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<p>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 (<i>n</i> = 21). These escape events were driven by three distinct mutational mechanisms involving (1) focal to large biallelic deletions at the <i>GPRC5D</i> gene locus; (2) monoallelic deletion coupled with <i>GPRC5D</i> single-nucleotide variants or insertions/deletions (indels) on the remaining allele; as well as (3) epigenetic <i>GPRC5D</i> promoter/enhancer silencing. Beyond biallelic deletions resulting in complete antigenic loss, we demonstrate that <i>GPRC5D</i> 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 <i>GPRC5D</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月15日

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

摘要

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.