Cancer on the mind

Glioblastoma remains a difficult cancer to treat, but the brain malignancy is seeing increasing attention in R&D

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There are several cancers that pose particular challenges for treatment—and, by extension, for drug discovery and development—either because of their genetic makeup, because they are often discovered late, or other reasons. One of those “other” reasons, and one that often leads to late diagnosis for some of those cancers, is location. And location is a big problem when it comes to brain cancer, including glioblastoma multiforme (GBM), the most aggressive cancer that originates within the brain.
After all, not only do tumors in the part of your body that controls much of that body’s functions mean that GBM and other brain cancers can cause a host of problems aside from mortality, but the brain is a notoriously risky place to be conducting surgery or beaming radiation—and the blood-brain barrier makes it challenging to properly deliver drugs.
But recent years have seen a host of new research and development—and promising progress—against brain cancers, the subject that dominates this Spotlight on Oncology section. And, while GBM may be the brain cancer that gets the most attention, we will begin with medulloblastoma, the most common brain cancer among young children.
Florida State University (FSU), where researchers recently saw their medulloblastoma research published in the Journal of Cancer, says that the scientists on its campus are “making important progress in the battle against [this] class of devilishly complex human pediatric brain cancers.”
While there is no brain tumor more common than medulloblastoma among young children, there are no specific and effective therapies for this dangerous disease. As FSU notes, physicians have to resort to invasive and heavy-handed treatments like surgery, radiation and chemotherapy, often at the expense of the child’s quality of life.
Medulloblastoma, which is divided into four subgroups, is partially caused when a mutation occurs in the “driver genes” that either promote or suppress cancerous tumor growth—these mutations can be inherited, sporadic or environmentally induced. A team of FSU researchers, led by Dr. Qing-Xiang “Amy” Sang, a professor of chemistry and biochemistry, wanted to learn more about these mutations. Using data from the Catalogue of Somatic Mutations in Cancer, they identified a series of cancer-causing driver gene mutations and discovered that medulloblastoma is perhaps an even more dynamic and variable tumor than expected.
“Most cancer is quite heterogeneous, but medulloblastoma is specifically very heterogeneous,” Sang said. “If you look at the driver gene mutation, it’s not as if the majority of medulloblastoma cases have the same mutation. In reality, 5 percent may have one mutation, 3 percent may have another mutation and a small percentage may have other mutations. That’s why you cannot treat it as one disease.”
The researchers pinpointed which driver gene mutations were occurring in which medulloblastoma subgroups using advanced bioinformatics tools and, in so doing, they discovered that in some cases, mutations that had been considered specific to one particular subgroup were causing significant disruption in “sister subgroups” as well.
According to FSU, while these findings were surprising, “they were exactly the kind of counterintuitive details the team was searching for.”
“What we focused on specifically in this paper are the driver genes that we weren’t expecting to see. We wanted to focus on some infrequent events and stress the heterogeneity of medulloblastoma tumors themselves. That’s important whenever we’re using targeted therapy for different subgroups,” said Mayassa Bou Dargham, a doctoral candidate at FSU and co-author for the study’s published paper, titled “Decoding Somatic Driver Gene Mutations and Affected Signaling Pathways in Human Medulloblastoma Subgroups.”
According to FSU, while medulloblastoma’s heterogeneity makes it a challenging cancer to characterize and treat, this research will begin the process of helping scientists better identify opportunities for targeted, individualized treatments, by providing “a more comprehensive and nuanced understanding of which mutations happen where and when—and which mutations might defy broadly accepted definition.”
Jack Robbins, who was an undergraduate when he co-authored the study, explained: “For medulloblastoma, a more personalized approach will have to happen. The goal we should be striving for is more MATCH-based trials in which we use molecular targets found from these different panels of driver events. These driver events extend past the genomic code and into epigenetic mechanisms that need to be further studied and assessed in the clinic to identify candidate therapies. We can hopefully give those therapies to patients who aren’t responding to the standard-of-care treatments.”
For those not familiar with it, NCI-MATCH, or MATCH, is a precision medicine cancer treatment clinical trial in which patients are assigned to receive treatment based on the genetic changes found in their tumors through genomic sequencing and other tests.
While the FSU researchers are proud of their findings, their work is only an initial step, with the next step in developing potential therapies being to develop credible laboratory models of human medulloblastoma tumor subgroups that can be used as evaluative tools in the search for potential therapeutics.
