Changes in bone marrow tumor and immune cells correlate with durability of remissions following BCMA CAR T therapy in myeloma
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PROVIDER: PRJNA863621 | ENA |
REPOSITORIES: ENA
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Project description:Chimeric antigen-receptor (CAR) T cells targeting B-cell maturation antigen (BCMA) lead to high response rates in myeloma, but most patients experience recurrent disease. We combined several high-dimensional approaches to study tumor/immune cells in the tumor microenvironment of myeloma patients pre- and post-BCMA-specific CAR T therapy. A lower diversity of pre-therapy T-cell-receptor (TCR) repertoire, presence of hyperexpanded clones with an exhaustion phenotype, and BAFF+PD-L1+ myeloid cells in the marrow correlated with shorter progression-free survival (PFS) following CAR T therapy. In contrast, longer PFS was associated with increased proportion of CLEC9A+ dendritic cells (DCs), and CD27+TCF1+ T cells with diverse T-cell receptors, followed by emergence of T cells expressing marrow-residence genes. Residual tumor cells at initial response express stem-like genes and tumor recurrence in patients with long PFS was associated with emergence of new dominant clones. These data illustrate dynamic interplay between endogenous T, infused CAR T, myeloid/DC and tumor compartments that impacts durability of response following CAR T therapy in myeloma.
2022-08-11 | GSE210079 | GEO
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:Chimeric antigen-receptor (CAR) T cells lead to high response rates in myeloma, but most patients experience recurrent disease. We combined several high-dimensional approaches to study tumor/immune cells in the tumor microenvironment (TME) of myeloma patients pre- and post-B-cell maturation antigen (BCMA)-specific CAR T therapy. Lower diversity of pretherapy T-cell receptor (TCR) repertoire, presence of hyperexpanded clones with exhaustion phenotype, and BAFF+PD-L1+ myeloid cells in the marrow correlated with shorter progression-free survival (PFS) following CAR T therapy. In contrast, longer PFS was associated with an increased proportion of CLEC9A+ dendritic cells (DC), CD27+TCF1+ T cells with diverse T-cell receptors, and emergence of T cells expressing marrow-residence genes. Residual tumor cells at initial response express stemlike genes, and tumor recurrence was associated with the emergence of new dominant clones. These data illustrate a dynamic interplay between endogenous T, CAR T, myeloid/DC, and tumor compartments that affects the durability of response following CAR T therapy in myeloma.SignificanceThere is an unmet need to identify determinants of durable responses following BCMA CAR T therapy of myeloma. High-dimensional analysis of the TME was performed to identify features of immune and tumor cells that correlate with survival and suggest several strategies to improve outcomes following CAR T therapy. See related commentary by Graham and Maus, p. 478. This article is highlighted in the In This Issue feature, p. 476.
| S-EPMC9627239 | biostudies-literature
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.
2024-07-10 | GSE271915 | GEO
Project description:Chimeric antigen receptor-T (CAR-T) cells directed against B-cell maturation antigen (BCMA) are an effective treatment for multiple myeloma, but short persistence and frequent relapses are challenges for this immunotherapy. This lack of durability has been attributed to the premature terminal differentiation of CAR-T cells which prevents the formation of long-lived memory cells that maintain anti-tumour responses. To improve long-term efficacy, we used CRISPR/Cas9-mediated gene editing to ablate the expression of the transcription factor Blimp-1 (Prdm1). In a murine model of advanced myeloma, Blimp-1 knockout (KO) CAR-T cells effectively slowed or even prevented disease progression, significantly outperforming control (Mock) CAR-T cells in improving survival. To understand this enhanced in vivo effectiveness, Blimp-1 KO CAR-T cells were characterised after being repeatedly challenged with tumour cells in vitro and subject to gene expression analysis.
2024-11-20 | GSE255977 | 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.
2021-08-27 | GSE182527 | GEO
Project description:In this work, we address the impact of CAR density on the in vitro and in vivo functionality of BCMA-CAR T cells. Phenotypic, functional, transcriptomic and epigenomic studies at bulk and single cell level revealed different profiles between CAR T cells with high and low expression of the CAR molecule (CARHigh and CARLow T cells). We analyzed the phenotype of CARHigh and CARLow T cell populations before and after stimulation with tumor cells. Sorted CD4+ and CD8+ CARHigh and CARLow T cell populations from six different CAR T cell productions were profiled using high-throughput RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin (ATAC-seq). To better understand the heterogeneity of CAR T cells and the influence of CAR level on their transcriptomic profile, we performed single cell transcriptomic analysis on 43,981 CAR T cells from three independent productions.
2022-10-05 | GSE197848 | GEO
Project description:In this work, we address the impact of CAR density on the in vitro and in vivo functionality of BCMA-CAR T cells. Phenotypic, functional, transcriptomic and epigenomic studies at bulk and single cell level revealed different profiles between CAR T cells with high and low expression of the CAR molecule (CARHigh and CARLow T cells). We analyzed the phenotype of CARHigh and CARLow T cell populations before and after stimulation with tumor cells. Sorted CD4+ and CD8+ CARHigh and CARLow T cell populations from six different CAR T cell productions were profiled using high-throughput RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin (ATAC-seq). To better understand the heterogeneity of CAR T cells and the influence of CAR level on their transcriptomic profile, we performed single cell transcriptomic analysis on 43,981 CAR T cells from three independent productions.
2022-10-05 | GSE197843 | GEO
Project description:In this work, we address the impact of CAR density on the in vitro and in vivo functionality of BCMA-CAR T cells. Phenotypic, functional, transcriptomic and epigenomic studies at bulk and single cell level revealed different profiles between CAR T cells with high and low expression of the CAR molecule (CARHigh and CARLow T cells). We analyzed the phenotype of CARHigh and CARLow T cell populations before and after stimulation with tumor cells. Sorted CD4+ and CD8+ CARHigh and CARLow T cell populations from six different CAR T cell productions were profiled using high-throughput RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin (ATAC-seq). To better understand the heterogeneity of CAR T cells and the influence of CAR level on their transcriptomic profile, we performed single cell transcriptomic analysis on 43,981 CAR T cells from three independent productions.
2022-10-05 | GSE197849 | 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.
2024-08-07 | GSE274185 | GEO