Better tools « Charlie Teo Foundation

Removing roadblocks to immunotherapy for GBM

Researcher name: Dr Jacky Yeung
Institution: Yale University, U.S.
Grant name: Better Tools Grant
Grant amount: Up to $418K
Grant years: 2023-2024

Meet the Researcher

Dr Jacky Yeung is a fellowship-trained neurosurgeon-scientist at Yale University who is an expert on the human brain connectome and studied brain tumour immunology under world-renowned immunologist Dr Lieping Chen. Dr Yeung is among the first to fully characterise the tumour immune microenvironment in malignant meningiomas (a rare brain cancer) and identified a major mechanism by which these tumours evade anti-tumour immunity.

Such a molecule has never been discovered before for changing the characteristic of a tumour blood vessel. Its potential for treating brain cancers is simply untapped. We know in real world clinical trials, regular immunotherapy does not work in brain cancers, but the addition of antibodies targeting CD93 may hold the key in unleashing the body's immune system to battle brain cancers with minimal side effects.

This project aims to resolve one of the greatest problems in tumour immunotherapy, by allowing infiltration of immune cells into the tumour microenvironment, which will enable other scientists to combine their own immunotherapeutic strategies for the treatment of brain cancers. In essence, this treatment strategy is an enabling tool for other immunotherapy researchers to work on further treatments for brain cancer patients.

Targeting CD93/IGFBP7 axis to normalise tumour vasculature and improve T cell trafficking in human gliomas

Tumour vasculature has been theorised to present chemical and physical impedance to effector T cell trafficking. Recently, Dr Yeung’s research group interrogated gene expression profiles in tumours under the treatment of VEGF inhibitors and identified CD93 as a potential target that mediates vascular normalization. The group identified a novel interaction between CD93 and IGFBP7, both overexpressed in tumour but not normal vasculature, that could be antagonised to improve drug delivery and increase immune infiltration.

Aggressive gliomas displayed poor response to nivolumab (anti-PD1 mAb) and overexpression of the IGFBP7/CD93 pathway has been associated with poor response to anti-PD therapies in other cancers. Blockade of the CD93/IGFBP7 using proprietary antibodies developed by the group successfully turned “cold” tumours into “hot” tumours with increased T cell infiltration in preclinical melanoma and pancreatic cancer models.

VEGF overexpression is commonly found in high-grade and recurrent gliomas so CD93-IGFBP7 would likely be induced in these aggressive tumours. Indeed, CD93 expression was recently found to be highly expressed in GBM vasculature, but not in normal brain vessels.

Targeting the CD93/IGFBP7 axis has the potential to enhance the effects of immunotherapy in malignant gliomas without unwanted side-effects of anti-VEGF therapy as CD93/IGFBP7 is downstream in signalling.

Treating GBM in a FLASH

Researcher name: A/Prof Cormode and A/Prof Dorsey
Institution: University of Pennsylvania, U.S.
Grant name: Better Tools Grant
Grant amount: Up to $295K
Grant years: 2022-2024

Meet the Researcher

A/Prof David Cormode is an Associate Professor of Radiology at University of Pennsylvania, Philadelphia, USA. A/Prof Cormode completed his PhD at University of Oxford, England in the U.K. and is the group leader of the Nanomedicine and Molecular Imaging Lab. In 2020, A/Prof Cormode was awarded the Distinguished Investigator at Academy for Radiology & Biomedical Imaging Research. His research focuses on the development of novel and multifunctional nanoparticle contrast agents for medical imaging applications.

A/Prof Jay Dorsey is an Associate Professor of Radiation Oncology at University of Pennsylvania, USA and Co-Leader of the Radiation Oncology Translational Center of Excellence at the Abramson Cancer Center. A/Prof Dorsey completed his MD and PhD at University of South Florida, USA and is the group leader of the Dorsey Lab. He is also a board-certified neurological radiation oncologist with 14 years’ experience. His research focuses on understanding the underlying mechanisms underpinning cancer resistance to radiation and chemotherapy and characterizing normal cellular responses to radiation therapy.