Cross-disciplinary collaborations may be a key to finding more effective therapies for this intractable disease. But another crucial key, Sang said, will be innovative ideas from a new generation of ambitious researchers. She remarked that this paper demonstrates the instrumental and field-defining contributions of student scientists.
A viral approach to GBM
In other recent brain cancer R&D news, Mustang Bio Inc., a company focused on the development of novel immunotherapies based on proprietary chimeric antigen receptor engineered T cell (CAR-T) technology and gene therapies for rare diseases, and Nationwide Children’s Hospital announced Feb. 20 that they have partnered and entered into an exclusive worldwide license agreement to develop an oncolytic virus (C134) for the treatment of glioblastoma multiforme.
A Phase 1 clinical trial evaluating C134, an attenuated herpes simplex virus type 1 (HSV-1) intended for treating recurrent GBM, is being conducted at the University of Alabama at Birmingham (UAB). The trial is led by Dr. James Markert, chairman of the Department of Neurosurgery at UAB, who developed C134 in collaboration with Dr. Kevin Cassady, an associate professor of pediatrics at Nationwide Children’s Hospital. C134 is a second-generation HSV-1 oncolytic virus that has improved replication in tumors in mouse models of GBM, but with the same toxicity profile as its first-generation predecessors. In these preclinical studies, it reportedly not only demonstrated direct antitumor activity, but also elicited an immune response that can reverse tumor-associated immunosuppression.
The subsequent clinical trials are aimed at investigating a combination treatment of MB-101 (IL13Rα2-specific CAR) and C134. These trials, Mustang Bio says, are supported by preclinical studies that have appeared to demonstrate the synergistic potential of an oncolytic virus, which can induce an anti-tumor immune response when combined with CAR-T therapy to target solid tumors.
“Oncolytic viruses often trigger an immune response directed at tumors that are otherwise refractory to single-agent immunotherapies. Our oncolytic virus C134 has demonstrated promising preclinical activity, and we look forward to working with Mustang to advance its development in the clinic,” Cassady said.
Added Dr. Manuel Litchman, president and CEO of Mustang Bio: “We are very pleased to partner with Nationwide Children’s Hospital to develop oncolytic virus C134. We also plan to evaluate oncolytic virus C134 in combination with MB-101 to explore the potential synergies of this novel combination to treat patients with glioblastoma.”
Consortium to study GBM survivors
Toward the end of 2018, the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group and Protagen AG announced a collaboration to utilize Protagen’s Cancer Immunotherapy Array to identify autoantibody biomarkers that investigate the immunological profile and immuno-competence of long-term glioblastoma survivors.
As the partners note, the overall prognosis of GBM patients remains poor. According to population-based data, median overall survival is still in the range of only one year and long-term survival is rare. However, a minority of glioblastoma patients survive for more than 60 months, and these individuals are referred to as long-term survivors. The U.S.-based Brain Tumor Funders Collaborative (BTFC) is supporting a large international research program that aims to better understand which individuals with GBM will ultimately become long-term survivors.
This new collaboration will find Protagen and the EORTC Brain Tumor Group specifically putting Protagen’s Cancer Immunotherapy Array to work in understanding the immunological profile of such patients, to learn how to predict such long-term survival and hopefully identify possible therapeutic targets.
“In our network we have followed and investigated this group of long-term glioblastoma survivors for many years. The focus has been to understand the molecular profile of these patients, and thus over the years we have gained a much better understanding,” said Prof. Michael Weller, head of the Brain Tumor Center at University Hospital Zurich and chairman of the EORTC Brain Tumor Group. “However, we really need to understand the immunological profile and the immuno-competence of these patients better. Thus, investigating these patients by utilizing Protagen’s Cancer Immunotherapy Array may enable us to define their immune-profile, so that we can assess their immuno-competence. This will help us, together with the data already collected, to potentially understand why these patients survive for so long and how this can be extrapolated to other patients suffering from glioblastoma.”
“Our unique Cancer Immunotherapy Array has already demonstrated its potential for the prediction of therapeutic response and immune-related adverse events in immuno-oncology,” added Dr. Peter Schulz-Knappe, Protagen’s chief scientific officer. “The extension into glioblastoma with a specific view to studying long-term survivors with one of the deadliest tumors provides a great opportunity to apply the array for the prediction of survival, but also to learn more about potential novel pathways for therapeutic intervention. Thus, we believe that applying our technology will result in a better understanding of the immunological profile of these long-term survivors, which will benefit all patients suffering from glioblastoma. We feel privileged that the EORTC Brain Tumor Group shares this vision, and are excited about the collaboration.”
