TCR-Engineered T Cells Directed against Ropporin-1 Constitute a Safe and Effective Treatment for Triple-Negative...

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• Triple-negative breast cancer (TNBC) presents a significant unmet need for novel therapeutic strategies.
• Ropporin-1 (ROPN1) is identified as a highly expressed and specific target in TNBC, absent in healthy tissues.

Purpose of the Study:

• To discover and validate Ropporin-1 (ROPN1) as a therapeutic target for triple-negative breast cancer (TNBC).
• To develop and preclinically assess T-cell receptor (TCR) engineered T cells targeting ROPN1 for TNBC treatment.

Main Methods:

• Immunopeptidomics and computational predictions identified human leukocyte antigen-A2-binding peptides.
• T-cell receptors (TCRs) were selected from naïve repertoires and engineered into T cells.
• In vitro tumoroid and in vivo tumor models were used to evaluate TCR-mediated cytotoxicity and efficacy.

Main Results:

• A highly specific TCR targeting the ROPN1 epitope FLYTYIAKV was identified, demonstrating no cross-reactivity.
• Engineered T cells effectively killed TNBC tumoroids and tumor cells in vivo, outperforming standard treatments.
• The TCR-T cell product met safety and efficacy standards in preclinical assays.

Conclusions:

• Ropporin-1 (ROPN1) is a validated therapeutic target for the majority of triple-negative breast cancer (TNBC) patients.
• Anti-ROPN1 TCR T cells represent a promising and specific immunotherapy for TNBC with favorable safety and potency.