Tag: glioblastoma

Categories : CancerTags :

Cancer-killing Virus Therapy Shows Promise for Glioblastomas

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Photo by Anna Shvets on Pexels

Results of a new clinical trial involving the injection of an oncolytic virus – a virus that targets and kills cancer cells – directly into the tumour, with intravenous immunotherapy shows great promise for patients with glioblastoma according to results published in Nature Medicine.

Drs Farshad Nassiri and Gelareh Zadeh, neurosurgeons at the University Health Network (UHN) in Toronto, found that this novel combination therapy can eradicate the tumour in select patients, with evidence of prolonged survival.

Investigative work by the authors also revealed a new genetic signature within tumour samples that has the potential to predict which patients with glioblastoma are most likely to respond to treatment.

“The initial clinical trial results are promising,” says Dr Zadeh. “We are cautiously optimistic about the long-term clinical benefits for patients.”

Glioblastoma is a notoriously difficult-to-treat primary brain cancer. Despite aggressive treatment, which typically involves surgical removal of the tumour and multiple chemotherapy drugs, the cancer often returns, at which point treatment options are limited.

Immune checkpoint inhibitors are effective treatments for a variety of cancers, but they have had limited success in treating recurrent glioblastoma. This novel therapy involves the combination of an oncolytic virus and immune checkpoint inhibition, using an anti-PD-1 antibody as a targeted immunotherapy.

First, the team zeroed in on the tumour using stereotactic techniques and injected the virus through a small hole and a purpose-built catheter. Then, patients received an anti-PD-1 antibody intravenously, every three weeks, starting one week after surgery.

“These drugs work by preventing cancer’s ability to evade the body’s natural immune response, so they have little benefit when the tumour is immunologically inactive – as is the case in glioblastoma,” explains Dr Zadeh.

“Oncolytic viruses can overcome this limitation by creating a more favourable tumour microenvironment, which then helps to boost anti-tumour immune responses.”

The combination of the oncolytic virus and immune-checkpoint inhibition results in a ‘double hit’ to tumours; the virus directly causes cancer cell death, but also stimulates local immune activity causing inflammation, leaving the cancer cells more vulnerable to targeted immunotherapy.

Dr Zadeh and colleagues evaluated the innovative therapy in 49 patients with recurrent disease, from 15 hospital sites across North America.

UHN, which is the largest research and teaching hospital in Canada and the only Canadian institution involved in the study, treated the majority of the patients enrolled in the trial.

The results show that this combination therapy is safe, well tolerated and prolongs patient survival. The therapy had no major unexpected adverse effects and yielded a median survival of 12.5 months – considerably longer than the six to eight months typically seen with existing therapies.

“We’re very encouraged by these results,” says Dr Farshad Nassiri, first author of the study and a senior neurosurgery resident at the University of Toronto. “Over half of our patients achieved a clinical benefit – stable disease or better – and we saw some remarkable responses with tumours shrinking, and some even disappearing completely. Three patients remain alive at 45, 48 and 60 months after starting the clinical trial.”

“The findings of the study are particularly meaningful as the patients in the trial did not have tumour resection at recurrence – only injection of the virus – which is a novel treatment approach for glioblastoma. So, it’s really remarkable to see these responses,” says Dr Zadeh.

“We believe the key to our success was delivering the virus directly into the tumour prior to using systemic immunotherapy. Our results clearly signal that this can be a safe and effective approach,” adds Dr Nassiri. 

The team also performed experiments to define mutations, gene expression, and immune features of each patient’s tumour. They discovered key immune features which could eventually help clinicians predict treatment responses and understand the mechanisms of glioblastoma resistance.

“In general, the drugs that are used in cancer treatment do not work for every patient, but we believe there is a sub-population of glioblastoma patients that will respond well to this treatment,” says Dr Zadeh. “I believe this translational work, combining basic bench science and clinical trials, is key to moving personalised treatments for glioblastoma forward.”

This is one of the few clinical trials with favourable results for glioblastoma over the last decade, and it was truly a team effort. 

“The trial would not have been possible without our incredible OR teams, research safety teams and researchers – including Dr Warren Mason and his team at Princess Margaret Cancer Centre – and our brave patients and their families. We’re also grateful to the Wilkins Family for providing the funds to enable us to complete trials that advance care for our patients,” says Dr Zadeh. 

The next steps for the group are to test the effectiveness of the combination therapy against other treatments in a randomised clinical trial.

“We are encouraged by these results, but there is still a lot of work ahead of us,” says Dr Nassiri. “Our goal, as always, is to help our patients. That’s what motivates us to continue this research.” 

Source: EurekAlert!