From the brain to the blood
Concluding with a bit of a deviation and a twist, we have research out of the University of Texas MD Anderson Cancer Center from fall of last year that deals with brain infections rather than cancer—but while it is not a brain cancer they were researching, their findings might lead to future therapeutics that will help some patients suffering from blood-based cancers.
As MD Anderson notes, the emerging treatment known as adoptive T cell therapy has proven effective in a Phase 2 clinical trial for treating progressive multifocal leukoencephalopathy (PML), a rare and often fatal brain infection sometimes observed in patients with cancer and other diseases in which the immune system is compromised. The study, led by Dr. Katy Rezvani, a professor in the Department of Stem Cell Transplantation and Cellular Therapy at the University of Texas MD Anderson Cancer Center, reportedly showed marked improvement in three PML patients infused with donor T cells targeting the BK virus. Findings were published in the Oct. 11 online issue of the New England Journal of Medicine.
Results from the proof-of-principle study demonstrated BK, a virus similar to the JC virus which causes PML, as the basis for a potentially viable therapy. Both viruses are named for the initials of the patients in which they were first identified.
“The JC and BK viruses are genetically similar and share proteins that can be targeted by the immune system,” said Rezvani. “Because of these similarities, we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”
Rezvani’s team developed a novel approach for the generation of BKV-specific T cells from healthy donors and established a bank of viral-specific T cells for immediate clinical use. The study treated three patients with third-party, partially human leukocyte antigen-matched (HLA) BK virus-specific T cells, taken from the GMP. HLAs are proteins found on the cell’s surface and are vital to immune system recognition.
As MD Anderson explains, PML is a member of the polyomavirus family and is caused by the JC virus, which, although commonly found in the general population, can be deadly or cause serious health issues in some blood cancer patients, including those with leukemia and lymphoma. The virus is also a problem for people with AIDS, multiple sclerosis, rheumatoid arthritis, lupus and other autoimmune diseases treated with biologic therapies.
PML attacks white matter in the brain called the myelin sheath, which protects nerve cells. There is currently no effective treatment for PML, which is fatal in the majority of patients. Symptoms can include clumsiness or loss of coordination, difficulty walking, facial drooping, vision loss, personality changes, trouble speaking and weak muscles.

Looking at the clinical side
A quick roundup of recent brain cancer clinical trial news
By DDNews Staff
The National Brain Tumor Society (NBTS), a nonprofit dedicated to the brain tumor community in the United States, announced in January a partnership with the Global Coalition for Adaptive Research (GCAR), a nonprofit organization that it says brings together “some of the world’s foremost clinical, translational and basic science investigators.” As part of this partnership, NBTS has provided GCAR with a $750,000 award to help launch and build patient awareness of the world’s first global “adaptive” clinical trial for brain cancer, GBM AGILE (Glioblastoma Adaptive Global Innovative Learning Environment).
“The past decade of scientific advances has moved glioblastoma research to a pivotal point which calls for a platform like GBM AGILE to get potentially breakthrough medicines to patients—who can’t afford to wait—faster than standard clinical trial designs,” said David Arons, CEO of NBTS. “GBM AGILE is a ‘game-changer’ for neuro-oncology and is an opportunity for NBTS to collaborate with multiple stakeholders in the brain tumor field to revolutionize the future for patients. This trial also represents the spirit of the NBTS Defeat GBM Research Collaborative program, which was specifically designed to accelerate precision medicine research and take more ‘shots on goal’ by supporting opportunities to find treatments and a cure for the most deadly and aggressive type of brain tumor, glioblastoma.”
GBM AGILE is designed as a learning system to more efficiently and rapidly identify effective therapies for glioblastoma (GBM). GBM AGILE’s innovative model is designed to enable multiple drugs and combinations of drugs to be screened simultaneously and over time. Drugs that show initial evidence of benefit to patients will seamlessly transition to a confirmatory stage designed to support registration approval. Drugs that are underperforming are dropped. The intent is to lower the cost, time and number of patients required to evaluate potentially new effective therapies for patients with GBM.
