Breakthrough Therapy Designation and Priority Medicines (PRIME) designation from the European Medicines Agency for the treatment of high grade gliomas (HGG). However, in September 2019, Tocagen announced that its phase III randomized, multi-centre clinical trial consisting of 380 patients with recurrent HGG failed the primary endpoint of overall survival compared to standard of care treatment. To get so far in the process and not yield significant results for survival is a significant setback. Shares in the company fell ~80%, half of its employees were made redundant, and the company set about restructuring.

Nanotechnology
Nanotechnology involves working with tiny particles (nanoparticles), which are thousands of times smaller than the width of a human hair and can be engineered and manipulated to have special properties and functions. One area the technology is making significant contributions is in the field of medicine, particularly in the development of new therapies for challenging diseases like glioblastoma. Nanotechnology-based therapies for GBM work by utilizing nanoparticles that are designed to specifically target cancer cells in the brain. These can be loaded with drugs or other therapeutic agents to kill or slow down the growth of cancer cells. Scientists design nanoparticles in such a way that they can cross the blood-brain barrier and reach tumour cells more efficiently. Once the particles reach the tumour cells, they release therapeutic agents in a controlled and targeted manner. This precision helps to minimize the damage to healthy brain cells and reduces side effects compared to traditional therapies. Nanoparticles can be engineered to respond to specific signals or conditions within the tumour environment, allowing for even greater precision in drug release. The technology also allows for non-invasive imaging and diagnosis of GBM. Scientists have developed nanoparticles that can be used as contrast agents in imaging techniques such as magnetic resonance imaging (MRI), which can help visualize the tumour and monitor its response to treatment over time. While more R&D is needed, the use of nanotechnology holds promise for improving outcomes and quality of life for patients with GBM and other challenging cancers.

Companies conducting nanotechnology R&D
MagForce, a publicly traded German medical device company is among the early developers of novel nanotechnology-based cancer treatments. Its lead offering, the NanoTherm therapy system, is the first and only nanotechnology-based therapy to receive European regulatory approval (CE marking) for the treatment of brain tumours. The system utilizes magnetic nanoparticles to heat and destroy tumour cells. The process involves injecting magnetic iron oxide nanoparticles into the tumour. Then, MagForce’s therapeutic device, the NanoActivator, is used to treat the affected area with an alternating magnetic field, which generates heat, leading to localized tumour cell destruction. The company is now working on a strategy to market its NanoTherm therapy outside Germany aided by a €35m loan from the European Investment Bank under the European Fund for Strategic Investments.

Imunon previously, Celsion Corporation is a New Jersey, US-based clinical-stage oncology-focused company that has been working on a nanoparticle-based multi-modal drug delivery system called ThermoDox®. The system utilizes heat-activated liposomal nanoparticles to deliver chemotherapy drugs directly to tumour sites, including GBM. The nanoparticles release the drug when exposed to focused ultrasound or radiofrequency ablation, which selectively activates the drug within the tumour. In September 2022, Celsion changed its name to Imunon. “With this name change, we are underscoring our commitment to create a new category of medicines. With a strong balance sheet supporting current operations into 2025, we are well positioned to build a differentiated company to deliver the promise of our mission”, said Corinne Le Goff, president, and CEO. In February 2023, the company announced the commencement of patient enrolment of a clinical trial to evaluate a therapy for ovarian cancer, another “difficult to treat cancer”.

BIND Therapeutics was a biotech co-founded in 2007 by Robert Langer, a pioneer of many new technologies and widely regarded for his contributions to biotechnology. BIND engineered a nanomedicine platform developing Accurins®, a novel targeted and programmable class of therapeutics designed to target specific cells or tissues and concentrate a therapeutic payload at the site of disease. In 2013, the company raised a US$70m in an IPO, and had early success with a Phase I clinical trial comprised of 28 patients. The study established the safety and tolerability of BIND-014 in patients with advanced or metastatic solid tumour cancers, and in 2015, its findings were presented at the American Association for Cancer Research (AACR) Annual Meeting. Despite this success, in May 2016 BIND filed for voluntary Chapter 11 of the US bankruptcy code and its assets were acquired by Pfizer for US$40m. The novel therapy continued to be developed but not for GBM; findings of a phase II clinical study comprised of 42 patients with metastatic prostate cancer, was published in the July 2018 edition of JAMA Oncology, and reported the median radiographic progression-free survival to be 9.9 months.

