Tag: glioblastoma

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A Way to Make Glioblastoma Cells Visible to Immune Cells

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MRI scan showing brain cancer. Credit: Michelle Monje, MD, PhD, Stanford University

Patients with glioblastoma typically survive less than two years after diagnosis, even with cutting-edge therapies. The latest immunotherapies have been unsuccessful, likely because glioblastoma cells have few, if any, natural targets for the immune system to attack.

In a cell-based study, scientists at Washington University School of Medicine have forced glioblastoma cells to display immune system targets, potentially making them visible to immune cells and newly vulnerable to immunotherapies. The strategy involves a combination of two drugs, each already FDA-approved to treat different cancers.

The study is online in the journal Nature Genetics.

“For patients whose tumours do not naturally produce targets for immunotherapy, we showed there is a way to induce their generation,” said co-senior author Ting Wang, PhD, professor of medicine and Department of Genetics head at WashU Medicine. “In other words, when there is no target, we can create one. This is a very new way of designing targeted and precision therapies for cancer. We are hopeful that in the near future we will be able to move into clinical trials, where immunotherapy can be combined with this strategy to provide new therapeutic approaches for patients with very hard-to-treat cancers.”

To create immune targets on cancer cells, Wang has focused on stretches of DNA in the genome known as transposable elements. In recent years, transposable elements have emerged as a double-edged sword in cancer, according to Wang. His work has shown that transposable elements play a role in causing tumours to develop even as they present vulnerabilities that could be exploited to create new cancer treatment strategies.

For this study, Wang’s team took advantage of the fact that transposable elements naturally can cause a tumour to churn out random proteins that are unique to the tumour and not present in normal cells. Called tumour antigens or neoantigens, these unusual proteins could be the targets for immunotherapies, such as checkpoint inhibitors, antibodies, vaccines and genetically engineered T cell therapies.

Even so, some tumours, including glioblastoma, have few immune targets produced naturally by transposable elements. To address this, Wang and his colleagues, including co-senior author Albert H. Kim, MD, PhD, neurosurgery professor, have demonstrated how to purposely force transposable elements to produce immune system targets on glioblastoma cells that normally lack them.

The researchers used a combination of two drugs that influence the epigenome, which controls gene activation. When treated with the two epigenetic therapy drugs, the tightly packed DNA molecules of the glioblastoma cells unfurled, triggering transposable elements to begin making the unusual proteins that could be used to target the cancer cells. The two drugs were decitabine, which is approved to treat myelodysplastic syndromes, a group of blood cancers; and panobinostat, which is approved for multiple myeloma, a cancer of white blood cells.

Before investigating this strategy in people, the researchers are seeking ways to target the epigenetic therapy so that only the tumour cells are induced to make neoantigens. In the new study, the researchers cautioned that normal cells also produced targets when exposed to the two drugs. Even though normal cells didn’t produce as many neoantigens as the glioblastoma cells did, Wang and Kim said there is a risk of unwanted side effects if normal cells create these targets as well.

In ongoing work, Wang and Kim are investigating how to use CRISPR molecular editing technology to induce specific parts of the genome in cancer cells to produce the same neoantigens from transposable elements that are common across the human population. Such a strategy could give many patients’ tumours – even different cancer types – the same targets that could respond to the same immunotherapy, while sparing healthy cells. There are then multiple possible ways to go after such a shared target, including checkpoint inhibitors, vaccines, engineered antibodies and engineered T cells.

Source: Washington University School of Medicine

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Surprising Finding in Glioblastomas: Islands of Potent Immune Cells in Bone Marrow

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Researchers from Germany have made a surprising discovery about the aggressive, lethal glioblastomas: in the vicinity of glioblastomas, they found islands of highly potent immune cells in the neighbouring bone marrow of the skull, which play a central role in defending against cancer. The new data may open up prospects for innovative therapies. On the other hand, they cast a shadow over conventional strategies.

