Malaghan Institute of Medical Research funded Research Programmes

Immune checkpoint inhibitors (ICI), such as anti-PD-L1, have revolutionised cancer treatment. ICI work by blocking “off-signals” on T cells – immune cells that can selectively recognise and destroy cancer cells. Internationally, a wide range of cancer types are treated with ICI, including lung, breast and skin cancers. Despite being highly successful therapies, the majority of patients are refractory to treatment. With increasing global cancer rates, and a growing focus on immunotherapy options, pharmaceutical companies are exploring ways to enhance the efficacy of ICI. This “ICI-refractory” market is currently estimated to be valued at US$38.7B with a compound annual growth rate of 11.3%. Conceptually, the administration of a small molecule that can activate the innate and adaptive immune response within a tumour is an attractive strategy to reverse ICI-resistance. However, systemic exposure to such agents is well documented to induce a proinflammatory response that can result in serious immune-related adverse effects. Our research collaboration has identified a series of tumour-activated immune stimulants that can be administered systemically. Using industry-standard ICI-refractory murine tumour models, we have observed a high proportion of complete tumour regressions and confirmed induction of long-term acquired immune memory in ‘cured’ mice. This can be achieved using our targeted immuno-stimulants as a single-agent, or in combination with ICI at very well-tolerated doses, indicating a broad safety margin. We propose to advance three distinct chemical classes through a medicinal chemistry lead optimisation programme. A lead candidate (and back-up) will be selected, patent-protected and mechanistically validated in extensive preclinical studies. The scientific data generated will underpin commercial investment in a start-up company that will take our immuno-oncology product into first-in-human studies to improve lung cancer treatment outcomes in Aotearoa New Zealand.