The breakthroughs in immunotherapy have been ground-breaking in oncology, leading to durable responses in patients with advanced disease. However, the sad fact remains that most cancers do not respond to these therapies. Clinical data generated over the last few years have shown that the visibility of a tumour to the immune system is one of the key determinants of whether a particular cancer will respond. Tumours presenting a high number of non-self cell surface markers (neoantigens) are exquisitely sensitive to T-cell checkpoint therapy because they are more likely to be recognized as ‘foreign’. However, the vast majority of cancers have low neoantigen expression and, as such, are non-responsive to immunotherapy. In order to make the next step change in oncology therapy there is an absolute requirement for a new generation therapies that address the tumour visibility problem.
Rather than targeting the immune system, Grey Wolf’s approach is to directly alter the tumour cells, illuminating them for attack and destruction by the immune system. Our primary approach is to target the aminopeptidase Endoplasmic Reticulum Associated Protease 1 (ERAP1) a key protein in the antigen presentation pathway shown to edit the neoantigen and antigen repertoire on tumour cells. Genetic data from genome wide association studies provide strong support for ERAP1’s role in antigen modulation in disease and potential overexpression in certain tumour types. In addition, data from multiple labs demonstrates the powerful immune-mediated anti-tumourogenic effect of ERAP1 inhibition or ablation in syngeneic mouse tumour models. Modulators of ERAP1 activity have the potential to offer a new treatment paradigm in oncology, significantly altering the neoantigen presentation on the surface of tumour cells and leading to greater recognition and destruction by the immune system.
ERAP2, a homologue of ERAP1, also plays a role in modulating the neoantigen and antigen repertoire and recent publications highlight its potential role in select cancer types. As experts in ERAP biology and drug design, Grey Wolf is also developing modulators of ERAP2 and exploring their potential as cancer therapeutics.