“We are proud to partner with the National Brain Tumor Society, one of the most respected voices in the GBM community,” commented Dr. Brian Alexander, co-founder of GCAR. “As one of the original champions of GBM AGILE, we want to recognize NBTS’s early contributions to the trial design. GCAR is deeply grateful for their confidence, financial support to help launch the trial, and devotion and continued commitment to finding better treatments for this devastating disease.”
In late 2018, GCAR announced a partnership with Bayer Oncology to include the company’s drug regorafenib as the first therapy entering the GBM AGILE platform, a trial that was expected to begin early this year. Ultimately, the trial will include multiple arms at clinical sites throughout the United States, Canada and Australia, expanding into Europe and Asia in the near future.
GBM AGILE was first conceived in 2015 by an international group of more than 130 clinicians, researchers, biostatisticians, imagers, pathologists, patient advocates and leaders from government and industry. NBTS co-sponsored and participated in the early planning meetings, including co-chairing the original GBM Advocates Committee while the trial was still in its early development stages under the management of the National Biomarker Development Alliance and Dr. Anna Barker of Arizona State University. Many of GCAR and GBM AGILE’s leaders also serve in numerous advisory roles to NBTS, including Dr. Alfred Yung of the MD Anderson Cancer Center, who currently is the organization’s distinguished research advisor, and Dr. Webster Cavenee of Ludwig Cancer Research, who serves on the strategic scientific advisory council for the Defeat GBM Research Collaborative.
(Ultra)sound and fury?
In other GBM trial news, CarThera, a French company that designs and develops innovative ultrasound-based medical devices to treat brain disorders, announced in January that it had secured approval from the French National Agency for Medicines and Health Products Safety (ANSM) to start a Phase 1/2 clinical trial of its SonoCloud-9 device in the treatment of recurrent glioblastoma.
The SonoCloud-9 (NCT 03744026) trial is an open-label, dose-escalation study to evaluate the safety and efficacy of temporarily opening the blood-brain barrier (BBB) in patients with recurrent glioblastoma, who are eligible for carboplatin chemotherapy, by using the implantable SonoCloud-9 device to emit low-intensity pulsed ultrasound. The study will be followed by an extension phase. Twenty patients will be enrolled over a one-year period. The trial will take place in two hospitals in France: Pitié Salpêtrière in Paris and Pierre Wertheimer in Lyon. Following regulatory approval in the United States, it will be extended to the MD Anderson Cancer Center in Houston and Northwestern Memorial Hospital in Chicago.
Local, temporary opening of the BBB using short-duration, low-intensity pulsed ultrasound delivered in a controlled manner is expected to make it easier for carboplatin to cross into the brain tissue, enabling better chemotherapy penetration of the tumor infiltration zone for greater efficacy.
“Lack of brain vessel permeability limits the impact of chemotherapy for glioblastoma,” explained Dr. Ahmed Idbaih, principal investigator and neuro-oncologist at Pitié-Salpêtrière hospital. “Combined with the SonoCloud-9 device, chemotherapy could be much more effective, ultimately improving the treatment of glioblastoma.”
The results of a previous clinical trial reportedly have shown that it was possible to safely and repeatedly open the BBB in patients using the SonoCloud device, on a temporary basis, prior to treatment with carboplatin. Preliminary analysis of the data from this trial also showed efficacy in terms of prolonging overall survival in patients in whom the BBB was opened. These encouraging results led CarThera to pursue using ultrasound to disrupt the BBB in larger regions of the brain to further improve the efficacy of this new method of treatment.
“This approval is a crucial step as it will allow patients with recurrent glioblastoma, for whom there are currently few treatment options, to benefit from increased penetration of the chemotherapeutic agent throughout the area affected by the tumor,” said Prof. Alexandre Carpentier, lead neurosurgeon at Pitié-Salpêtrière hospital, inventor of the SonoCloud device and CarThera’s founder.
“This trial paves the way for effective chemotherapies that to date have been used infrequently in glioblastoma, owing to their limited diffusion into the brain, or for other combinations such as antibodies or kinase inhibitors, in a variety of brain disorders,” added Frédéric Sottilini, CEO of CarThera.
A start and positive review
MediciNova Inc. announced in early January that the first glioblastoma patient had enrolled in the clinical trial of MN-166 (ibudilast) in combination with temozolomide (TMZ), or Temodar, for the treatment of recurrent GBM. The principal investigators are Dr. Patrick Y. Wen, a professor of neurology at Harvard Medical School and director of the Neuro-Oncology Division at the Dana-Farber Cancer Institute (DFCI) in Boston, and Dr. Kerrie McDonald, an associate professor and head of biomarkers and translational research at the Lowy Cancer Research Centre, University of New South Wales, Australia.
