A “hot” issue: TGF -β and checkpoint inhibitor resistance

Most human solid tumours are immunologically cold and far less likely to respond to immune checkpoint inhibitors (ICIs) than immunologically hot ones. EpicentRx’s AdAPT-001 is an oncolytic virus currently in a Phase I/II anticancer trial. In this article, Bryan Oronsky, Chief Development Officer, and Tony Reid, Chief Executive Officer of EpicentRx, explain how AdAPT-001 uses tumour cells as a factory to make the TGF-beta trap that it carries. This trap neutralises the immunosuppressive protein, transforming growth factor–β to ‘heat up’ tumours and sensitise them to ICIs.

One of the greatest challenges – and greatest opportunities – in oncology is how to make ICIs, often described as therapies that remove the brakes on the immune system, work for all patients, rather than a select few. The reality is that despite the hope and hype that surrounds them, ICIs are only active in a fraction of patients with individual tumour types like melanoma and non-small cell lung cancer. In contrast, breast, pancreatic, prostate, brain, sarcoma and colorectal cancers tend to respond poorly or not at all to checkpoint blockade.¹ Worse still, some patients with slow-growing disease at baseline not only fail to respond to ICIs, but seem to rapidly “go south” on them; with tumour growth and metastatic spread increasing drastically and suddenly during treatment, which is an indication that the ICI was likely responsible for the dramatic downturn, also known as hyperprogression.²