Tumour-Treating Fields
Tumour-Treating Fields (TTFields) is an innovative treatment approach used for certain types of cancer, including GBM. It is a therapy that utilizes electromagnetic fields to disrupt the growth and division of cancer cells and involves the use of a device that generates low intensity alternating electric fields, which are designed to interfere with the process of cell division; a crucial step in the growth and spread of cancer cells. By applying electric fields to the tumour site, TTFields aim to disrupt cancer cells' ability to multiply and form new tumour masses. The significance of the technology for GBM lies in its potential to provide an additional treatment option that can complement existing therapies and can be used in combination with traditional treatments: surgery, radiation therapy and chemotherapy. One of its advantages is that it specifically targets cancer cells while sparing healthy tissues. The electric fields disrupt the division of actively dividing cells, which is a characteristic of cancer. Healthy cells, which typically have a slower rate of division, are less affected. This approach may lead to fewer side effects compared to other treatment modalities. Clinical studies have shown that TTFields can improve overall survival and progression-free survival in patients with glioblastoma when used in combination with standard treatments. The therapy has been approved by regulatory agencies, including the FDA, for the treatment of GBM and is being increasingly integrated into clinical practice.

Companies conducting TTFields R&D
Novocure is a pioneering MedTech oncology company that developed and commercialized the Optune®, a non-invasive portable device, which delivers TTFields therapy and has been approved by the FDA for the treatment of GBM. The company was founded in Haifa, Israel in 2000 by Yoran Palti, (Professor of Physiology and Biophysics at the Technion Israel Institute of Technology in Haifa). NovaCure grew to become a Nasdaq traded corporation with a market value of >US$7bn, >1,300 employees, annual revenues of ~US$0.54bn, and operations in the US, Europe, and Asia.

Palti hypothesized that alternating electric fields in the intermediate frequency range could disrupt cancer cell division and cause cancer cell death. He set up a home laboratory, where he demonstrated that, when applied at tumour cell-specific frequencies (200 kHz for GBM), alternating electric fields disrupt cell division, leading to cancer cell death but sparing healthy cells. The results motivated him to set up Novocure. The company’s second-generation Optune device has design improvements intended to enhance patients’ experience with TTFields treatment. The device consists of a set of adhesive patches or arrays that are placed directly on the patient's scalp over the area where the tumour is located. These are connected to a portable device that generates the electric fields. It weighs ~1.2 kg (~2.7 lbs) and is worn continuously while the patient carries on with their daily activities while receiving treatment.

On 6 June 2023, NovoCure’s shares crashed ~43% after the failure of a clinical trial of Optune on non-small cell lung cancer (NSCLC) patients. The company plans to file for US Premarket Approval (PMA) for TTFields in treating NSCLC later this year, and expects to announce results from three other late-stage studies of its device targeting other indications by the end of 2024.

QV Bioelectronics is a UK-based start-up founded in 2018 by a biomedical engineer and a neurosurgeon. The company’s lead offering, referred to as GRACE, (Glioma Resection Advanced Cavity Electric field therapy), employs electric field therapy like that of NovoCure, to slow the growth of GBM. Different to NovoCure’s Optune, GRACE is positioned to be implanted into patients already undergoing surgery. After surgery, it delivers therapy to the tumour resection margins where most of the glioblastoma recurrence takes place. The device is expected to operate without causing harm to healthy brain cells. To-date, QV has raised ~£3.5m, (~US$4.5m) and has received ~£2M (~US$2.5) in non-dilutive grants, including £860k (~US$1M) in March 2023 from Innovate UK, the UK’s national innovation agency. The company plans to use recent proceeds to expand its preclinical studies, finalise the initial design of GRACE, and develop a commercial strategy and regulatory pipeline as it prepares for clinical grade testing.