“What we have found is surprising and fundamentally new,” says Björn Scheffler, German Cancer Consortium (DKTK) researcher at the Essen site. Until now, the body’s own defences have always been thought of as a holistic system that sends its troops to different parts of the body as required. “However,” says Scheffler, “our data show that highly potent immune cells gather in regional bone marrow niches close to the tumour and organise the defence from there. At least this is the case with glioblastomas.”

Immune system on site

Based on new findings from animal experiments, the Essen team took tissue samples from the bone marrow near the tumor in the skull from untreated patients with glioblastoma. “However, the methods for this first had to be established,” reports first author Celia Dobersalske, emphasizing the fact that the new research results were obtained from human tissue samples.

The researchers hit the bull’s eye in their search: Bone marrow niches in close proximity to the glioblastoma appear to be the reservoir from which the anti-tumour defence is recruited. Apart from active lymphoid stem cells that develop into immune cells, the researchers also found mature cytotoxic T lymphocytes (CD8 cells) in the bone marrow close to the tumour. “These are highly effective immune cells that play a central role in the defence against cancer,” adds Celia Dobersalske. They can recognize and destroy malignant cells.

The CD8 cells in the bone marrow near the tumour had an increased number of receptors on their surface, which control the proliferation of mature T lymphocytes. In line with this, descendants of the same cell clones – one clone originates from one and the same cell – were detected both in the bone marrow and in the tumour tissue. This is clear evidence that the immune cells gathered on site are fighting the glioblastoma. “And they are successful – at least for a while,” says Björn Scheffler. “We were able to show that the course of the disease correlates with the activity of the local CD8 cells.”

Valuable immune cells destroyed?

This finding not only turns conventional ideas about how the immune system works on their head. The treatment concepts for glioblastoma must also be reconsidered in light of the new data. “Until now, we hadn’t even considered the skullcap in our considerations. How could we, since there was no evidence that highly potent immune cells could be hiding there,” says senior author Scheffler.

“When we opened the skull, we may have destroyed important immune cells in the process,” confirms Ulrich Sure, Director of the Department of Neurosurgery and member of the Essen research team. “In view of the new findings, we find ourselves in a dilemma: we have to gain access to the tumour in order to remove it and also to be able to confirm the diagnosis. There is currently no other way than through the skull. But we are thinking about how we can minimise damage to the local bone marrow in the future.”

On the other hand, the discovery of the local immune system opens up opportunities for innovative therapies. In particular, so-called checkpoint inhibitors are coming back into play. These are immunotherapeutic agents that aim to boost the body’s own cancer defenses. However, checkpoint inhibitors tested to date have shown little effect on glioblastomas.

“Various explanations have been suggested as an explanation, but perhaps we also need to rethink things in this respect,” says Björn Scheffler. “We now know that highly potent immune cells are indeed present on site. We were able to prove that they are fit to fight tumours, but they are not capable of destroying the tumour on their own. This is where we can start. One challenge will be to deliver drugs in sufficient concentration to the regional bone marrow niches at the right time. If we succeed, we may have a chance of controlling the growth of glioblastomas and improving our patients’ chances of survival.”

Source: German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)

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mRNA Cancer Vaccine Unleashed on Glioblastomas in First Human Trial

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In a first-ever human clinical trial of four adult patients, an mRNA cancer vaccine developed at the University of Florida quickly reprogrammed the immune system to attack glioblastoma, the most aggressive and lethal brain tumour.

The results mirror those in 10 pet dog patients suffering from naturally occurring brain tumours whose owners approved of their participation, as they had no other treatment options, as well as results from preclinical mouse models. Next, the researchers will test the treatment in a Phase 1 paediatric clinical trial.

This breakthrough, published in Cell, represents a potential new way to recruit the immune system to fight notoriously treatment-resistant cancers using an iteration of mRNA technology and lipid nanoparticles, similar to COVID vaccines, but with two key differences: use of a patient’s own tumour cells to create a personalised vaccine, and a newly engineered complex delivery mechanism within the vaccine.

