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

Area of Science:

• Oncology
• Immunotherapy
• Genetics

Background:

• Tumor-intrinsic adaptations and resistant clones impede durable remissions in multiple myeloma following T cell-targeted immunotherapies.
• G-protein-coupled receptor, class C, group 5, member D (GPRC5D) is a target for T cell-engager (TCE) therapy in multiple myeloma.

Purpose of the Study:

• To investigate the mechanisms of tumor escape and resistance following anti-GPRC5D TCE therapy in multiple myeloma.
• To characterize the genomic and epigenomic alterations driving GPRC5D antigen loss or dysfunction.

Main Methods:

• Integrated genomic, transcriptomic, and epigenomic analysis of clonal plasma cells from relapsed multiple myeloma patients.
• Analysis of GPRC5D gene locus alterations, including deletions, single-nucleotide variants, and indels.
• Assessment of epigenetic silencing of GPRC5D promoter/enhancer regions.

Main Results:

• Antigenic drift in GPRC5D was observed in 68.4% of relapsed multiple myeloma cases post-anti-GPRC5D TCE therapy.
• Three primary mechanisms of GPRC5D alteration were identified: biallelic deletion, monoallelic deletion with allelic mutation, and epigenetic silencing.
• Mutations affected GPRC5D epitopes or protein trafficking, leading to ER trapping; multiple subclones with distinct alterations co-emerged.
• Varying anti-GPRC5D TCEs differentially targeted mutant subclones, highlighting their distinct roles in overcoming resistance.

Conclusions:

• Tumor cells evolve distinct genomic and epigenomic mechanisms to evade anti-GPRC5D TCE therapy in multiple myeloma.
• Convergent evolution of GPRC5D alterations leads to therapeutic resistance.
• Understanding these resistance mechanisms is crucial for developing strategies to achieve durable remissions.