Multimodal antigenic escape to GPRC5D-targeted T-cell engagers in multiple myeloma [scATAC-seq]
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PROVIDER: PRJNA1284750 | ENA |
REPOSITORIES: ENA
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Project description:Tumor intrinsic adaptations with emerging resistant clones following T cell targeted immunotherapies pose a major barrier to durable remissions in multiple myeloma (MM). 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. These escape events were driven by three distinct mutational mechanisms involving i) focal to large biallelic deletions at the GPRC5D gene locus, ii) monoallelic deletion coupled with GPRC5D single nucleotide variants (SNVs) or insertions/deletions (indels) on the remaining allele, as well as iii) epigenetic GPRC5D promoter/enhancer silencing. Beyond biallelic deletions resulting in complete antigenic loss, we demonstrate that GPRC5D SNVs and indels mutate anti-GPRC5D TCE binding epitopes or more commonly affect G-protein couple receptor family conserved motifs critical for protein membrane trafficking resulting in endoplasmic reticulum (ER) GPRC5D trapping. Multiple subclones bearing distinct genomic alterations at GPRC5D locus co-emerged within individual cases, depicting their convergent evolutionary trajectories. Importantly, anti-GPRC5D TCEs with varying epitope specificity, affinity, and valency differentially targeted mutant subclones, underscoring their non-redundant functional roles in overcoming resistance
2025-07-05 | GSE301287 | GEO
Project description:Tumor intrinsic adaptations with emerging resistant clones following T cell targeted immunotherapies pose a major barrier to durable remissions in multiple myeloma (MM). 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. These escape events were driven by three distinct mutational mechanisms involving i) focal to large biallelic deletions at the GPRC5D gene locus, ii) monoallelic deletion coupled with GPRC5D single nucleotide variants (SNVs) or insertions/deletions (indels) on the remaining allele, as well as iii) epigenetic GPRC5D promoter/enhancer silencing. Beyond biallelic deletions resulting in complete antigenic loss, we demonstrate that GPRC5D SNVs and indels mutate anti-GPRC5D TCE binding epitopes or more commonly affect G-protein couple receptor family conserved motifs critical for protein membrane trafficking resulting in endoplasmic reticulum (ER) GPRC5D trapping. Multiple subclones bearing distinct genomic alterations at GPRC5D locus co-emerged within individual cases, depicting their convergent evolutionary trajectories. Importantly, anti-GPRC5D TCEs with varying epitope specificity, affinity, and valency differentially targeted mutant subclones, underscoring their non-redundant functional roles in overcoming resistance
2025-07-05 | GSE301286 | GEO
Project description:Multimodal antigenic escape to GPRC5D-targeted T-cell engagers in multiple myeloma [scRNA-seq]
| PRJNA1284751 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below. B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G protein coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T. To examine the tumor intrinsic factors that promote MM antigen escape, we performed combined bulk and single cell whole genome sequencing/ copy number variation analysis of 30 patients treated with anti-BCMA and/ or -GPRC5D CAR T/ TCE. In two cases, MM relapse post TCE/ CAR T was driven by BCMA negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected non-truncating missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCEs, despite detectable surface BCMA protein expression. Here, we also report the first four cases of MM relapse with biallelic mutations of GPRC5D following anti-GPRC5D TCE, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA or GPRC5D negative or mutant clones is an important tumor intrinsic driver of relapse post targeted therapies. Mutational events on BCMA confer distinct sensitivities towards different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.