Categories : CancerTags :

Gel Delivery Method Achieves 100% Cure for Glioblastomas in Mice

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Photo by Anna Shvets on Pexels

Anticancer drugs delivered by a novel gel cured 100% of mice with glioblastoma, one of the deadliest and most common brain tumours in humans. The results are published today in Proceedings of the National Academy of Sciences.

“Despite recent technological advancements, there is a dire need for new treatment strategies,” said chemical and biomolecular engineer Honggang Cui, who led the research. “We think this hydrogel will be the future and will supplement current treatments for brain cancer.”

Cui’s John Hopkins University team combined an anticancer drug and an antibody in a solution that self-assembles into a gel to fill the tiny grooves left after a brain tumour is surgically removed. The gel can reach areas that surgery might miss and current drugs struggle to reach to kill lingering cancer cells and suppress tumour growth.

The gel also seems to trigger an immune response that a mouse’s body struggles to activate on its own when fighting glioblastoma. When the researchers rechallenged surviving mice with a new glioblastoma tumour, their immune systems alone beat the cancer without additional medication. The gel appears to not only fend off cancer but help rewire the immune system to discourage recurrence with immunological memory, researchers said.

Surgery is still necessary; applying the gel directly in the brain without surgical resection resulted in a 50% survival rate.

“The surgery likely alleviates some of that pressure and allows more time for the gel to activate the immune system to fight the cancer cells,” Cui said.

The gel solution consists of nano-sized filaments made with paclitaxel, an FDA-approved drug for breast, lung, and other cancers. The filaments provide a vehicle to deliver an antibody called aCD47. By blanketing the tumour cavity evenly, the gel releases medication steadily over several weeks, and its active ingredients remain close to the injection site.

By using that specific antibody, the team is trying to overcome one of the toughest hurdles in glioblastoma research. It targets macrophages, a type of cell that sometimes supports immunity but other times protects cancer cells, allowing aggressive tumour growth.

One of the go-to therapies for glioblastoma is a wafer developed in the 1990s, with the commercial name Gliadel. This FDA-approved, biodegradable polymer also delivers medication into the brain after surgical tumour removal.

Gliadel showed significant survival rates in laboratory experiments, but the results achieved with the new gel are some of the most impressive the Johns Hopkins team has seen, said Betty Tyler, a co-author and associate professor of neurosurgery at the Johns Hopkins School of Medicine who played a pivotal role in the development of Gliadel.

“We don’t usually see 100% survival in mouse models of this disease,” Tyler said. “Thinking that there is potential for this new hydrogel combination to change that survival curve for glioblastoma patients is very exciting.”

The new gel offers hope for future glioblastoma treatment because it integrates anticancer drugs and antibodies, a combination of therapies researchers say is difficult to administer simultaneously because of the molecular composition of the ingredients.

“This hydrogel combines both chemotherapy and immunotherapy intracranially,” Tyler said. “The gel is implanted at the time of tumour resection, which makes it work really well.”

Johns Hopkins co-author Henry Brem, who co-developed Gliadel in addition to other brain tumour therapies currently in clinical trials, emphasised the challenge of translating the gel’s results in the lab into therapies with substantial clinical impacts.

“The challenge to us now is to transfer an exciting laboratory phenomenon to clinical trials,” said Brem, who is neurosurgeon-in-chief at Johns Hopkins Hospital.

Source: John Hopkins University

Categories : CancerTags :

New Way to Assess Immune Checkpoint Effectiveness

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Chromosomes prepared from a malignant glioblastoma visualized by spectral karyotyping (SKY) reveal an enormous degree of chromosomal instability — a hallmark of cancer.
Credit: Thomas Ried, NCI Center for Cancer Research, National Cancer Institute, National Institutes of Health

Researchers have used a new machine learning and protein profiling system to identify vulnerabilities in glioblastomas and to assess immune checkpoint blockade treatment effectiveness.

Neoadjuvant immune checkpoint blockade (ICB) is a promising treatment for melanoma and other cancer types, and has recently been shown to provide a modest survival benefit for patients with recurrent glioblastoma. To improve the treatment efficacy, researchers are looking for vulnerabilities in surgically removed glioblastoma tissues, but this has been difficult due to the vast differences within the tumours and between patients.

To tackle this problem, researchers at Institute for Systems Biology (ISB) and their collaborators developed a new way to study tumours. The method builds mathematical models using machine learning-based image analysis and multiplex spatial protein profiling of microscopic compartments in the tumour.

The team used this approach to analyse and compare tumour tissues gathered from 13 patients with recurrent glioblastoma and 23 patients with high-risk melanoma. Both groups had been treated with neoadjuvant ICB. Using melanoma to guide the interpretation of glioblastoma analyses, they were able to identify the proteins that correlate with tumour-killing T cells, tumour growth, and immune cell-cell interactions.

