Discriminating Th17.1 cell driven sarcoidosis-like inflammation from relapse after anti-BCMA CAR T cells in multiple myeloma
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001006133 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Background: Autologous CD19 CAR T cell therapy leads to durable responses and improved survival in patients with relapsed or refractory large B cell lymphoma (R/R LBCL). Among approved CAR T cell products, axicabtagene ciloleucel (axi-cel; CD19/CD28) has greater real-world efficacy and cytokine-associated toxicity than tisagenlecleucel (tisa-cel; CD19/4-1BB), for reasons that are poorly understood. Methods: Here we report single cell RNA sequencing (scRNA-seq) of 57 pre-infusion CAR T cell products from axi-cel (n=39) and tisa-cel (n=18) patients treated as standard-of-care for R/R LBCL, and their biological associations with clinical outcomes. In vitro CAR manufacturing conditions mimicking those known for axi-cel and tisa-cel were performed using CD19/CD28z or CD19/4-1BBz constructs. Results: ScRNA-seq revealed that axi-cel and tisa-cel are markedly different products. Axi-cel is comprised of more CD4 central memory, CD8 central memory, and CD8 effectors, whereas tisa-cel is comprised of more proliferative CD4 and CD8 cells. Across multiple T cell subsets, axi-cel had greater expression of immune response pathways and protein synthesis and trafficking pathways vs. tisa-cel. On comparison of infusion product CAR transgene-positive (CAR+) cells to CAR transgene-negative (CAR-) T cells, axi-cel CAR+ cells had vastly different gene expression than axi-cel CAR- cells. Unexpectedly, tisa-cel CAR+ cells were highly similar to tisa-cel CAR- cells. Under recapitulated CAR-T manufacturing conditions known to be utilized for axi-cel and tisa-cel, we found that CAR+ cells differed from CAR- cells early after manufacturing yet became more similar to CAR- cells after prolonged expansion. Prolonged time in expansion culture, as utilized during tisa-cel manufacturing, greatly decreased naïve and central memory T cell subsets. Conclusions: Following manufacture, axi-cel is less differentiated and has greater immune activation compared to tisa-cel, potentially accounting for its greater efficacy and toxicity in patients. Our data support the conclusion that tisa-cel is adversely affected by its manufacturing rather than by the CAR construct.
2025-07-30 | GSE297676 | GEO
Project description:We performed the first in-depth, comparative and prospective biomonitoring of Multiple Myeloma (MM) patients (N=39) receiving ciltacabtagene autoleucel (cilta-cel) or idecabtagene vicleucel (ide-cel) chimeric antigen receptor T cells (CAR T) in the real-world setting. In cilta-cel patients response rates were higher and atypical neurotoxicities/infections more frequent. Peak CAR T counts were significantly higher in cilta-cel patients, driven by CD4+ CAR expansion, correlating with clinical responses. Expansion of cilta-cel cells was associated with higher CAR and CD27 expression while, in contrast to ide-cel, there was no correlation between TIM3 expression and CAR T proliferation. Cilta-cel CAR T expansion was followed by a CAR-specific switch from proliferation-associated genes to genes/surface markers indicating effector/memory function. The longer persistence of cilta-cel CAR T was associated with increased IL-7R expression; in vitro data showed persistent antigen-independent activation and higher metabolic activity of cilta-cel vs. ide-cel CAR T. Among cilta-cel-treated patients experiencing atypical neurotoxicities, central nervous system (CNS)-infiltrating, effector-type CAR T presented a distinct inflammatory phenotypic/cytokine-expression profile. This in-depth biomonitoring report following real-world cilta-cel or ide-cel highlights intrinsic biological differences between BCMA-targeting CAR T products, potentially explaining differences in clinical activity and toxicity. Our findings may guide optimization of cellular immunotherapy strategies in MM.
2025-05-28 | GSE298012 | GEO
Project description:We performed the first in-depth, comparative and prospective biomonitoring of Multiple Myeloma (MM) patients (N=39) receiving ciltacabtagene autoleucel (cilta-cel) or idecabtagene vicleucel (ide-cel) chimeric antigen receptor T cells (CAR T) in the real-world setting. In cilta-cel patients response rates were higher and atypical neurotoxicities/infections more frequent. Peak CAR T counts were significantly higher in cilta-cel patients, driven by CD4+ CAR expansion, correlating with clinical responses. Expansion of cilta-cel cells was associated with higher CAR and CD27 expression while, in contrast to ide-cel, there was no correlation between TIM3 expression and CAR T proliferation. Cilta-cel CAR T expansion was followed by a CAR-specific switch from proliferation-associated genes to genes/surface markers indicating effector/memory function. The longer persistence of cilta-cel CAR T was associated with increased IL-7R expression; in vitro data showed persistent antigen-independent activation and higher metabolic activity of cilta-cel vs. ide-cel CAR T. Among cilta-cel-treated patients experiencing atypical neurotoxicities, central nervous system (CNS)-infiltrating, effector-type CAR T presented a distinct inflammatory phenotypic/cytokine-expression profile. This in-depth biomonitoring report following real-world cilta-cel or ide-cel highlights intrinsic biological differences between BCMA-targeting CAR T products, potentially explaining differences in clinical activity and toxicity. Our findings may guide optimization of cellular immunotherapy strategies in MM.