This project combines three game-changing approaches to treating brain cancer: (1) a novel form of radiotherapy – known as FLASH radiotherapy – which uses a rapid, ultra-high dose rate radiotherapy beam. This shortens treatment time and minimises damage to healthy brain tissue (2) injection of a drug-loaded gel (called a hydrogel) into the tumour resection cavity to attack and kill residual cancer cells that could not be surgically removed and (3) the hydrogel loaded with a compound effective at attacking GBM stem cells, the tumour cells responsible for tumour recurrence.

This project aims to show the effectiveness of drug-loaded gel (known as hydrogel) as a therapy for brain cancer patients, and explore the effectiveness of combining the hydrogel treatment with a rapid, high-dose rate radiotherapy technology. For patients, this combined treatment approach has the potential to minimise treatment time for patients while sparing healthy brain tissue damage. Most importantly, the drug compound in this study has already been shown to effectively kill GBM and glioma stem cells known to drive recurrence, meaning this treatment approach may prevent tumour recurrence.

FLASH radiotherapy and radiation-responsive hydrogel drug delivery as a novel combination therapy for glioblastoma

Glioblastoma (GBM) patients, despite an aggressive treatment strategy, invariably have recurrence of the primary tumour, leading to death. Seeking improved treatments for GBM and the potential glioma stem cells (GSCs) implicated in recurrence, the team performed a high-throughput screen of a large bioactive drug library and found that the drug Quisinostat effectively targets GSCs and GBM cells at nanomolar concentrations. The team also tested this drug and confirmed efficacy in patient-derived GBM organoids and in mouse GBM models, however, the team observed dose-limiting systemic side effects. Therefore, the team now seek to leverage their collective expertise to develop a therapeutic strategy centered on administration of a radiation-responsive drug loaded hydrogel (RR-gel) to the tumour resection cavity. Such an approach will result in high concentrations of drug deposited directly to the target site, while avoiding unnecessary systemic doses to other organs. Furthermore, since radiotherapy is also part of the standard of care, a hydrogel that synergizes with radiation (e.g. increases the effects of radiotherapy and/or releases drug in response to radiotherapy) will improve treatment outcomes.

The team’s promising preliminary data shows that such a hydrogel can effectively control GBM tumours. Moreover, the team plans to integrate the hydrogel with FLASH radiotherapy, a novel form of radiotherapy that involves ultra-fast delivery of radiation treatment at dose rates several orders of magnitude higher than those conventionally used and has the potential to decrease normal tissue toxicity. The team proposes to develop improved versions of our radiation-responsive hydrogel system, characterize them and test them in vitro and in vivo for their anti-GBM efficacy, in combination with FLASH radiotherapy. The team will use spectral CT to monitor the hydrogel in vivo. The safety of the treatment will be extensively assessed. Overall, the team seeks to develop a breakthrough therapy for GBM.

Early Diagnosis of Childhood Brain Cancer Using a Simple Blood Test

Researcher name: Prof Craig Horbinski
Institution: Northwestern University, U.S.
Grant name: Better Tools Grant
Grant amount: Up to $276K
Grant years: 2022-2024

Meet the Researcher

Prof Craig Horbinski is a Professor of Pathology and Neurosurgery at Northwestern University, Chicago, Illinois, USA. Prof Horbinski completed his MD, PhD at the State University of New York at Buffalo, and holds several Director roles at Northwestern University including Director of Neuropathology, Director of the Neuropathology Fellowship program, and Director of the Northwestern Nervous System Tumour Bank. He has almost 20 years of clinical and research experience, with a research focus on the use of molecular testing in brain tumours to improve diagnostic and prognostic accuracy and achieve the goal of personalised medicine.