“Instead of us injecting single particles, we’re injecting clusters of particles that are wrapping around each other like onions, like a bag full of onions,” said senior author Elias Sayour, MD, PhD, a UF Health paediatric oncologist who pioneered the new vaccine, which like other immunotherapies attempts to “educate” the immune system that a tumour is foreign. “And the reason we’ve done that in the context of cancer is these clusters alert the immune system in a much more profound way than single particles would.”

Among the most impressive findings was how quickly the new method, delivered intravenously, spurred a vigorous immune-system response to reject the tumour, said Sayour, principal investigator of the RNA Engineering Laboratory within UF’s Preston A. Wells Jr. Center for Brain Tumor Therapy and a UF Health Cancer Center and McKnight Brain Institute investigator who led the multi-institution research team.

“In less than 48 hours, we could see these tumours shifting from what we refer to as ‘cold’ – immune cold, very few immune cells, very silenced immune response – to ‘hot,’ very active immune response,” he said. “That was very surprising given how quick this happened, and what that told us is we were able to activate the early part of the immune system very rapidly against these cancers, and that’s critical to unlock the later effects of the immune response.”

Glioblastoma is among the most devastating diagnoses, with median survival around 15 months. Current standard of care involves surgery, radiation and some combination of chemotherapy.

The new publication is the culmination of promising translational results over seven years of studies, starting in preclinical mouse models and then in a clinical trial of 10 pet dogs that had spontaneously developed terminal brain cancer and had no other treatment options. That trial was conducted with owners’ consent in collaboration with the UF College of Veterinary Medicine. Dogs offer a naturally occurring model for malignant glioma because they are the only other species that develops spontaneous brain tumors with some frequency, said Sheila Carrera-Justiz, DVM., a veterinary neurologist at the UF College of Veterinary Medicine who is partnering with Sayour on the clinical trials. Gliomas in dogs are universally terminal, she said.

After treating pet dogs that had spontaneously developed brain cancer with personalised mRNA vaccines, Sayour’s team advanced the research to a small Food and Drug Administration-approved clinical trial designed to ensure safety and test feasibility before expanding to a larger trial.

In a cohort of four patients, RNA was extracted from each patient’s own surgically removed tumour, and then messenger RNA, or mRNA was amplified and wrapped in the newly designed high-tech packaging of biocompatible lipid nanoparticles, to make tumour cells “look” like a dangerous virus when reinjected into the bloodstream and prompt an immune-system response. The vaccine was personalised to each patient with a goal of getting the most out of their unique immune system.

“The demonstration that making an mRNA cancer vaccine in this fashion generates similar and strong responses across mice, pet dogs that have developed cancer spontaneously and human patients with brain cancer is a really important finding, because oftentimes we don’t know how well the preclinical studies in animals are going to translate into similar responses in patients,” said Duane Mitchell, M.D., PhD, director of the UF Clinical and Translational Science Institute and the UF Brain Tumor Immunotherapy Program and a co-author of the paper. “And while mRNA vaccines and therapeutics are certainly a hot topic since the COVID pandemic, this is a novel and unique way of delivering the mRNA to generate these really significant and rapid immune responses that we’re seeing across animals and humans.”

While too early in the trial to assess the clinical effects of the vaccine, the patients either lived disease-free longer than expected or survived longer than expected. The 10 pet dogs lived a median of 139 days, compared with a median survival of 30 to 60 days typical for dogs with the condition.

The next step will be an expanded Phase I clinical trial to include up to 24 adult and paediatric patients to validate the findings. Once an optimal and safe dose is confirmed, an estimated 25 children would participate in Phase 2, said Sayour.

Despite the promising results, the authors said one limitation is continued uncertainty about how best to harness the immune system while minimising the potential for adverse side effects.

“I am hopeful that this could be a new paradigm for how we treat patients, a new platform technology for how we can modulate the immune system,” Sayour said. “I am hopeful for how this could now synergise with other immunotherapies and perhaps unlock those immunotherapies. We showed in this paper that you actually can have synergy with other types of immunotherapies, so maybe now we can have a combination approach of immunotherapy.”