2025-05-28 | GSE298011 | GEO
Project description:Purpose: To compare cell states amoung three populations of interest among circulating CAR T cells in patients with lymphoma. Methods: Nine patients with large B-cell lymphoma (LBCL) were treated with axicabtagene ciloleucel (axi-cel), a commercial CD19-targeted CAR T-cell therapy. On day 7, fresh peripheral blood mononuclear cells were stained with an antibody panel for fluorescence-activated cell sorting (FACS), a panel for cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), and a viability dye. Single live CAR+ T cells were sorted from each patient, counted, processed for 5' single-cell RNA-sequencing with feature barcoding and TCR clonotype analysis on the 10X Genomics platform, and sequenced by the Stanford Genomics Facility (HighSeq 4000) or Novogene (NovaSeq 6000). Results: We found that circulating CD4+ and CD8+ CAR T cells that express CD57 and T-bet are clonally expanded and display features of effector T cells. In contrast, CD4+ CD57- CAR T cells that express Helios expand polyclonally and display features of T regulatory cells. Conclusions: This study provides insights into cell states of circulating CAR T cells on day 7 that associate with clinical response or toxicity in LBCL patients treated with axi-cel.
2022-07-28 | GSE168940 | GEO
Project description:Axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of relapsed/refractory large B-cell lymphoma (LBCL), has comparable efficacy across conventional LBCL markers. We analysed whether pre- and posttreatment tumour immune contexture determines clinical outcomes for axi cel–treated patients in the ZUMA-1 pivotal study. Longitudinal evaluation of the tumour microenvironment (TME) uncovered dynamic patterns that occurred rapidly after axi-cel (within 2 weeks) in responders—pronounced enhancement of T- and myeloid cell signatures and diminution of B cell signature. Clinical response and overall survival associated with high CD8+ T-cell density (Immunoscore) and immune gene expression (Immunosign21) in TME pretreatment, which was paralleled by blood CAR T-cell levels posttreatment. High density of regulatory T cells in TME pretreatment associated with reduced axi-cel–related neurologic toxicity. At relapse, the TME evolved toward an immune-detrimental contexture with decreased T-cell–related and increased counterregulatory immune signatures and B cell lineage antigens. A TME rich in T-cell attractive chemokines (CCL5, CCL22), gamma-chain receptor cytokines (IL-15, IL-7, IL-21), and interferon regulated molecules associated with T-cell infiltration and markers of activity, a result validated in 2 independent datasets totalling ≈300 LBCL samples. These findings advance mechanistic understanding of CAR T-cell therapy and foster biomarker development and treatment optimizations.
2022-09-23 | GSE197977 | 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: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
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:The phase 3 ZUMA-7 trial in second-line large B-cell lymphoma demonstrated superiority of anti-CD19 CAR T-cell therapy (axicabtagene ciloleucel; axi-cel) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B-cell gene expression signature (GES) and CD19 expression significantly associated with improved event-free survival (EFS) for axi-cel (P=.0002 for B-cell GES; P=.0165 for CD19 expression) but not SOC (P=.9374 for B-cell GES; P=.5526 for CD19 expression). Axi-cel showed superior EFS over SOC irrespective of B-cell GES and CD19 expression (P=8.56e–9 for B-cell GES high; P=.0019 for B-cell GES low; P=3.85e–9 for CD19 gene high; P=.0017 for CD19 gene low). Low CD19 expression in malignant cells correlated with a tumor GES consisting of immune suppressive stromal and myeloid genes, highlighting the inter-relation between malignant cell features and immune contexture substantially impacting axi-cel outcomes. Tumor burden, lactate dehydrogenase, and cell-of-origin impacted SOC more than axi-cel outcomes. T-cell activation and B-cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.
2024-02-26 | GSE248835 | GEO
Project description:To evaluate whether the findings of our pre-clinical study hold true in patients treated with CAR19/IL-15 NK cells, we isolated and profiled CAR-NK cells and B cells from peripheral blood collected at multiple timepoints from two patients diagnosed with CD19+ relapse/refractory hematological malignancies and treated with CAR19/IL-15 NK cells (11). Each patient received one infusion of CAR-NK cells
2025-09-09 | GSE224915 | GEO