TCR-engineered T-cells directed against Ropporin-1 constitute a safe and effective treatment for triple-negative breast cancer in near-clinical models
Kortleve, D.; Hammerl, D.; van Brakel, M.; Wijers, R.; Roelofs, D.; Kroese, K.; Timmermans, M.; Liao, C.-Y.; Trapman-Jansen, A.; Foekens, R.; Michaux, J.; de Beijer, M.; Buschow, S. I.; Demmers, J. A.; Kok, M.; Danen, E. H. J.; Bassani-Sternberg, M.; Martens, J. W.; Abbott, R. J. M.; Debets, R.
Show abstract
Triple-negative breast cancer (TNBC) shows an urgent need for new therapies. We discovered Ropporin-1 (ROPN1) as a target to treat TNBC with T-cells. ROPN1 showed high and homogenous expression in 90% of primary and metastatic TNBC but not in healthy tissues. HLA-A2-binding peptides were detected via immunopeptidomics and predictions and used to retrieve T-cell receptors (TCRs) from naive repertoires. Following gene introduction into T-cells and stringent selection, we retrieved a highly specific TCR directed against the epitope FLYTYIAKV that did not recognize non-cognate epitopes from alternative source proteins. Notably, this TCR mediated killing of three-dimensional tumoroids in vitro and tumor cells in vivo and outperformed standard-of-care drugs. Finally, the T-cell product expressing this TCR and manufactured using a clinical protocol fulfilled standard safety and efficacy assays. Collectively, we have identified and preclinically validated ROPN1 as a target and anti-ROPN1 TCR T-cells as a treatment for the vast majority of TNBC patients.
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