Part 2

Glioblastoma research: Government Support and the Rise of Innovative Players

Universities and research institutions engaged in GBM R&D

In addition to companies, which we described in Part 1 of this Commentary, universities and research institutions around the world are actively engaged in R&D efforts aimed at exploring novel therapies for glioblastoma. American universities and research institutes are particularly well placed as the US leads the world in investment in biomedical research. For instance, its National Institutes of Health (NIH) annually invests >US$40bn in medical research throughout the US. However, China is catching up (see below). One leading American institution that benefits from this US policy is the Massachusetts Institute of Technology (MIT), where researchers have been investigating innovative approaches such as nanotechnology-based drug delivery systems and targeted therapies to combat glioblastoma. In the UK, the University of Oxford has made significant strides in developing immunotherapies and personalized treatments for GBM. In Canada, the University of Toronto’s researchers are focussed on novel gene therapies and the development of targeted nanoparticles for improved drug delivery to GBM tumours. In Australia, the University of Sydney’s Brain and Mind Centre is actively involved in the exploration of stem cell-based therapies and advanced imaging techniques to better understand the tumour’s biology and improve treatment outcomes. These academic institutions, together with many others globally, are actively searching for breakthrough therapies for patients battling glioblastoma. University medical research groups can receive funding from medical research charities, as well as governments. However, a private company may licence a technology from a university or research institute and fund, or co-fund, clinical trials.

The Case for increased government funding for GBM R&D

In Part 1, we described how glioblastoma is characterized by its rapid progression, resistance to conventional treatments, and complex biological nature, which contribute to the difficulty in developing effective therapies. The intricate interplay between tumour cells and the brain, along with the blood-brain barrier, makes drug delivery and targeted treatment options particularly challenging. Given the multifaceted obstacles involved, it seems unreasonable to expect private entities to solely bear the burden of funding R&D for such a rare and complex disease. Glioblastoma affects a relatively small number of individuals, limiting the potential market for pharmaceutical companies and MedTechs. The high costs associated with R&D, clinical trials, and regulatory approval create a significant financial risk for private investors. The lack of substantial profitability prospects may discourage private entities from allocating resources to GBM research. In contrast, governments have a vested interest in public health and can allocate funding based on societal needs rather than immediate profitability.

Government-funded research can foster collaboration among scientists, clinicians, and institutions. By providing a platform for shared knowledge, data, and resources, governments are well positioned to facilitate scientific breakthroughs for complex conditions. GBM research would benefit from collective efforts, allowing scientists to efficaciously pool their expertise to accelerate progress. Government funding can enable the establishment of research consortia, collaborative networks, and specialized centres dedicated to glioblastoma R&D. Developing innovative therapies for the condition requires sustained long-term commitment. Private entities may be inclined to prioritize shorter-term projects with faster returns on investment. In contrast, governments have the capacity to pursue research with longer horizons and tolerate greater risks. By investing in long-term R&D, governments can support the exploration of unconventional ideas, disruptive technologies, and novel approaches that may yield significant advancements in glioblastoma treatment. Also, government involvement in funding R&D can prioritize the development of therapies that are accessible and affordable to all patients. Private entities may choose high-profit-margin treatments, potentially leading to a lack of affordability for many individuals. Government-funded R&D initiatives can ensure that breakthroughs in GBM treatment reach the wider population, reducing health disparities and ensuring equitable access to potentially life-saving interventions.

Chinese R&D in novel GBM therapies

In a thought-provoking book, Technocracy in America, Parag Khanna presents an argument that challenges the conventional wisdom surrounding economic systems and their impact on technological development. Khanna highlights the success of China’s blend of market economy and state-owned enterprises in fostering the growth of cutting-edge medical technologies. Drawing comparisons with Western liberal democracies, Khanna suggests that China’s technocratic approach, characterized by strategic direction and state-led initiatives, offers distinct advantages in driving advancements in the high-tech medical sector. Khanna prompts us to reassess our assumptions about the most effective pathways to progress in the realm of medical technology.

