Gene expression profile at single cell level of bone marrow cells in 5TGM1 multiple myeloma mouse model treated with CD24 CAR-T cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE226956 | GEO | 2023/03/13
REPOSITORIES: GEO
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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:Despite the acknowledged effectiveness of BCMA chimeric antigen receptor T (CAR-T) cells in killing multiple myeloma (MM) cells, predicting treatment responsivity to BCMA CAR-T therapy remains a challenge. In this study, we demonstrated that the best overall responses (BORs) of patients over the 15-month follow-up are positively correlated with the abundance and targeted cytotoxic activity of CD8+ effector CAR-T cells on day 28 after CAR-T cell infusion. Additionally, favorable responses are associated with attenuated immunosuppression mediated by regulatory T cells (Tregs), enhanced CD8+ effector T cell cytotoxic activity, and elevated type 1 conventional dendritic cell (cDC1) antigen presentation ability. Our study sheds light on MM microenvironment dynamics after BCMA CAR-T therapy, offering clues for predicting treatment responsivity.
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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
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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:B-cell maturation antigen (BCMA) is a prominent tumor-associated target for chimeric antigen receptor (CAR)-T cell therapy in multiple myeloma (MM). We describe the case of a MM patient, enrolled in the CARTITUDE-1 trial (NCT03548207), who developed a progressive movement disorder with features of parkinsonism approximately three months after BCMA-targeted ciltacabtagene autoleucel CAR-T cell infusion, associated with CAR-T cell persistence in the blood and cerebrospinal fluid, and basal ganglia lymphocytic infiltration. We demonstrate BCMA expression on neurons and astrocytes in the basal ganglia of the patient. Public transcriptomic datasets further confirm BCMA RNA expression in the caudate of normal human brains, suggesting this may be an on-target effect of anti-BCMA therapy. Given reports of three patients with grade ≥3 parkinsonism on the phase 2 cilta-cel trial and of grade 3 parkinsonism in the idecabtagene vicleucel (ide-cel) package insert, our findings support close neurological monitoring of patients on BCMA-targeted T cell therapies.
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Project description:Multiple myeloma is characterized by frequent clinical relapses following conventional therapy. Recently, chimeric antigen receptor T (CAR-T) cells targeting B-cell maturation antigen (BCMA) has been established as a treatment for patients with relapsed or refractory disease. However, while >70% of patients initially respond to this treatment, clinical relapse and disease progression occurs in most cases. Recent studies showed persistent expression of BCMA at the time of relapse, indicating that immune intrinsic mechanisms may contribute to this resistance. While there were no pre-existing T cell features associated with clinical outcomes, we found that patients with a durable response to CAR-T cell treatment had greater persistence of their CAR-T cells compared to patients with transient clinical responses. They also possessed a significantly higher proportion of CD8+ T effector memory cells. In contrast, patients with short-lived responses to treatment have increased frequencies of cytotoxic CD4+ CAR-T cells. These cells expand in vivo early after infusion but express exhaustion markers (HAVCR2 and TIGIT) and remain polyclonal. Finally, we demonstrate that non-classical monocytes are enriched in the myeloma niche and may induce CAR-T cell dysfunction through mechanisms that include TGFβ. These findings shed new light on the role of cytotoxic CD4+ T cells in disease progression after CAR-T cell therapy.
2024-07-29 | GSE246342 | GEO
Project description:Multiple myeloma is characterized by frequent clinical relapses following conventional therapy. Recently, chimeric antigen receptor T (CAR-T) cells targeting B-cell maturation antigen (BCMA) has been established as a treatment for patients with relapsed or refractory disease. However, while >70% of patients initially respond to this treatment, clinical relapse and disease progression occurs in most cases. Recent studies showed persistent expression of BCMA at the time of relapse, indicating that immune intrinsic mechanisms may contribute to this resistance. While there were no pre-existing T cell features associated with clinical outcomes, we found that patients with a durable response to CAR-T cell treatment had greater persistence of their CAR-T cells compared to patients with transient clinical responses. They also possessed a significantly higher proportion of CD8+ T effector memory cells. In contrast, patients with short-lived responses to treatment have increased frequencies of cytotoxic CD4+ CAR-T cells. These cells expand in vivo early after infusion but express exhaustion markers (HAVCR2 and TIGIT) and remain polyclonal. Finally, we demonstrate that non-classical monocytes are enriched in the myeloma niche and may induce CAR-T cell dysfunction through mechanisms that include TGFβ. These findings shed new light on the role of cytotoxic CD4+ T cells in disease progression after CAR-T cell therapy.
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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.
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2021-01-11 | GSE164551 | GEO
Project description:Multiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T-cells in leukemia and lymphoma, CAR T-cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to low expression of BCMA on myeloma cells, suggesting that novel approaches to better address antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the pro-inflammatory cytokine interleukin-18 (IL-18) and multi-antigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T-cells targeting the myeloma-associated antigens BCMA and B-cell activating factor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed. In contrast, IL-18-secreting CAR T-cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T-cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type I and II interferon signaling, and utilized macrophages to mediate anti-myeloma activity. Simultaneous targeting of weakly expressed BCMA and BAFF-R with dual-CAR T-cells enhanced T-cell:target cell avidity, increased overall CAR signal strength, and stimulated anti-myeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multi-antigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.
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