2023-06-29 | GSE226336 | GEO
Project description:Multiple myeloma (MM) immune escape resulting from B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates MM resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging clinical data also suggests that downregulation of G protein coupled receptor family C group 5 member D (GPRC5D), another promising target antigen expressed on MM cells, is observed in patients at relapse post anti-GPRC5D CAR T, but the genomic mechanisms that underlie GPRC5D loss has not been described. In order to examine the tumor intrinsic factors that promote MM antigen escape, we performed combined bulk whole genome sequencing and single cell copy number variation analysis on CD138+ cells from bone marrow aspirates of patients before and after relapse from anti-BCMA or -GPRC5D CAR T/ TCE. We describe five cases with distinct biallelic events on TNFRSF17 at MM relapse after CAR T/ TCE. In addition to focal biallelic deletions at the TNFRSF17 locus acquired at relapse, BCMA negative clones can emerge from the selective expansion of subclones with homozygous TNFRSF17 loss that exist prior to any anti-BCMA therapy exposure. Furthermore, we corroborate with functional data to demonstrate that three different non-truncating mutations in the extracellular domain of BCMA negates the efficacies of BCMA directed TCEs and mediate disease relapse in patients. With respect to GPRC5D, we report four cases of MM relapse with biallelic loss of GPRC5D following anti-GPRC5DxCD3ε. Our data support that immunoselection of BCMA negative or mutant clones post anti-BCMA therapies may be more frequent than currently accepted in the field, and that an all or none screening approach for BCMA expression is inadequate to detect pertinent mutations that affect patient response to targeted therapies. We also highlight the importance of developing immunotherapies targeting novel and non-redundant epitopes or antigens in MM
2023-06-29 | GSE226327 | GEO
Project description:Multiple myeloma (MM) immune escape resulting from B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates MM resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging clinical data also suggests that downregulation of G protein coupled receptor family C group 5 member D (GPRC5D), another promising target antigen expressed on MM cells, is observed in patients at relapse post anti-GPRC5D CAR T, but the genomic mechanisms that underlie GPRC5D loss has not been described. In order to examine the tumor intrinsic factors that promote MM antigen escape, we performed combined bulk whole genome sequencing and single cell copy number variation analysis on CD138+ cells from bone marrow aspirates of patients before and after relapse from anti-BCMA or -GPRC5D CAR T/ TCE. We describe five cases with distinct biallelic events on TNFRSF17 at MM relapse after CAR T/ TCE. In addition to focal biallelic deletions at the TNFRSF17 locus acquired at relapse, BCMA negative clones can emerge from the selective expansion of subclones with homozygous TNFRSF17 loss that exist prior to any anti-BCMA therapy exposure. Furthermore, we corroborate with functional data to demonstrate that three different non-truncating mutations in the extracellular domain of BCMA negates the efficacies of BCMA directed TCEs and mediate disease relapse in patients. With respect to GPRC5D, we report four cases of MM relapse with biallelic loss of GPRC5D following anti-GPRC5DxCD3ε. Our data support that immunoselection of BCMA negative or mutant clones post anti-BCMA therapies may be more frequent than currently accepted in the field, and that an all or none screening approach for BCMA expression is inadequate to detect pertinent mutations that affect patient response to targeted therapies. We also highlight the importance of developing immunotherapies targeting novel and non-redundant epitopes or antigens in MM
2023-06-29 | GSE226335 | GEO
Project description:T cell engagers (TCEs) are transformational oncology therapies but limited in use due to the induction of cytokine release syndrome (CRS). In comparison to T cells, natural killer (NK) cells produce less cytokines upon activation, leading to the exploration of NK cell engagers (NKCEs). However, why NK cells secrete less cytokines such as tumor necrosis factor (TNF) and how NKCEs perform directly against TCEs remain unclear. Here we report that relative to T cells, NK cells have reduced trafficking and processing of TNF. Systematic development and benchmarking studies show that NKCEs can be optimized to engage multiple activating receptors and incorporate the interleukin (IL)-2, thereby increasing their potency and durability. Furthermore, comparative studies of NKCE, IL-2, and TCE therapy in animal tumor models reveal both common and different therapeutic benefits. Our results provide a blueprint for development of multifunctional NKCEs that may serve as an alternative to current TCE therapies.
2025-03-16 | GSE264122 | GEO
Project description:antigenic KPC model_bulk pancreas RNASeq
| PRJNA544120 | ENA
Project description:e dissolved eight antigenic nanoparticles to release their loaded components and assayed the protein species in them
2024-05-25 | PXD052576 |
Project description:B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G-protein-coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T therapy. To examine the tumor-intrinsic factors that promote MM antigen escape, we performed combined bulk and single-cell whole-genome sequencing and copy number variation analysis of 30 patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapy. In two cases, MM relapse post-TCE/CAR T therapy was driven by BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected, nontruncating, missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCE therapies, despite detectable surface BCMA protein expression. In the present study, we also report four cases of MM relapse with biallelic mutations of GPRC5D after anti-GPRC5D TCE therapy, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA- or GPRC5D-negative or mutant clones is an important tumor-intrinsic driver of relapse post-targeted therapies. Mutational events on BCMA confer distinct sensitivities toward different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.
| S-EPMC10504087 | biostudies-literature