This project is game-changing because A/Prof. Huang’s lab have developed the world’s first-in-class designer peptide that disrupts communication between neurons and GBM cells, a crucial aspect often overlooked in brain cancer treatment. Notably, the peptide demonstrates efficacy even in chemo-resistant tumours, offering hope to patients with limited treatment options.

This project holds immense promise in offering hope and tangible benefits to people battling brain cancer. This approach not only inhibits tumour growth with minimal apparent toxicity but also holds potential in overcoming resistance to standard chemotherapy, providing renewed hope for patients facing limited treatment options. Additionally, by activating the immune system, the project offers the possibility of harnessing the body's own defences to fight the cancer, paving the way for more effective and comprehensive treatment strategies for individuals affected by GBM.

While immunotherapy has proven effective in treating various types of cancer, GBM remains a challenge due to its immunosuppressive environment. A novel peptide has been engineered to disrupt the EAG2 and Kvβ2 potassium channel complex, a key communication facilitator between neurons and GBM cells, showing strong effectiveness in treating GBM, including temozolomide-resistant GBMs. Interestingly, preliminary data suggests that this peptide not only reduces neoplastic cells but also remodels the immune microenvironment, increasing tumour-associated macrophages/microglia and T cells. Additionally, the treatment induces the expression of pro-inflammatory factors, suggesting an enhanced immune response.

The overarching aims in this grant includes:

Aim 1. Determine the impact of designer peptide treatment on GBM immune microenvironment.

Aim 2. Determine the therapeutic efficacy of combining designer peptide and immunotherapy.

This project is a game-changer in GBM research, taking a unique approach by focusing on how GBM tumours perceive their environment and how this perception contributes to their aggressive nature. The team has engineered a platform that allows researchers to examine how specific environments influence tumour behaviour. This leads to the creation of more representative models, enabling us to study the tumour in conditions that closely mimic its native environment, thereby facilitating optimal drug development.

It’s widely recognized that therapeutic development for GBM has stagnated partly due to the use of preclinical models that do not accurately represent native tumour conditions. This project addresses this issue head-on by engineering and utilizing more informative models that better mimics the conditions of actual brain tumours. The development of more informative brain cancer models will enhance the reliability of preclinical drug testing, providing more accurate indications of a therapy’s effectiveness in a clinical setting.

Glioblastoma (GBM), a lethal adult brain cancer, exhibits phenotypic plasticity, allowing it to adapt and evade therapeutic interventions. This project aims to understand and target GBM’s plasticity to develop effective therapeutic strategies. The interplay between GBM’s mechanosensory responses to its microenvironment and its ability to transition into a stem cell-like state is proposed as a survival mechanism. The project aims to fabricate and implement defined and modular microenvironments to unravel the intricate interplay between the tumours microenvironment and Glioblastoma behaviour. Using engineered brain matrix mimetic in vitro models, the research will dissect the mechanisms underlying GBM transition between different cellular states. The goal is to discover key molecular players that can serve as potential targets for future drug development.

The overarching aims of this grant includes:

Aim 1: Determine how mechanical cues guide GBM plasticity.

Aim 2: Dissect mechanotransduction pathways that regulate phenotypic plasticity.

Aim 3: Screening drugs for GBM plasticity within organs-on-a-chip.

This project is a game-changer because it uses a new field of science called synthetic biology to turn bacteria into a living medicine for GBM therapy. The project will test different types of engineered bacteria that have been shown to be safe and good at setting up home in tumours. The team has developed advanced genetic circuits in live bacteria, which will be tested in GBM models for the first time, potentially enabling safe and effective treatment in the brain by controlling how and when the bacteria deliver anti-cancer medicines to the tumour, grow, and interact with the immune system.

This project can help people with brain cancer by offering an out-of-the-box and potentially more effective treatment approach. By engineering bacteria to carry powerful anti-cancer molecules for GBM, the project aims to develop treatments that can get past the blood brain barrier and reach parts of the tumour that are usually out of reach for conventional therapies. This could lead to more effective treatments and better outcomes for patients with GBM. The use of engineered bacteria can have a big impact on the treatment of brain cancer by improving the effectiveness of the treatment and kick-starting the immune system in the local area. The project’s findings could also push forward the whole field of brain cancer research, paving the way for testing new types of engineered bacteria for GBM therapy that could ultimately help patients and fill the gaps in current GBM treatment options.

Glioblastoma multiforme (GBM) is a highly lethal adult brain cancer, with treatment hindered by the blood-brain barrier. Certain bacteria, like E. coli Nissle 1917, can bypass the blood-brain barrier and grow within necrotic tumour cores, offering a unique therapeutic opportunity. While these bacteria have shown safety and tumour colonization, their efficacy is limited, leading to a shift towards engineering bacteria to deliver therapeutic payloads. The Danino lab has previously engineered bacteria to express various therapeutic agents with significant efficacy across multiple cancer models. Preliminary data shows that bacteria can colonize GBM mouse models, leading to a proposal to engineer bacteria to deliver cytotoxic and immunotherapeutic payloads for GBM, while improving their safety and control systems.

The overarching aims of this grant includes:

Aim 1: Characterize engineered strains to reduce toxicity of bacteria in GBM models
Aim 2: Optimize therapeutic payloads and genetic circuitry for bacterial delivery in GBM models.