Many attempts have been made to analyse short DNA fragments from the blood that are associated with cancer. The critical limitation is that these cancer-associated DNA fragments are very low in concentration, and are hidden amongst a sea of other ‘background’ DNA within the blood. This project takes a game-changing approach by analysing longer DNA fragments and comparing the patterns with thousands of known brain tumours to accurately identify the type of brain tumour. This project will also investigate the DNA content across several blood components such as platelets and white blood cells. This approach has never been tested in childhood brain cancer patients.

This blood test technology aims to help children with brain cancer by providing a non-invasive diagnostic that: (1) identifies those children showing neurological symptoms who need brain scans; (2) assist surgeons in surgical planning; (3) identifies those children who may be able to avoid surgery, since some tumours do not benefit from surgery. In addition, this blood test may potentially show whether a tumour is responding to treatment, and whether it is growing back or not.

Methylation profiling of circulating DNA in paediatric brain tumour patients

Most children with brain tumours first come to medical attention with headaches and other neurological symptoms. Because imaging is expensive, a child is often just treated for their symptoms, hoping they get better, without actually being diagnosed. But sometimes, the disease ends up being a brain tumour. Treating these tumours can be difficult, since the developing brain is very sensitive to neurosurgery, radiation, and chemotherapy. We need an earlier, cheaper, and easier test to reliably diagnose and subclassify paediatric brain tumours. This would not only help identify children who do need brain scans, it would also help neurosurgeons if they knew exactly what kind of tumour they were dealing with while planning surgery. This might even help some children avoid surgery altogether, since some tumours don’t benefit from surgery, or if the blood test says it’s unlikely to even be a tumour. It would also be helpful if that same test could tell whether a tumour is responding to treatment, and whether it is growing back or not.

The Nervous System Tumour Bank at Northwestern University in Chicago recently collaborated with scientists from Toronto to show that a new blood test, called “cell-free methylated DNA immunoprecipitation and high-throughput sequencing” (cfMeDIP-seq), could accurately diagnose the presence and type of brain tumour in adult patients. This technique detects fragments of tumour DNA in the circulating blood, and tests it to see if it matches any pattern of DNA in a large reference library consisting of thousands of brain tumours. While cfMeDIP-seq is already being developed for use in adults with brain tumours, it has not yet been explored in children. Northwestern Medicine, in partnership with Lurie Children’s Hospital of Chicago, has the required technical expertise and paediatric brain tumour patient volume to advance cfMeDIP-seq for the care of children with CNS tumours.

A New Approach to Evaluating Immunotherapy

Researcher name: Dr Jessica Buck
Institution: Telethon Kids Institute, AUS
Grant name: Better Tools Grant
Grant amount: Up to $199K
Grant years: 2022-2024

Meet the Researcher

Dr Jessica Buck is an early career research fellow at the Brain Tumour Research Team at the Telethon Kids Institute and the University of Western Australia in Perth, WA. Jessica completed her doctorate at the University of Oxford, UK, and was named as one of the Superstars of STEM by Science and Technology Australia in 2021. Dr Buck is an inspiration to young Aboriginal women in STEM, routinely hosting and mentoring students. Jessica has experience in both preclinical neuroscience and oncology research with a current focus on finding more effective, less harmful treatments for children with brain cancer.

To do this, the team will use laboratory models that incorporate a 'complete' immune system. Having an immune system is essential for testing new immunotherapies, and allows development of brain-specific childhood approaches. This project will study the childhood brain tumour microenvironment, especially the immune compartment, during cancer growth and treatment to uncover the best timing to administer immunotherapy to childhood cancer patients.

This project will develop a new model for testing immunotherapy in the childhood cancer setting. This will help children with brain cancer from three perspectives (1) allowing for identification of more effective childhood cancer-specific treatments (2) improve our understanding of child-specific toxicities and (3) enhance our ability to translate the most effective therapies into the clinic faster.

