Advances in immunotherapy such as immune checkpoint blockade have radically improved clinical outcomes in some diseases such as melanoma, but similar advances have not occurred in other solid cancers. Checkpoint inhibitors are generally only effective in cancer patients with high levels of immune infiltrate. Since the majority of cancers have only a low level of tumor-infiltrating lymphocytes (TIL), alternative immunotherapy approaches are required.
One approach that can be used in patients with low/absent TILs is to genetically engineer a patient’s own T-cells to recognise cancer antigens. While these so-called chimeric antigen receptor (CAR) T-cells have been highly successful in certain haematological cancers, results in solid tumours have been less impressive to date. Studies in the Darcy program have found that this is largely due to several factors which include the immunosuppressive tumour microenvironment, tumour antigen heterogeneity and poor persistence and trafficking of the CAR T-cells to the tumour site.
The focus of the Darcy program is to test several genetic and pharmacological strategies to significantly enhance the function of CAR T-cells against current and new cancer antigen targets. These studies involve the development and testing of innovative approaches that enable CAR T-cells to persist longer and localise more effectively at tumour deposits and engage the endogenous immune system to overcome heterologous tumours. The team has developed state of the art self-antigen syngeneic mouse models and human xenogeneic models for testing these new approaches. The impact of this work that arises from the program is highlighted in recent work published in premier scientific journals including Nature Immunology (2020) and Nature (2024, 2025).
The close links of the Darcy program with oncologists at the Peter Mac and role with the newly established Centre of Excellence for Cellular Immunotherapy and funding support from industry collaborators are instrumental in driving translation of the most promising findings into the clinic. The Darcy program led the first CAR T-cell trial performed in Australia targeting the Lewis Y antigen in acute myeloid leukemia patients (Richie et al Mol Ther 2013) and in solid cancers [NCT03851146, ACTRN12622001542785]. Another trial is planned for 2026.
Current projects
Consumer representative
The Darcy program actively includes consumers in its planning and execution of projects. For example we have established close collaborative links with consumers Mrs Leslie Gilham and Ms Maree Bethel who are both named Associate Investigators on our project with the National Breast Cancer Foundation. These consumers have provided us with feedback regarding subtypes of patients likely to benefit from this proposal and how it will be received. We provide financial assistance for meetings with the consumers. Being based at the Peter MacCallum Cancer Centre we have constant interaction with patients, particularly through our collaboration with oncologists such as Professor Sherene Loi. Our engagement with consumers is acknowledged in published papers.
