The Potential and Challenges of Exploiting the Vast But Dynamic Neoepitope Landscape for Immunotherapy

Els M. E. Verdegaal, Sjoerd H. van der Burg

Somatic non-synonymous mutations in the DNA of tumor cells may result in the presentation of tumor-specific peptides to T cells. The recognition of these so-called neoepitopes now has been firmly linked to the clinical success of checkpoint blockade and adoptive T cell therapy. Following proof-of-principle studies in preclinical models there was a surge of strategies to identify and exploit genetically defined clonally expressed neoepitopes. These approaches assume that neoepitope availability remains stable during tumor progression but tumor genetics has taught us otherwise. Under the pressure of the immune system, neoepitope expression dynamically evolves rendering neoepitope specific T cells ineffective. This implies that the immunotherapeutic strategy applied should be flexible in order to cope with these changes and/or aiming at a broad range of epitopes to prevent the development of escape variants. Here, we will address the heterogeneous and dynamic expression of neoepitopes and describe our perspective and demonstrate possibilities how to further exploit the clinical potential of the neoepitope repertoire.