Endogenous viral elements constitute a complementary source of antigens for personalized cancer immunotherapy

Cancer immunotherapies have greatly improved the treatment of several cancers, albeit a large fraction of patients still does not benefit from such treatments. Personalized therapies are envisioned to lead to improved outcomes, yet they have largely been leveraging neoepitopes arising from missense somatic mutations, and as such primarily patients with relatively high tumor mutational burden (TMB) are suitable. With the goal to enhance and broaden its application, we present a pipeline, ObsERV, for the design of personalized cancer immunotherapies based on epitopes derived from endogenous retroviral elements (EVEs). We show that EVE-derived peptides are presented as antigens on tumors and can be predicted by ObsERV. Preclinical testing of ObsERV demonstrates induction of durable poly-functional CD4+ and CD8+ T-cell responses as well as long-term tumor protection. We find signs that the EVE antigen burden may stratify low-TMB cancer patients into groups of differential overall survival, indicating that EVEs serve as a additional tumor antigen source. Furthermore, we find through gene set enrichment analysis, that the expression of Myc targets is correlated with the EVE burden for low-TMB patients indicating that Myc may regulate the expression of epigenetically primed EVEs. Finally, we demonstrate in a pan-cancer analysis that the EVE antigen burden does not correlate with TMB and appears to be cancer type specific. As such, EVEs may facilitate and improve the design of personalized immunotherapy especially for low-TMB patients. ### Competing Interest Statement CG, MAP, PG, EJL, SF, DKK, JVK, BR and TT are employed by Evaxion Biotech A/S that holds IP for identifying neoepitopes and personalized immunotherapy. AWP is on the scientific advisory board of Evaxion Biotech A/S. NJB has a patent application (PCT/GB2020/050221) on methods for cancer prognostication and a patent on methods for predicting anti-cancer response (US14/466,208). The remaining authors declare no competing interests.