Using paediatric mice to model paediatric brain tumours

Very few new cancer drugs have been identified for children. We believe this is partially because children are treated as “small adults” in cancer drug discovery. Without exception, cancer drugs are tested in adult clinical trials, with trials in children only performed later, if at all. Furthermore, virtually all preclinical studies have been conducted in adult mice rather than paediatric mice. This completely ignores differences that exist between adults and children in the developmental stage of their brain, immune system, organs, and tumour microenvironment. we will develop world-first techniques to more accurately evaluate new childhood cancer therapies in paediatric mice, rather than in adult mice as is done currently. We hypothesise this will better identify childhood cancer-specific treatments and child-specific toxicities, improving our ability to translate the best therapies into the clinic faster. In particular, our pipeline will enable the testing of promising new immunotherapies in paediatric mice for the first time. Using our paediatric models, we will pioneer the development of preclinical standard-of-care protocols, including radiotherapy, for paediatric mice that mimic clinical protocols. This will then give us clinically-relevant and age-appropriate model systems with which we can overlay and evaluate new immunotherapies, thus expediting their translation to upfront clinical trials. Our long-term vision is that introduction of effective new therapies will afford a reduction in the dose of toxic chemotherapies and radiotherapy currently used for standard-of-care, so that all brain cancer patients can live long, happy, and healthy lives.

Navigating the Immune System Towards the Brain Cancer

Researcher name: Prof Amy Heimberger
Institution: Northwestern University, U.S.
Grant name: Better Tools Grant
Grant amount: Up to $499K
Grant years: 2022-2024

Meet the Researcher

Prof Amy Heimberger is a neurosurgeon and scientist at Northwestern University, USA. Prof Heimberger completed her medical degree at Washington University, USA and leads a laboratory focused on identifying new targets for immunotherapy treatment in brain cancer. Prof Heimberger is at the frontier of her field: she is the scientific director of the Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Cancer Center, she received the Abhijit Guha Award in recognition of her significant contribution and accomplishments in the medical field and serves on the National Cancer Advisory Board in the USA.

This project will be the first study of its kind to investigate how effective this new therapy – called STING – will be in eradicating GBM tumours. This project is game-changing from two perspectives (1) this project will explore a new therapeutic approach never tested before in brain cancer and (2) by directly injecting into the tumour, the drug will directly infiltrate the tumour, thus avoiding the issues of passing through the blood brain barrier. This means a much lower dose may be administered while also avoiding unwanted side effects.

This project aims to find a solution for GBM, which currently has no effective therapies. If proven effective, this therapy will open up opportunities for GBM patients to be successfully treated with immunotherapy, which to date has shown little success. Also, once this project determines the therapy is safe and effective in preclinical models, it will advance into a Phase I clinical trial where the drug will be available for GBM patients.

Preclinical validation of a STING agonist to treat Glioblastoma

The prognosis of glioblastoma patients is poor with a median overall survival (OS) of around 21 months. Whereas radiation, chemotherapy and tumour-treating fields are established treatments at initial diagnosis; at recurrence, there are no effective therapies. Immunotherapy for cancer has had unparalleled progress in achieving long-term remissions, even in cases of advanced metastatic disease. Immunotherapy has been adopted as the standard of care for several tumours. In contrast, immunotherapy has not shown efficacy in treating glioblastoma, partly due to immunosuppression. These mechanisms include tumour infiltration by immunosuppressive cells, malfunction or lack of immune-promoting or cancer-killing cells, and frequent use of immunosuppressive drugs such as corticosteroids, among other factors. Recent studies revealed that an immune-promoting protein named stimulator of interferon genes, or STING, can trigger the anti-tumoral immune response in gliomas and melanoma. The project will explore whether STING activation is an effective immunotherapy for gliomas and whether this treatment can be further enhanced by combining it with other immune-promoting strategies/drugs such as PD-1 blockade or signal transducer and activator of transcription 3 (STAT3) inhibition. Here, we propose to investigate this and wish to ultimately determine whether STING agonist drugs are safe and well-tolerated when delivered into the tumours of patients with recurrent glioblastoma, a disease stage that has no effective therapies.