Source: University of Florida

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Removing a Protein Lets Glioblastoma Chemo Remain Effective for Longer

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New research by the University of Sussex could help to increase life expectancy and improve treatment for glioblastoma. In the study, published in the Journal of Advanced Science, researchers have discovered that an understudied protein, called PANK4, is able to block cancer cells from responding to chemotherapeutic treatment for the highly intrusive brain cancer, glioblastoma.

Scientists at Sussex have demonstrated that if the protein is removed, cancer cells respond better to temozolomide, the main chemotherapy drug for the treatment of glioblastoma.

Prof Georgios Giamas, Professor of Cancer Cell Signalling at the University of Sussex explains: “Glioblastoma is a devastating brain cancer, and researchers are working hard to identify ways to delay progression of the disease, and tackle cell resistance to treatment. As this is the first time that PANK4 has been linked to glioblastoma, the next step is to develop a drug targeting this protein to try to reverse chemo-resistance and restore sensitivity, ensuring that patients receive the best treatment and have better outcomes.”

Glioblastoma is one of the most aggressive forms of brain cancer. Approximately 250 000 – 300 000 globally are diagnosed with it annually, with a best-case survival rate of just one to 18 months after diagnosis.

Following surgery to remove the tumour, glioblastoma patients are typically treated with radiation and the chemotherapeutic drug, temozolomide. Although patients initially respond well to the drug, the cancer cells quickly develop resistance to this treatment.

The University of Sussex scientists led an international research team to understand the possible reasons for this resistance, helping to guide future therapies to improve quality of life and increase life expectancy for those with glioblastoma.

The team identified a protein called PANK4 which, when removed from the cancer cells, can lead to the cell’s death, and saw patients better responding to temozolomide. Linked to this, the researchers found that patients expressing high levels of the PANK4 protein had lower survival rates.

Dr Viviana Vella, research fellow at the University of Sussex explains: “There are a multitude of under-investigated proteins that may hold great potential for therapeutic intervention. Our study sheds light on this understudied protein, PANK4, unveiling a protective role in temozolomide-resistant cancer cells. Ultimately, PANK4 depletion represents a vulnerability that can now be exploited to restore sensitivity to the drug and improve treatment.”

Source: University of Sussex

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Little-studied Cell in the Brain could be Driver of Glioblastoma

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Glioblastoma is one of the most treatment-resistant cancers, with those diagnosed surviving for less than two years. In a new study in NPJ Genomic Medicine, researchers at the University of Notre Dame have found that a largely understudied cell could offer new insight into how the aggressive, primary brain cancer is able to resist immunotherapy.

“A decade ago, we didn’t even know perivascular fibroblasts existed within the brain, and not just in the lining of the skull,” said senior author Meenal Datta, assistant professor of aerospace and mechanical engineering at Notre Dame.

“My lab’s expertise is examining tumours from an engineering and systems-based approach and looking at the novel mechanical features in rare cancers that may have been understudied or overlooked.”

Using standard bioinformatics and newer AI-based approaches, Datta’s TIME Lab began analysing different genes expressed in the tumour microenvironment related to the extracellular matrix – or the scaffolding cells create to support future cell adhesion, migration, proliferation and differentiation – and other various cell types.

What they found was a surprising, fairly new cell type: perivascular fibroblasts.

These fibroblasts are typically found in the blood vessels of a healthy brain and deposit collagen to maintain the structural integrity and functionality of brain vessels.

“It was a serendipitous discovery,” said first author Maksym Zarodniuk, graduate student in the TIME Lab and the bioengineering doctorate programme.

“We started in a completely different direction and stumbled upon this population of cells by using a combination of both bulk and single-cell RNA sequencing analyses of patient tumours.”

In their data, researchers were able to identify two groups of patients: those with a higher proportion of perivascular fibroblasts and those with significantly less.

They found that brain cancer patients with more perivascular fibroblasts in their tumours were more likely to respond poorly to immunotherapies and have poor survival outcomes.