The scientific rationale for this clinical trial is based on positive results from preclinical studies conducted by McDonald and her team, in which MN-166 and TMZ combination treatment significantly increased GBM cell apoptosis and cell cycle arrest in an in-vitro study. Combination treatment of MN-166 (ibudilast) with TMZ reportedly resulted in significantly extended survival times compared to TMZ monotherapy in a GBM animal model study, with complete tumor regression observed in two out of 16 mice. This is the first clinical trial to evaluate the safety, tolerability and preliminary efficacy of MN-166 (ibudilast) in combination with temozolomide for the treatment of recurrent GBM.
“We are very excited to study ibudilast with TMZ combination treatment as we believe ibudilast’s mechanisms of action and good penetration of the blood-brain barrier could benefit patients with recurrent GBM,” said Dr. Patrick Y. Wen, principal investigator.
“Earlier studies indicate that macrophage migration inhibitory factor (MIF) and phosphodiesterase (PDE)-4 may factor in proliferation of GBM tumors,” added McDonald. “MIF was found to be highly expressed within GBM cells, and especially around necrotic areas and in close proximity to blood vessels. Ibudilast in combination with TMZ resulted in significant blockage of MIF expression, increased apoptosis, and longer survival in vivo.”
And, closing out our trial-related GBM roundup, late last year came news from VBI Vaccines Inc., a commercial-stage biopharmaceutical company developing next-generation infectious disease and immuno-oncology vaccines, that the independent data and safety monitoring board (DSMB) had completed its second safety assessment of the ongoing Phase 1/2a clinical study of VBI-1901 in recurrent GBM. The DSMB reviewed the complete safety data from the fully enrolled, intermediate-dose patient cohort, and unanimously recommended the continuation of the study without modification.
Following this recommendation, VBI initiated enrollment in the high-dose arm of the study. One final, pre-specified DSMB review is expected to occur after completion of enrollment in the high-dose cohort, concluding the dose-escalation phase of the study.
“We are encouraged by the sustained clean safety profile of VBI-1901 as concluded by this second DSMB assessment,” said Jeff Baxter, VBI’s president and CEO. “These positive safety reviews are critical milestones for the program and for patients diagnosed with this extremely aggressive tumor who currently have no effective treatment options.”

AI-driven GBM discovery
SEONGNAM, South Korea & MOUNTAIN VIEW, Calif.—1ST Biotherapeutics Inc., a preclinical-stage biotechnology company focused on neurodegenerative diseases, immuno-oncology and orphan diseases, and twoXAR Inc., an artificial intelligence (AI)-driven biopharmaceutical company, announced Jan. 3 an agreement to jointly discover and develop novel, efficacious treatments to address unmet medical needs in glioblastoma multiforme.
Under the agreement, twoXAR will use its proprietary AI technology to identify a set of drug candidates with the potential to slow, stop or reverse the progression of glioblastoma. twoXAR and 1ST Biotherapeutics will select candidates from this set to test in preclinical efficacy models of glioblastoma. Following identification of one or more candidates based on those evaluated, 1ST Biotherapeutics will use its team’s expertise in drug development to optimize candidates and finalize the creation of novel, efficacious treatments. Further details of the agreement were not disclosed.
“1ST Biotherapeutics is focused on efficiently building a pipeline of first-in-class therapeutic candidates with high likelihood of clinical success,” said Jamie Jae Eun Kim, CEO of 1ST Biotherapeutics. “The twoXAR team has a track record of rapidly identifying testable novel treatments that can lead to first-in-class therapeutics. This collaboration is an opportunity to combine twoXAR’s AI-driven drug discovery approach and the 1ST Biotherapeutics team’s expertise in chemistry and pharmacology to discover and develop effective molecular therapeutics for glioblastoma patients.”
“We are pleased to collaborate with 1ST Biotherapeutics, because we share common goals of efficiently discovering and developing novel therapeutics for diseases with high unmet medical need, such as glioblastoma,” commented Andrew A. Radin, co-founder and CEO of twoXAR. “The 1ST Biotherapeutics team’s deep medicinal chemistry and drug development experience in CNS and oncology diseases provides a strong complement to twoXAR’s data-driven discovery approach.”

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