National Centre for Asbestos Related Diseases

Exploiting the Immunogenic Momentum of Cytotoxic Chemotherapy

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Much progress has been made in unravelling immune-suppressive mechanisms that act in the tumour microenvironment, and new immunotherapeutic treatments have shown great promise for profound and durable responses.

In particular, antibodies targeting immune checkpoint molecules have shown impressive efficacy against several cancers.

Cancer Chemo-immunotherapy: Exploiting the Immunogenic Momentum of Cytotoxic Chemotherapy. NHMRC 1067113

Until recently, the consensus was immunotherapeutic approaches could not be combined with cytotoxic chemotherapy. Findings from our group and others have unequivocally shown that chemotherapeutics can have immune-stimulating properties, such as the induction of immunogenic tumour cell death, depletion of suppressive cell types and downregulation of T cell-inhibitory molecules.

We plan to exploit the immunogenic potential of the canonical classes of chemotherapeutics through blockade of immune checkpoints using defined antibodies in murine cancer models, allowing us to find which combinations offer a beneficial effect on the immune response. Also we will use our unique dual tumour cancer model in which bilaterally inoculated AB1 tumours respond symmetrically to checkpoint blockade, such that with appropriate doses, tumours progress or resolve to a full cure. This model allows us to surmount a major problem of analysis; that we are unable to determine what is happening immunologically in a tumour at the time of therapy and also know the fate of that tumour. Thus, we will determine which immune-modulatory effects of therapy are crucial for an effective anti-tumour response, by real-time analysis of the effector populations in regressing versus non-regressing tumours. Lastly, we will find which treatment schedules are optimal for translation to the clinic.

This project will establish the most potent combinations of chemotherapy and immune checkpoint-blockade; better understand the mechanism of action of these drugs, develop new biomarkers; and enable us to make rational predictions about which drugs and schedules can proceed into the clinic.

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