Further study revealed that perivascular fibroblasts support the creation of an immunosuppressive tumour microenvironment, allowing the cancer to better evade the immune system.

The fibroblasts may also help the cancer resist therapies such as chemotherapy that targets cell division by promoting stem-like cancer cells that rarely divide, which are believed to be a major source of tumour relapse and metastasis.

“Moving forward, we want to do new experiments to confirm what we found in this paper and provide some good ground to start thinking about how to improve response to immunotherapy,” Zarodniuk said.

Because perivascular fibroblasts are a part of a healthy brain’s vasculature, Datta believes that these cells are breaking off and getting close to or infiltrating the glioblastoma tumour.

However, instead of supporting healthy brain function, these fibroblasts are getting reprogrammed and helping the tumour instead.

“Most people think about the brain as being very soft, with soft cells and a soft matrix. But by putting down these fibroblasts and making these very fibrous proteins, it gives us an entirely different perspective on the structure of the brain and how it can be taken advantage of by cancer cells originating in the same organ,” Datta said.

Source: University of Notre Dame

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An Electrifying Solution to Destroy Glioblastomas

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In Nature Nanotechnology, researchers report a new way to target and kill cancer cells in glioblastomas, hard-to-treat brain tumours, using electrically charged molecules to trigger self-destruction, that could be developed into a spray treatment used during surgery.

Researchers from the University of Nottingham found a new way to harness the extraordinary capabilities of bio-nanoantennae: gold nanoparticles intricately coated with specialised redox active molecules to induce apoptosis, in cancer cells on electrical stimulation.

The research focuses on patient-derived glioblastoma cells, an elusive and formidable form of brain cancer that has long evaded effective treatment. The five-year survival rate for glioblastoma is only 6.8% and the estimated average length of survival is about only 8 months from diagnosis.

The bio-nanoantennae were able to specifically target glioblastoma cells, leaving healthy cells unscathed. This unprecedented level of precision opens up new possibilities for developing treatment for glioblastoma during surgical resection of the tumour, when the bio-nanoantennae would be sprayed or injected.

The researchers, which included experts from the Schools of Engineering, Physics and Medicine have now established what is thought to be the first ‘quantum therapeutic’, which taps into the potential of quantum signalling to combat cancer.

Dr Frankie Rawson led the research and explains: “The team showed that cancer cells succumb to the intricate dance of electrons, orchestrated by the enchanting world of quantum biology. With the advent of bio-nanoantennae, this vision of real-world quantum therapies edge closer to reality. By precisely modulating quantum biological electron tunnelling, these ingenious nanoparticles create a symphony of electrical signals that trigger the cancer cells’ natural self-destruction mechanism.”

The team has now secured MRC impact acceleratory funding, have filed patent, to begin translating the technology to this eventual clinical application. Further rigorous research and validation are essential to ensure the safety and effectiveness of bio-nanoantennae for human use.

Dr Ruman Rahman from the School of Medicine and co-author of the study, adds: “Treating glioblastoma tumours has long presented challenges for clinicians and prognosis for patients is still poor, which is why any research showing the promise of a new effective treatment is hugely exciting. This research has shown the possibilities presented by quantum therapeutics as a new technology to communicate with biology. The fusion of quantum bioelectronics and medicine brings us one step closer to a new treatment paradigm for disease.”

Source: University of Nottingham

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In A First, Immunotherapy for Glioblastoma Successfully Tested in Mice

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Immunotherapy has dramatically improved survival against many cancers but efforts to use it against glioblastomas have to date proven fruitless. Now, Salk scientists have found the immunotherapy treatment anti-CTLA-4 leads to considerably greater survival of mice with glioblastoma. Furthermore, they discovered that this therapy was dependent on immune cells called CD4+ T cells infiltrating the brain and triggering the tumour-destructive activities of other immune cells called microglia, which permanently reside in the brain.

The findings, published in the journal Immunity, show the benefit of harnessing the body’s own immune cells to fight brain cancer and could lead to more effective immunotherapies for treating brain cancer in humans.

