Enhancing innate anti-tumour immunity: lessons from virotherapy and STING agonism 1

Hello, my name is Kevin Harrington. I'm a Professor in Biological Cancer Therapies at the Institute of Cancer Research, and a Clinical Oncologist at the Royal Marsden Hospital in London. It's my pleasure today to discuss with you Enhancing Innate Anti-Tumour Immunity: Lessons from Virotherapy and STING Agonism.

These are my declarations of interest.

I'm going to begin the discussion by thinking about the question of whether or not we should be using systemically administered agents or whether or not we should be delivering them by local injection. To illustrate this, I will talk about two separate virus therapies that are in clinical development. On the left-hand side of the slide, you see the oncolytic reovirus agent, pelareorep, which has been delivered in a number of clinical studies by intravenous injection. The virus can colonise tumours leading to infection and setting up virus factories. These viruses will grow within tumour cells that have an abnormality in the activation status of the RAS pathway—either through RAS mutation or through constitutive activation of the EGFR-MAP kinase ERK pathway. Viruses will grow within these tumour cells, with such abnormalities leading to their lysis and their killing, and potentially, activation of anti-tumour immune responses. On the right-hand side of the slide, in contrast, I show you an approach related to direct intratumoral injection of an agent, so through local delivery. Here, the idea is that the virus infects a directly injected tumour deposit, replicates within it, lysing the tumour cells. Releasing new viruses for ongoing infection, danger-associated molecular patterns and pathogen-associated molecular patterns for immune activation, and also tumour-associated antigens that can be picked up by dendritic cells within the tumour microenvironment. Those dendritic cells will become activated, mature and migrate to locoregional lymph nodes where they will demonstrate those antigens to T cells within the lymph nodes. If there is one T cell that expresses a cognate T cell receptor against that antigen, that T cell can become activated, can replicate—generating thousands, indeed, millions of copies of that T cell that can be released back into the systemic circulation to return to the locally injected disease, to locoregional lymph nodes containing the disease, and to more distant deposits to mediate a systemic anti-tumour effect. So in effect, local vaccination for a systemic therapy benefit.