Co-lead author Dr Yue Lu described the research : “This work reveals similarities shared between glioblastoma and melanoma, immunosuppressive factors that are unique to the glioblastoma microenvironment, and potential co-targets for enhancing the efficacy of neoadjuvant immune checkpoint blockade.”

“This framework can be used to uncover pathophysiological and molecular features that determine the effectiveness of immunotherapies,” added Dr Alphonsus Ng, co-lead author of the paper.

ISB, UCLA and MD Anderson collaborated on the study, the findings of which were published in Nature Communications. Brain cancer represents one of the toughest settings for immunotherapy success. Collaboration between scientists and clinicians provides a great opportunity for improving patient care and achieving a deep understanding of cancer immunotherapy.


“We believe that the integrated biological, clinical and methodological insights derived from comparing two classes of tumors widely seen as at the opposite ends of the spectrum with respect to immunotherapy treatments should be of interest to broad scientific and clinical audiences,” said corresponding author and ISB President, Dr Jim Heath.

Source: PRWeb

Journal information: Yue Lu et al, Resolution of tissue signatures of therapy response in patients with recurrent GBM treated with neoadjuvant anti-PD1, Nature Communications (2021). DOI: 10.1038/s41467-021-24293-4

Categories : CancerTags :

Glioblastoma Induces ‘Stockholm Syndrome’ to Subvert Body’s Defences

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Glioblastoma, an aggressive form of brain cancer, has been found to corrupt immune cells and make the tumour harder to treat.

Most people diagnosed with glioblastoma die in a short period of time after their diagnosis, but some glioblastoma patients see great benefits from chemotherapy and survive beyond expectations. Researchers at the University of Minnesota have revealed the reason for this in a new study published in the Proceedings of the National Academy of Sciences.

“Deciphering the molecular underpinning of these exceptional responses may hold the key to transforming the hope for miracles into the reality of an expected cure for glioblastoma patients,” said lead author Clark C Chen, MD, PhD, Lyle French Chair in Neurosurgery and head of the Department of Neurosurgery at the University of Minnesota Medical School.

Examining the gene expression profiles of glioblastoma samples from approximately 900 glioblastoma patients, the researchers sought to identify unique features associated with exceptional responders, defined as glioblastoma patients who survive more than two years after treatment.

“We utilized different state-of-the-art analytics to study these samples, including methods innovated by Dr. Aaron Sarver, a member of the University of Minnesota Institute of Health Informatics. Impressively, these analytics converged on a single observation, a paucity of microglia and macrophages,” Dr Chen said.

Specialised immune cells, microglia and macrophages act as scavengers, spotting and removing out-of-place cells in healthy brains. They travel to abnormal cancer cell sites to mount a defence, and can form over half the cells in a glioblastoma sample.

“If microglia and macrophages normally fend off cancer cells, more of them should allow the body to better fend off the tumor. So, we expected to see more of them in the exceptional responders; however, we found the contrary,” said Jun Ma, a researcher in the Department of Neurosurgery at the U of M Medical School and a co-first author of this study.

In order to resolve this paradox, the research team then demonstrated that glioblastoma cells can recondition the surrounding microglia and macrophages, corrupting their normal anticancer functions. Where they once fought off cancer growths, these immune cells are now re-programmed by glioblastoma cells to promote tumour growth.

“It is frightening to consider the possibility that cancer cells can ‘brainwash’ our own immune cells and convert them from cells that fight cancer to cells that promote cancer,” said Judith Varner, a co-senior author of the study and professor of pathology at the University of California, San Diego. “Fortunately, we have figured out how glioblastoma cells subvert our immune system and can now reverse this cellular version of the ‘Stockholm syndrome.'”

Stockholm syndrome is characterised as when a captive begins to identify closely with their captors, as well as with their agenda and demands, however there is little evidence for it being a true psychological phenomenon.

A protein known as phosphoinositide-3-kinase gamma isoform (PI3Kγ) could hold the key to cure this cellular “Stockholm syndrome” and possibly glioblastoma. This protein, when activated, is the switch that corrupts their anti-cancer role. Having studied this process for many years, Varner has pioneered drugs that restore the anti-tumour activities of microglia and macrophages.

“In our animal glioblastoma models, treatment with drugs targeting PI3Kγ consistently resulted in impressively durable responses to chemotherapy,” Chen said. “We are eager to translate these findings into a human trial, with the hope of transforming every glioblastoma patient into an exceptional responder.”