Glioblastoma, the most common and deadly form of brain cancer, grows rapidly to invade and destroy healthy brain tissue. The tumour sends out cancerous tendrils into the brain that make surgical tumour removal extremely difficult or impossible.

“There are currently no effective treatments for glioblastoma – a diagnosis today is basically a death sentence,” says Professor Susan Kaech, senior author and director of the NOMIS Center for Immunobiology and Microbial Pathogenesis. “We’re extremely excited to find an immunotherapy regimen that uses the mouse’s own immune cells to fight the brain cancer and leads to considerable shrinkage, and in some cases elimination, of the tumour.”

For some tumours, immunotherapy can be used, in which the body’s own immune cells to seek and destroy cancer cells, leading to strong, lasting anti-cancer responses for many patients. Kaech sought new ways of harnessing the immune system to develop more safe and durable treatments for brain cancer.

Her team found three cancer-fighting tools that have been somewhat overlooked in brain cancer research that may cooperate and effectively attack glioblastoma: an immunotherapy drug called anti-CTLA-4 and specialized immune cells called CD4+ T cells and microglia.

Anti-CTLA-4 immunotherapy works by blocking cells from making the CTLA-4 protein, which, if not blocked, inhibits T cell activity. It was the first immunotherapy drug designed to stimulate our immune system to fight cancer, but it was quickly followed by another, anti-PD-1, that was less toxic and became more widely used. Whether anti-CTLA-4 is an effective treatment for glioblastoma remains unknown since anti-PD-1 took precedence in clinical trials. Unfortunately, anti-PD-1 was found to be ineffective in multiple clinical trials for glioblastoma – a failure that inspired Kaech to see whether anti-CTLA-4 would be any different.

As for the specialized immune cells, CD4+ T cells are often overlooked in cancer research in favour of a similar immune cell, the CD8+ T cell, because CD8+ T cells are known to directly kill cancer cells. Microglia live in the brain full time, where they patrol for invaders and respond to damage – whether they play any role in tumour death was not clear. When treated with anti-CLA-4, mice with glioblastoma had longer lifespans than those receiving anti-PD-1.

Upon investigation, they found that after anti-CTLA-4 treatment, CD4+ T cells secreted a protein called interferon gamma that caused the tumour to throw up “stress flags” while simultaneously alerting microglia to start eating up those stressed tumour cells. As they gobbled up the tumour cells, the microglia would present scraps of tumour on their surface to keep the CD4+ T cells attentive and producing more interferon gamma, creating a cycle that lasts until the tumour is destroyed.

“Our study demonstrates the promise of anti-CTLA-4 and outlines a novel process where CD4+ T cells and other brain-resident immune cells team up to kill cancerous cells,” says co-first author Dan Chen, a postdoctoral researcher in Kaech’s lab.

To understand the role of microglia in this cycle, the researchers collaborated with co-author and Salk Professor Greg Lemke. For decades, Lemke has investigated critical molecules, called TAM receptors, used by microglia to send and receive crucial messages. The researchers found that TAM receptors told microglia to gobble up cancer cells in this novel cycle.

“We were stunned by this novel codependency between microglia and CD4+ T cells,” says co-first author Siva Karthik Varanasi, a postdoctoral researcher in Kaech’s lab. “We are already excited about so many new biological questions and therapeutic solutions that could radically change treatment for deadly cancers like glioblastoma.”

Connecting the pieces of this cancer-killing puzzle brings researchers closer than ever to understanding and treating glioblastoma.

“We can now reimagine glioblastoma treatment by trying to turn the local microglia that surround brain tumours into tumour killers,” says Kaech. “Developing a partnership between CD4+ T cells and microglia is creating a new type of productive immune response that we have not previously known about.”

Next, the researchers will examine whether this cancer-killing cell cycle is present in human glioblastoma cases. Additionally, they aim to look at other animal models with differing glioblastoma subtypes, expanding their understanding of the disease and optimal treatments.

Source: Salk Institute

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Cancer-killing Virus Therapy Shows Promise for Glioblastomas

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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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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

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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