Funding: Tour de Cure, $100,000 AUD (2025-2027)
Lay synopsis: Immunotherapies are widely used to treat a growing number of tumour types. However, for most cancers, fewer than half of recipients will benefit, and ways to improve immunotherapy outcomes are urgently required. We have shown, in mice with tumours, that 5 days of low-dose radiotherapy can modify tumour blood vessels to allow more tumour-killing immune cells into tumours. Although this radiotherapy is not curative by itself, when we also give the mice immunotherapy we see 100% cures.
We have so far only studied this type of treatment in one type of cancer and wish to test out treatment in several additional tumour types to help us understand how broadly useful our treatment may be. We will use different types of mice to represent the diversity seen between different cancer patients in the clinic. We will also look for common features of cancers that do or do not respond to radio-immunotherapy, helping doctors and patients choose the treatments that are most likely to work. If successful, this work could improve outcomes and provide hope for the majority of those cancer patients who receive ICI but do not achieve a response.
Scientific synopsis: Although immune checkpoint inhibitor (ICI) immunotherapies are clinically approved for a growing number of cancers, fewer than half of recipients benefit and improved efficacy is urgently needed. We have shown, in mice with mesothelioma, that 5 consecutive daily doses of low-dose radiotherapy (LDRT) can improve tumour blood vessel function – increasing blood flow, perfusion, oxygenation and immune cell infiltration. Remarkably, LDRT paired with clinically analogous ICI gives 100% cures – even though neither alone is effective. Whilst promising for mesothelioma, we predict our findings have wider implications for solid tumours in general.
AIM 1: Study additional cancer types, in various mouse strains, to indicate how widely applicable our treatment may be whilst helping to account for diverse genetic backgrounds like those seen in the clinic.
AIM 2: Identify predictive biomarkers i.e., common features distinguishing tumours that will respond to radio-immunotherapy versus ones that will not – BEFORE treatment.
OVERALL HYPOTHESIS: Efficacy of radio-immunotherapy will vary across tumour models, and responses can be predicted based on features readily identifiable in pre-treatment tumours.
IMPLICATIONS FOR TREATMENT: This work could improve outcomes for the majority of those cancer patients who receive ICI, but do not achieve a response. Biomarker identification can help doctors and patients select the most effective therapies based on the features of that patient’s disease. In the medium term, we can feed our data back into development of a clinical trial; we would anticipate a rapid projected time to clinical translation since both radiotherapy and ICI are widely used. Of further significance, radiation is usually used at cell-killing doses in the context of immunotherapy; our treatment has the unique benefit of using lower, sub-cytotoxic doses that should reduce damage to non-tumour tissues – potentially letting oncologists treat tumours in traditionally hard-to-irradiate locations such as the lung.