Projects lead: Dr Miles Andrews
Cancer ecosystems biology: zooming out of the tumour-immune microenvironment to incorporate patient and environment factors in immuno-oncology.
Much is known about the damaging genomic and molecular events that give rise to cancer cells. Much is also known about how cancer cells interact with their immediate tumour microenvironment (TME). However, significantly less is known about how the patient as a whole, and their environment, impact cancer trajectories. Multiple emerging lines of evidence indicate that cancer-extrinsic factors like patient sex, body composition, diet, and gut microbiota, all exert major influences on cancer outcomes, but the molecular and cellular mechanisms involved are very poorly understood.
This project seeks to improve cancer outcomes by linking established cancer-intrinsic biology to emerging cancer-extrinsic biology, thereby building more complete ecosystem-level models of cancer behaviour. Central to the theme of this project will be parallel evaluation of several sub-themes, each addressing the mechanisms of a ‘distinct’ but interacting patient or environmental factor. Current sub-themes include exploration of the impact of steroidal sex hormones on treatment response and whether androgen blockade has application as an adjunct therapy to cancer immunotherapy. We are also exploring the interplay between sex hormones and adipokines in melanoma, noting apparent interactions between sex and obesity in clinical cohorts. How gut or tumour microbiota impact cancer immunity at a local or systemic level are of high interest, with particular focus on their contribution to immunotherapy-related toxicity.
Liquid biomarkers for cancer immunotherapy - a project of the Translational Research in Immunotherapy Patients (TRIP) program
Cancer immunotherapy has revolutionised the way that many cancers are treated and improved clinical outcomes. Yet many patients do not respond to treatment, and treatment-related side effects are common. Current methods to predict response and toxicity are very limited, meaning that many patients receive therapy that does not benefit them, and may cause harm.
Better predictive biomarkers for immunotherapy are needed. Blood is an attractive specimen type in which to identify biomarkers as it is easy to obtain and can be sampled on multiple occasions throughout a patient’s treatment. Using patient cohorts and biospecimens collected via the Alfred Cancer Biobank, we are investigating the utility of novel chemical and cellular biomarkers in blood samples of patients receiving immunotherapy-based treatment. Current projects focus on patients with lung and skin (melanoma or non-melanoma) cancers, evaluating circulating markers of immune phenotypes, non-coding RNA (microRNA), hormones and metabolites, against known clinical outcomes.
Optimising the management of immune-related adverse events
Due to its mechanism of action, cancer immunotherapy can cause a wide range of inflammatory side-effects, called immune-related adverse events (irAEs); some irAEs can be permanent or life-threatening. No useful methods currently exist to predict who will experience irAEs, let alone what type or how severe. With rapidly increasing numbers of patients receiving cancer immunotherapy, several critical questions arise:
- How should patients with underlying inflammatory/auto-immune conditions be managed?
- What is the best choice of immunosuppressive drug for an individual patient experiencing irAE?
- Can irAE be anticipated and prevented?
This project aims to understand the immunological mechanisms underlying major irAEs and identify novel biomarkers that can assist in predicting irAEs before they occur or become clinically significant. This project will use established pre-clinical models of melanoma to comprehensively characterise the immunological effects of multiple immunosuppressive drug classes in the context of cancer immunotherapy. By modelling patient-derived immune phenotyping against experimentally-derived immunosuppressive drug fingerprints, these studies will generate new methods for selecting the optimal drug to prevent or treat irAE. Additional application to patients with an underlying need for immunosuppression, such as those with pre-existing autoimmune diseases or organ transplant recipients, are supported by existing collaborations and will advance the safe use of immunotherapy in these at-risk populations.
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