The development of a ‘Healthy China 2030’ is central to the Chinese Government’s agenda for health and development, and has the potential to reap benefits for the rest of the world. President Xi Jinping has put health at the centre of the country’s policy-making machinery, making the need to include health in all policies an official government policy. The Chinese government has expressed a commitment to supporting biomedical R&D, including efforts aimed at addressing rare diseases like glioblastoma. Specific initiatives may receive funding and support through programmes such as the National Natural Science Foundation of China (NSFC), China's National Key R&D Programmes (NKPs), and collaborations between domestic academic institutions, research centres, and pharmaceutical companies. In China, efforts are underway to develop innovative immunotherapeutic approaches, including immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapy, and peptide-based vaccines. These approaches aim to enhance the immune system's ability to recognize and eliminate GBM cells. China is also exploring gene therapy approaches for GBM treatment. One notable example is the use of genetically modified viruses to deliver therapeutic genes directly into tumour cells. Researchers have conducted clinical trials, such as using oncolytic adenoviruses and retroviruses, to induce tumour cell death and stimulate the immune response against glioblastoma. Nanotechnology-based strategies are being explored to improve drug delivery and enhance the efficacy of GBM treatment. Scientists are developing nanoparticles and nanostructured systems capable of crossing the blood-brain barrier and delivering therapeutic agents directly to the tumour site, which aim to increase drug accumulation in tumours while minimizing systemic side effects. China is also involved in stem cell-based therapies that hold promise for glioblastoma treatment. Researchers are investigating the use of neural stem cells, mesenchymal stem cells, and induced pluripotent stem cells for targeted drug delivery, immune modulation, and regenerative purposes. These approaches aim to improve patient outcomes and overcome treatment resistance to GBM. Further, Chinese researchers are investigating the potential of traditional Chinese medicine (TCM) for glioblastoma treatment. Studies have focused on identifying bioactive compounds from medicinal plants and evaluating their anti-tumour effects, as well as exploring the synergistic effects of TCM in combination with conventional therapies.

Takeaways

This Commentary describes some of the ongoing developments of novel therapies for GBM mainly at the company level and suggests reasons why it is unreasonable for private companies to bear the main burden of finding therapies for glioblastoma. We also suggest that ongoing R&D initiatives at the company level should be approached with caution as their effectiveness and safety are still being investigated through clinical trials. Further, we mention that universities and research institutes worldwide are actively engaged in R&D programmes, involving multidisciplinary teams dedicated to various aspects of GBM. These efforts encompass understanding the underlying biology, exploring innovative treatment strategies, conducting clinical trials, and investigating novel therapeutic approaches. Further, we suggest that because GBM is a public health issue, governments might consider increasing their investments in, and their coordination of, GBM R&D. The Commentary draws attention the Parag Khanna’s book, Technocracy in America, which encourages us to re-examine our assumptions about the most effective policies to accelerate the development of medical technology and suggests that China’s model of state capitalism appears to have advantages over Western liberal democracies.

Regarding medical R&D landscape at the company level, it seems reasonable to suggest that the unique challenges and market dynamics associated with glioblastoma may lead to a more significant presence of smaller MedTechs and start-ups in this field. Such entities often possess the ability to focus on niche areas and take risks in pursuing innovative solutions. Their streamlined decision-making processes and flexibility in allocating resources specifically to GBM research, driven by scientific curiosity, patient advocacy, and potentially disruptive innovation, provide them with a competitive advantage. Conversely, many large diversified MedTechs may be less inclined to invest in GBM R&D compared to more prevalent cancers such as breast, lung, or colon cancer. This is primarily due to the relative rarity of GBM, resulting in a smaller patient population. From a business perspective, the smaller market size may be less financially attractive to established MedTechs seeking larger patient populations with higher profit potential. The highly complex and challenging nature of glioblastoma, including its location, infiltrative behaviour, and resistance to standard treatments, poses significant obsacles in developing effective therapies. The complexity and risks associated with GBM R&D present substantial challenges for many companies with more extensive resources and stakeholders to manage, as the potential for failure or setbacks is higher.

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Beyond the Battle: Illuminating Glioblastoma - Unmasking its challenges and promising horizons

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