DIPG is a deadly paediatric brain cancer located in a critical area of the brain, making surgical removal challenging and radiotherapy minimally effective. Despite global efforts to develop new treatments, survival rates have stagnated for decades. Recently, therapies using chimeric antigen receptor (CAR) T cells have shown promise, reducing symptoms and tumour size in DIPG patients, but the benefits are not long-lasting. To enhance the effectiveness of these therapies, A/Prof. Anne Rios’ project aims to use artificial intelligence, genomics, advanced 3D imaging technology, and a novel patient representative DIPG 3D organoid model for experimental testing to improve the overall efficacy of CAR T cell therapy.

This project is game-changing because it combines novel DIPG organoids that strongly resemble patient tumours, artificial intelligence, and 3D imaging technology to analyse the behaviour of individual functional cells in a way that hasn’t been done before. This innovative approach could provide crucial insights into how cellular immunotherapies work and how we can further exploit them towards improving therapy design for DIPG patients.

This project could potentially help patients with DIPG by enhancing the effectiveness and durability of T cell therapies. The use of DIPG organoids to model the function of these immunotherapies can provide clinicians and scientists with better indications on how these therapies will perform in patients and the changes we need to make.

DIPG is a lethal paediatric brain cancer with limited treatment options due to its critical location in the brain and tumour complexity. Recent efforts have focused on developing CAR T cell therapies, which have shown initial success but lack long-term efficacy. To improve this, the Rios Lab have developed a new human DIPG organoid model to study DIPG and test long-term CAR T cell treatments. Through applying BEHAV3D on this model, a comprehensive imaging platform to profile T Cells at single cell resolution, the Rios lab have revealed a potent cytotoxic T cell cluster, termed ‘super-engager’ T cells, which show promise for enhanced DIPG targeting. However, balancing therapeutic effectiveness, safety, and long-term responses requires further testing. This project aims to enhance control over the input cells delivered to patients and introduce an innovative strategy for producing superior engineered T cell products.

The overarching aims of this grant includes:

Aim 1. Implementing a selection strategy to enrich for the potent super-engager GD2 CAR T cell phenotype.
Aim 2. Leveraging the BEHAV3D comprehensive imaging platform to dynamically profile the most promising selected T cell products and confirm their super-engager behavioural profile.

Oncolytic viruses, which have a good safety profile and can induce anti-tumour immune responses, are emerging as a promising category of bio-therapeutic agents. A recent clinical trial led by A/Prof. Marta Alonso showed that the combination of oncolytic viral therapy and radiotherapy is non-toxic and can prolong survival for DIPG patients. However, the results are still not curative for all subjects. To enhance the efficacy of oncolytic virotherapy for DMGs, there is an urgent need to amplify the anti-tumour immune response. In this grant, A/Prof. Alonso aims to develop the next generation of oncolytic viruses for DIPG that will target both the DIPG tumour and remodel the tumour microenvironment to enhance efficacy.

Oncolytic viruses are akin to trojan horses in that they quietly infiltrate and kill cancer cells from the inside. Intriguingly, the Alonso lab have been able to take this one step further in that they attach ‘weapons’ to these oncolytic viruses, such that when these oncolytic viruses infect cancer cells, they can ‘release’ these additional weapons to further stimulate the immune system and remodel the tumour microenvironment to be less hospitable for the DIPG tumours. This project is game-changing as it will be the world’s first project that will not only engineer oncolytic viruses to target both the DIPG tumour and tumour microenvironment, but also develop oncolytic viruses as a general platform to deliver a wide range of therapeutics to paediatric brain tumours.

This project brings hope to patients with DIPG. DIPG tumours are notoriously difficult to treat because the tumours are ‘cold’, meaning they lack the immune response needed for many treatments to work effectively. Oncolytic viral therapy has the potential to ‘warm up’ these cold tumours by killing cancer cells and activating the tumour microenvironment, thereby enhancing the body’s immune response against the cancer cells. This approach, combined with the use of nanobodies that inhibit TIM-3, an immunosuppressive molecule in the tumour microenvironment, could significantly improve therapeutic efficacy. Thus, this innovative strategy offers a beacon of hope for a more effective treatment for brain cancer patients.

DIPGs are aggressive paediatric brain tumours that lack effective treatment. Oncolytic viruses, such as Delta-24-RGD, have shown promise in a recent clinical trial, demonstrating safety and efficacy, particularly when combined with radiotherapy. To enhance the antitumour immune response, Delta-24-RGD can be armed with immune ligands (Delta-24-ACT), such as 4-1BBL, leading to increased survival rates. However, to achieve a curative effect for all subjects, additional transgenes need to be incorporated into Delta-24-ACT, potentially through the use of nanobodies. One such nanobody targets Tim-3, an immunosuppressive molecule in the tumour microenvironment, which its targeting has shown to boost the anti-tumour immune response.

The overarching aims of this grant includes:

Aim 1:Developing and characterizing a human TIM3 nanobody as a therapy for DMGs.
Aim 2: Construction of the Delta-24-TIMker-ACT oncolytic virus and evaluation of its anti-tumour effect and mechanism of action in DMG models.