Source: Medical Xpress

Journal information: Jie Li et al, PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2009290118

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Wrapping up Tumours With Micromesh Nets

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An innovative new nanomedicine has been developed that wraps up tumours in a micromesh net, conforming to the surface of tumor masses and efficiently delivering drugs.

The scientists at the IIT (Istituto Italiano di Tecnologia (Italian Institute of Technology) who developed the mesh described it in the journal Nature Nanotechnology.

Brain tumors are rare but they are some of the most aggressive and difficult to treat. In particular, glioblastoma multiforme (GBM), which is a grade 4 glioblastoma has the most severe prognosis: the average survival is just over 12 months and only 5% of the patients survive beyond 5 years.

GBM typically affects men and women between 45 and 75 years of age. Furthermore, unlike other malignancies, there has been no significant diagnostic and therapeutic improvements for this malignancy over the past 30 years. In fact, both the incidence of new cases and the number of deaths has remained practically unchanged. The only therapeutic strategy currently used is based on surgery, which consists of removing a part of the tumor mass and reducing intracranial pressure, followed by radiotherapy and/or chemotherapy.

The biomedical system developed by IIT and its collaborators can play a very important role in the fight against the disease, representing a possible effective alternative to the few pharmacological treatments used to date.

The microMESH is a micrometric-scale polymeric net, made from biodegradable materials and wraps around the tumour mass, enclosing it. In fact, the micrometric thick polymeric fibers are very flexible and are arranged to form regular openings, which are also on the same scale as cancer cells. This unique feature allows the microMESH to achieve a closer interaction with the tumor mass, increasing the therapeutic efficacy.

Its structure consists of two separate compartments in which different drugs can be loaded which are released towards the tumor mass in an independent, precise, and prolonged fashion. Combining different therapies: chemotherapy, nanomedicine, and immunotherapy enables the microMESH to ‘attack’ glioblastoma.

This work has been carried out by a team led by Prof Paolo Decuzzi, head of the IIT Laboratory of Nanotechnology for Precision Medicine, in collaboration with the Neural Stem Cell Biology Laboratory of Dr Rossella Galli at the San Raffaele Hospital in Milan and a team led by Prof Gerald Grant at the Lucile Packard Children’s Hospital of Stanford University.

The group will continue to develop the microMESH by integrating different types of drugs and therapies to tackle other types of tumors. In the short term, their major objective will be to validate the technology on glioblastoma patients.

Source: News-Medical.Net

Journal information: Mascolo, D. D., et al. (2021) Conformable hierarchically engineered polymeric micromeshes enabling combinatorial therapies in brain tumours. Nature Nanotechnology. doi.org/10.1038/s41565-021-00879-3.

Categories : Cancer New Compounds and TreatmentsTags :

Novel Glioblastoma Drug Can Cross The Blood-brain Barrier

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An experimental spherical nucleic acid (SNA) drug was able to penetrate the blood-brain barrier and trigger glioblastoma tumour cell death in an early clinical trial.

Glioblastoma is the most common and aggressive brain tumour, accounting for 16% of cases. It affects 3.2 per 100 000 people, at an average age of 64 years although it can appear at any time.

The new drug, NU-0129, is the first SNA drug developed for systemic use. The SNA groups RNA or DNA around a nanoparticle. A revolutionary new class of drugs, it can be adapted to a number of neurological diseases such as Parkinson’s.

“We showed the drug, NU-0129, even at very small doses, causes tumour cells to undergo what’s called apoptosis or programmed cell death,” said lead investigator Dr Priya Kumthekar, associate professor of neurology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine physician. “It’s a remarkable finding in humans that confirms what we had previously seen in our animal studies.”

The study participants received the drug intravenously prior to surgery to remove the tumour. The researchers team studied the tumours to determine how well the drug crossed the blood-brain barrier and its effect on their cells.

“This unique 3D design has the ability to infiltrate tumor cells to correct the genes inside and make them susceptible for therapy-induced killing,” said senior author Alexander Stegh, an associate professor of neurology at Northwestern.

Unusually, the drug was developed entirely within the university without involving pharmaceutical licensing.
“We want to move the technology forward as quickly as possible because there are patients with a disease with no current cure,” Kumthekar said.

Dr Leon Platanias, director of the Lurie Cancer Center, said, “These exciting findings for the first time support the potential of spherical nucleic acids for drug delivery to brain tumors. They may prove to have important long-term translational implications for the treatment of these tumours.”

Source: Medical Xpress

Journal information: P. Kumthekar el al., “A first-in-human phase 0 clinical study of RNA interference–based spherical nucleic acids in patients with recurrent glioblastoma,” Science Translational Medicine (2021). stm.sciencemag.org/lookup/doi/ … scitranslmed.abb3945