Human endogenous retrovirus E antigen (HERV-E)

The Human endogenous retrovirus E (HERV-E) antigen is a tumor-specific target derived from ancient retroviral sequences integrated into the human germline millions of years ago [1, 7]. While typically silenced in healthy adult tissues through epigenetic mechanisms like DNA methylation, HERV-E is selectively reactivated in approximately 80% of clear cell renal cell carcinomas (ccRCC) [1, 2, 6]. This reactivation is primarily driven by the hypomethylation of its 5'-long terminal repeat (LTR) promoter and the aberrant activity of the transcription factor HIF-2α in cancer cells [1, 3]. The resulting transcription leads to the presentation of immunogenic peptides, such as CT-RCC-1, on the surface of tumor cells via HLA-A*11 molecules [2, 3]. HERV-E is currently being investigated as a primary target for adoptive cell therapies, specifically T cells engineered with a TCR designed to recognize these retroviral-derived antigens [2, 5]. Early-phase clinical trials have demonstrated that HERV-E TCR-transduced T cells can induce tumor regression in patients with metastatic ccRCC without evidence of significant off-target toxicities, highlighting the antigen's high tumor specificity [1, 5]. Because it is essentially absent in normal tissues, HERV-E represents a unique class of tumor-associated antigens that may circumvent the common challenge of on-target, off-tumor toxicity in immunotherapy [6, 11].

Other names

CT-RCC antigenCT-RCC-1Human endogenous retrovirus E envelope proteinERVE-1HERV-E env

Adoptive T-cell therapy utilizing T cells engineered with a T-cell receptor (TCR) specific to the HERV-E-derived peptide CT-RCC-1, which is presented on HLA-A*11 molecules to induce tumor-specific cytotoxicity [2, 3, 5].