Immunotherapies, including immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR)-T cells, are revolutionizing cancer treatment paradigms, with the potential for long-term control, and possibly even cure, of aggressive cancers. However, only a fraction of patients responds to such therapies. A better understanding of the requirements for cancer immunotherapy success will allow improvements to these therapies to allow more patients to benefit.
Successful anti-tumour immune responses, including those induced by cancer immunotherapies, require T cells to physically enter tumour tissues. This homing of T cells to tumours is a complex and tightly regulated process, wherein the first critical step is for a circulating T cell to become tethered to the inner lumen of a tumour blood vessel. This requires the vessel to express E- or P-selectin adhesion molecules, and the T cell to express CD15s (sialyl-Lewis-X), a small sugar molecule that decorates certain glycoproteins and glycolipids on the T cell surface.
In this two-part talk, I will firstly present our recent findings on the importance of the CD15s/E-selectin molecular axis in clinical response to ICI (anti-PD1) therapy in melanoma patients. We have discovered that expression levels of these molecules in blood and tumour accurately predict therapeutic outcome, and used single cell profiling and multispectral immunofluorescence to deeply characterise the rare CD15s+ T cell subset associated with therapeutic success.
Secondly, I will discuss our CAR-T cell program aimed at developing novel treatments for brain cancers, including glioblastoma in adults and diffuse midline glioma in children. I will provide an update on our ongoing Australian clinical trials, and discuss pre-clinical studies aiming to boost CAR-T cell homing to brain tumours via modulation of the CD15s/E-selectin axis, ultimately enhancing treatment success.