A precision guided CAR T-cell therapy will enter its first human trial after securing MRFF funding, with researchers aiming to overcome one of the biggest barriers to treating solid tumours.
A next-generation CAR T-cell therapy designed to overcome one of the biggest obstacles in treating solid tumours will move into a first-in-human clinical trial after Peter MacCallum Cancer Centre researchers secured $17.7 million through the Medical Research Future Fund.
The Frontier Health and Medical Research Grant will support a program led by Professor Paul Beavis and Professor Jane Oliaro to clinically validate the centre’s “precision guided” CAR T-cell platform in patients with multiple myeloma before expanding into solid tumours, with breast and lung cancers among the anticipated targets.
Although CAR T-cell therapy has transformed the treatment of several blood cancers by genetically engineering a patient’s own T cells to recognise and destroy malignant cells, translating that success to solid tumours has remained elusive.
Solid cancers present physical barriers to immune cell infiltration, suppress T-cell function within the tumour microenvironment and increase the risk of severe systemic inflammatory toxicities when immune-stimulating molecules are administered.
The Peter Mac platform, known as Precision Guided Munition (PGM) CAR-T, aims to address those limitations by using CRISPR gene editing to rewire the engineered T cells so they deliver their immune payload only when they encounter tumour cells.
Rather than continuously producing cytokines or releasing them throughout the body, the modified cells activate endogenous cytokine genes only after the CAR engages its target antigen.
Professor Beavis, co-head of Peter Mac’s Cancer Immunology Program, said the technology was developed with Professor Phil Darcy to improve both efficacy and safety.
“This allows us to engineer CAR-T cells to have increased efficacy and an improved safety profile,” he said.
Compared to conventional CAR T-cells, PGM CAR T-cells are engineered to localise the “cytokine response” to the targeted cancer. It is thought this could improve efficacy and reduce toxicities in both blood and solid tumour cancers.
“Our technique can precisely deliver a cytokine payload directly into the tumour site, resulting in enhanced tumour killing and reduced toxicity,” said Professor Beavis.
“This MRFF grant will allow us to clinically validate our PGM CAR-T technology in multiple myeloma and expand its use to solid cancers.”
The technology was described in a Nature paper published in July 2025. In preclinical models, the researchers used CRISPR to insert CAR signalling elements into endogenous cytokine gene loci, effectively converting the T-cells’ own genes into tumour-activated therapeutic switches.
The study demonstrated that cytokine production occurred predominantly after tumour recognition rather than constitutively, leading to greater expansion and persistence of CAR T-cells within tumours.
In multiple mouse models, the engineered cells produced stronger anti-tumour responses than conventional CAR T-cells while avoiding the high circulating cytokine levels linked to treatment-related toxicity.
The approach also remodelled the tumour microenvironment by recruiting and activating other immune cells, suggesting the platform could overcome the immunosuppressive conditions that have limited CAR T-cell activity in solid cancers.
The researchers reported that the technology was modular, allowing different cytokines or immune payloads to be inserted depending on the cancer being targeted, potentially broadening its application across a range of malignancies.
Related
Peter Mac executive director of cancer research Professor Ricky Johnstone said the project exemplified translational research, taking a fundamental laboratory discovery through to patient testing.
“This project really embodies what research at Peter Mac is about,” he said.
“Professor Beavis and his team conducted the fundamental discovery research, and this funding will enable him to work with Professor Oliaro and the Centre of Excellence in Cellular Immunotherapy to translate this discovery into a novel CAR T-cell product for testing in a first-in-human trial at Peter Mac.”
The product will be manufactured by Cell Therapies Pty Ltd, with the initial multiple myeloma trial to be led by Professor Simon Harrison. Associate Professor Ian Parish and Professor Edwin Hawkins from WEHI are also members of the multidisciplinary research team.
More than 2700 Australians are diagnosed with multiple myeloma each year. Despite advances in immunotherapy, the disease remains incurable for most patients, with a five-year survival rate of approximately 61%.
