Shared PRAME Epitopes are T-Cell Targets in NUT Carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Immunotherapy

Background:

• NUT carcinoma (NC) is a rare, highly lethal solid tumor lacking effective treatments.
• NC is driven by NUTM1 fusion genes, predominantly BRD4::NUTM1, which leads to oncogene overexpression.

Purpose of the Study:

• To identify actionable, cancer-specific antigens in NC for therapeutic development.
• To investigate the potential of T-cell receptor (TCR) therapies targeting these antigens.

Main Methods:

• Integrated genomics, immunopeptidomics, and computational biology.
• Analysis of BRD4::NUTM1 fusion gene activity and antigen presentation.
• Development and testing of a PRAME epitope-specific TCR-based bispecific molecule.

Main Results:

• PRAME was identified as the primary transcribed and HLA Class I-presented cancer/testis antigen in NC.
• BRD4::NUTM1 fusion drives high PRAME expression in NC.
• A PRAME-targeting TCR-based bispecific molecule demonstrated potent T-cell activity against PRAME+ NC.

Conclusions:

• PRAME is a therapeutically actionable target in NUT carcinoma.
• TCR-based therapeutics targeting PRAME offer a promising new strategy for treating NC.
• This approach holds potential for challenging fusion-driven malignancies.