Multimodal antigenic escape to GPRC5D-targeted T cell engagers in multiple myeloma

Tumor-intrinsic adaptations with emerging resistant clones following T cell-targeted immunotherapies pose a major barrier to durable remissions in multiple myeloma. Through integrated genomic, transcriptomic and epigenomic interrogation of clonal plasma cells, we observed antigenic drift in 68.4% of relapsed cases following anti-GPRC5D T cell-engager (TCE) therapy (n = 21). These escape events were driven by three distinct mutational mechanisms involving (1) focal to large biallelic deletions at the GPRC5D gene locus; (2) monoallelic deletion coupled with GPRC5D single-nucleotide variants or insertions/deletions (indels) on the remaining allele; as well as (3) epigenetic GPRC5D promoter/enhancer silencing. Beyond biallelic deletions resulting in complete antigenic loss, we demonstrate that GPRC5D single-nucleotide variants and indels mutate anti-GPRC5D TCE-binding epitopes or more commonly affect G-protein-coupled receptor family conserved motifs critical for protein membrane trafficking resulting in endoplasmic reticulum GPRC5D trapping. Multiple subclones bearing distinct genomic alterations at GPRC5D locus co-emerged within individual cases, depicting their convergent evolutionary trajectories. Of note, anti-GPRC5D TCEs with varying epitope specificity, affinity and valency differentially targeted mutant subclones, underscoring their nonredundant functional roles in overcoming resistance.

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Publication Details

Journal
Nature Medicine
Published
2026-01-15
DOI
https://doi.org/10.1038/s41591-025-04175-8
Primary Topic
Multiple Myeloma Research and Treatments
Type
article
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article

Multimodal antigenic escape to GPRC5D-targeted T cell engagers in multiple myeloma

Sheri Skerget, David Jung, Gerone A. Gonzales, Jan Eckmann et al.
Nature Medicine
Multiple Myeloma Research and Treatments
article

Multimodal antigenic escape to GPRC5D-targeted T cell engagers in multiple myeloma

Sheri Skerget, David Jung, Gerone A. Gonzales, Jan Eckmann, Pina Colarusso, Marietta Truger, Lawrence Boise, Sacha Benaoudia, Mansour Poorebrahim, Elie Barakat, Jan Hendrik Frenking, Dylan Greening, Christine Riedhammer, M. S. Raab, Hervé Avet‐Loiseau, Nizar Jacques Bahlis, Yunje Cho, Jitka Somandin, Corre Jill, Francesco Maura, Leo Rasche, Paola Neri, Konstantina Taouxi, Deeksha Vishwamitra, Noemie Leblay, Niels Weinhold, Hermann Einsele, Jihong Jeong, Efstathios Kastritis, Holly Lee, Sara-Sheena Engel, Johnathan Canton, Sungwoo Ahn, Elham Hasheminasabgorji, K. Martin Kortüm
article en

Abstract

Tumor-intrinsic adaptations with emerging resistant clones following T cell-targeted immunotherapies pose a major barrier to durable remissions in multiple myeloma. Through integrated genomic, transcriptomic and epigenomic interrogation of clonal plasma cells, we observed antigenic drift in 68.4% of relapsed cases following anti-GPRC5D T cell-engager (TCE) therapy (n = 21). These escape events were driven by three distinct mutational mechanisms involving (1) focal to large biallelic deletions at the GPRC5D gene locus; (2) monoallelic deletion coupled with GPRC5D single-nucleotide variants or insertions/deletions (indels) on the remaining allele; as well as (3) epigenetic GPRC5D promoter/enhancer silencing. Beyond biallelic deletions resulting in complete antigenic loss, we demonstrate that GPRC5D single-nucleotide variants and indels mutate anti-GPRC5D TCE-binding epitopes or more commonly affect G-protein-coupled receptor family conserved motifs critical for protein membrane trafficking resulting in endoplasmic reticulum GPRC5D trapping. Multiple subclones bearing distinct genomic alterations at GPRC5D locus co-emerged within individual cases, depicting their convergent evolutionary trajectories. Of note, anti-GPRC5D TCEs with varying epitope specificity, affinity and valency differentially targeted mutant subclones, underscoring their nonredundant functional roles in overcoming resistance.

Nature MedicineVol. 32(3)
Roche (Switzerland) (CH), Pohang University of Science and Technology (KR), Johnson & Johnson (United States) (US), Memorial Sloan Kettering Cancer Center (US), Emory University (US), University of Calgary (CA), German Cancer Research Center (DE), National and Kapodistrian University of Athens (GR), Heidelberg University (DE), University Hospital Heidelberg (DE), Institute of Cancer Research (CA), Munich Leukemia Laboratory (Germany) (DE), Institut universitaire du cancer de Toulouse Oncopole (FR), Universitätsklinikum Würzburg (DE), CS Diagnostics (DE)
Openalex Percentile: Top 88%
Multiple Myeloma Research and Treatments
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