Preclinical development of TCR Engineered T cells Targeting Endogenous RetroVirus Antigens in triple negative breast cancer – TEC-Breast

Human Endogenous Retroviruses (HERVs) represent 8% of our genome and result from ancient infections by retroviruses. Since HERVs are silenced in normal cells while aberrantly expressed in some tumors, they may represent a source of tumor antigens able to induce strong immune responses. However, exploiting HERVs to provide new immunotherapies against cancer has not been achieved so far.
After developing a new bioinformatics method to analyze HERV expression in tumors vs normal tissues, we identified HERV-derived epitopes shared between patients in Triple Negative Breast Cancer (TNBC). We selected the most shared epitope candidates with evidence of translation. These HERV epitopes induce high-avidity CD8+ T cells ex vivo capable of killing TNBC cells (natural presentation of the peptide on HLA molecules) and patient-derived organoids but not normal breast epithelial cells. Moreover we identified HERV-specific tumor infiltrating lymphocytes in TNBC patient samples. Therefore, we identified HERV-derived epitopes of major interest for the development T cell-based immune therapies in TNBC.
The T Cell Receptor (TCR) sequences of high-avidity T cells targeting four different validated HERV epitopes (P1, P2, P4, and P6 respectively) were identified and engineered to be transduced into human T cells. Using an optimized lentiviral system, we successfully generated HERV-specific engineered TCR-T cells that secrete effector cytokines in response to antigenic stimulation and that specifically recognize and eliminate TNBC tumor cells in vitro.
Based on these promising results, our objective is to provide the proof-of-concept that the use of HERV-specific TCR-T cells is a valid therapeutic strategy for the treatment of TNBC by: (i) generating a set of high avidity HERV-specific TCR-T cells, (ii) demonstrating their functionality/specificity both in vitro and in in vivo mouse models, and (iii) exploring the therapeutic benefit of the combination with immune checkpoint inhibitors.