Regan studied Biomedical Science at the University of Auckland, completing a Master’s degree in developing a pre-clinical model to evaluate prodrugs in the treatment of hepatocellular carcinoma at the Auckland Cancer Society Research Centre (ACSRC), University of Auckland.
Part of the Cancer Immunotherapy programme, led by Professor Ian Hermans, Regan is completing a collaborative PhD project between the ACSRC and MIMR on combining immunotherapy with hypoxia-activated prodrugs, to improve immunotherapy effectiveness, and it is sponsored by the Maurice Wilkins Centre.
My research interests are tumour hypoxia and cancer immunotherapy. Despite recent clinical successes and approval of numerous checkpoint blockades, the objective response rate as a single therapy associated with such treatment is only around 10-40% across different tumour types. This indicates the presence of underlying mechanisms of resistance which limits the development of a long-term immunity against tumours and the necessity to overcome antagonism within the tumour microenvironment to elicit a robust anti-tumour immune response.
My research project is titled “modulating tumour hypoxia with hypoxia-activated prodrugs to improve immunotherapy effectiveness”. The activation of T-cell response is regulated by various stimulatory and inhibitory receptors expressed on the cell surface. The interactions between inhibitory receptors and their ligands prevent over-activation of T-cell responses but these are often exploited by tumours to suppress the anti-tumour immune response. Checkpoint blockade acts by inhibiting the interactions between these immunosuppressive molecules and thus relieves the T-cells from such negative regulations. This therapeutic approach has been shown to elicit robust and durable T-cell responses even in patients with advance-staged cancer. However, only a minority of patients experience durable responses indicating the anti-tumour T-cell response must encounter antagonism within the tumour-microenvironment. Accumulating evidence suggests that tumour hypoxia can suppress the immune response within the tumour microenvironment through several mechanisms. We therefore hypothesise that the eradication of hypoxic tumour cells by using hypoxia-activated prodrugs (HAPs) that are specifically activated under low-oxygen conditions can improve the outcome of checkpoint blockades.
We identified suitable murine tumour cell lines that are sensitive to HAP candidates under hypoxia. Subsequent in vivo studies have shown that treatment with HAPs reduced the hypoxic fractions within these tumours and improved anti-tumour activity when combined with checkpoint blockade. Investigation of the immune cell populations in different mouse tissues demonstrated favourable changes in the percentage and number of different T-cell subsets and suppressor cells after the administration of HAP. This indicates relief from immunosuppression due to killing of hypoxic cells. Further studies have also shown increased antigen-specific T-cell proliferation in the lymph nodes and spleen after HAP administration. These results suggest that HAP and checkpoint blockades may synergise to improve anti-tumour activity and further investigations into the functionalities of T-cells in the tumour and spleen are underway.