TCR-engineered T-cells directed against Ropporin-1 constitute a safe and effective treatment for triple-negative breast cancer in near-clinical models

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.

Competing Interest Statement

This research was conducted according to the requirements of objectivity and integrity standards. DH is listed as inventor for European patent application no. P128827EP00. MK has received research support from BMS, Roche, AstraZeneca, personal fees from AstraZeneca, Daiichi Sankyo, Domain Therapeutics, Alderaan, BMS, MSD, Gilead, Roche outside the submitted work (all paid to the NKI/AVL). RD has received research support from MSD and Bayer, personal fees from Bluebird Bio, Genticel, other support from Pan Cancer T B.V. outside the submitted work (all paid to the Erasmus MC Cancer Institute) and is listed as inventor for European patent applications P130556EP00 and P128827EP00. All other authors (DK, MvB, RW, DR, KK, MT, CYL, ATJ, RF, JM, MdB, SIB, JAD, MK, EHJD, MBS, JWM, RJMA) declare no competing interests.