Tumor Intrinsic Mechanisms of Antigen Escape to Anti-BCMA and Anti-GPRC5D Targeted Immunotherapies in Multiple Myeloma
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PROVIDER: PRJNA939715 | ENA |
REPOSITORIES: ENA
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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:scCNVseq Datasets Supporting Tumor Intrinsic Mechanisms of Antigen Escape to Anti-BCMA and Anti-GPRC5D Targeted Immunotherapies in Multiple Myeloma
| PRJNA939710 | ENA
Project description:scRNAseq Datasets Supporting Tumor Intrinsic Mechanisms of Antigen Escape to Anti-BCMA and Anti-GPRC5D Targeted Immunotherapies in Multiple Myeloma
| PRJNA939723 | ENA
Project description:Chimeric antigen receptor T-cells (CAR-T) targeting B-cell-maturating-antigen (TNRFSF17, BCMA) show unprecedented overall response rates of up to 100% in heavily pretreated relapsed-refractory Multiple Myeloma (RRMM). However, the efficiency of the treatment is hindered by the rapid emergence of tumor-intrinsic mechanisms of resistance. We herein describe a patient with RRMM and extramedullary disease (EMD) who underwent Idecabtagene vicleucel BCMA CAR-T therapy. The patient rapidly achieved very good partial response including full resolution of EMD, but aggressively relapsed 5 months after CAR T cell infusion. Single cell RNA sequencing and immunohistochemistry on the re-emerging tumor cells demonstrated loss of target expression on mRNA and protein levels, and whole genome sequencing revealed the homozygous deletion of Chr 16p1313, including the BCMA locus. Clonal heterogeneity of BCMA could be observed in 32 RRMM patients from our institution. In three of them heterozygous deletion of BCMA could be confirmed, with none of them having underwent prior anti-BCMA therapy. Thus, our report not only provides first evidence of BCMA loss as the underlying mechanism of disease relapse following BCMA targeted immunotherapy in MM. It furthermore identifies a subset of patients at risk to develop biallelic BCMA inactivation thus linking genomic instability in MM to relapse from targeted immunotherapies.
2020-12-30 | GSE143317 | GEO
Project description:RNASeq: lenalidomide-treated anti-BCMA CAR T cells
| PRJNA450645 | ENA
Project description:T cell immunotherapies trigger neutrophil activation to eliminate tumor antigen escape variants
| PRJNA933612 | ENA
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
Project description:Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with Multiple Myeloma
| PRJNA600009 | ENA