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.