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Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies I

ABSTRACT: Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies I

PROVIDER: PRJNA952195 | ENA |

REPOSITORIES: ENA

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Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies

Project description:Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies

| PRJNA952188 | ENA

Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies II

Project description:Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies II

| PRJNA952196 | ENA

Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies II

Project description:IFNγ neutralization by the clinically approved monoclonal antibody emapalumab mitigates severe toxicity related to CAR-T therapy Emapalumab does not impair CAR.CD19 T-cell activation signaling

2023-05-04 | GSE228922 | GEO

Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies I

2023-05-04 | GSE228921 | GEO

Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-05-04 | GSE228924 | GEO

Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies.

Project description:Chimeric antigen receptor T (CAR-T) cell therapy may achieve long-lasting remission in patients with B-cell malignancies not responding to conventional therapies. However, potentially severe and hard-to-manage side effects, including cytokine release syndrome (CRS), neurotoxicity and macrophage activation syndrome, and the lack of pathophysiological experimental models limit the applicability and development of this form of therapy. Here we present a comprehensive humanized mouse model, by which we show that IFNγ neutralization by the clinically approved monoclonal antibody, emapalumab, mitigates severe toxicity related to CAR-T cell therapy. We demonstrate that emapalumab reduces the pro-inflammatory environment in the model, thus allowing control of severe CRS and preventing brain damage, characterized by multifocal hemorrhages. Importantly, our in vitro and in vivo experiments show that IFNγ inhibition does not affect the ability of CD19-targeting CAR-T (CAR.CD19-T) cells to eradicate CD19+ lymphoma cells. Thus, our study provides evidence that anti-IFNγ treatment might reduce immune related adverse effect without compromising therapeutic success and provides rationale for an emapalumab-CAR.CD19-T cell combination therapy in humans.

| S-EPMC10256701 | biostudies-literature

UBIQUITIN LIGASE STUB1 DESTABILIZES IFNγ-RECEPTOR COMPLEX TO SUPPRESS TUMOR IFNγ SIGNALING

Project description:The cytokine IFNγ differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about 36 regulation of its receptor (IFNγ-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFNγ-R1 cell surface abundance, we identified STUB1 as an E3 ubiquitin ligase for IFNγ-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFNγ-R1/JAK1 complex through IFNγ-R1K285 and JAK1K249. Conversely, STUB1 inactivation amplifies IFNγ signaling, sensitizing tumor cells to cytotoxic T cells in vitro. This was corroborated by an anticorrelation between STUB1 expression and IFNγ response in ICB-treated patients. Consistent with the context-dependent effects of IFNγ in vivo, anti-PD-1 response was increased in heterogenous tumors comprising both wildtype and STUB1-deficient cells but not full STUB1 knockout tumors. These results uncover STUB1 as a critical regulator of IFNγ-R1, and highlight the context-dependency of STUB1-regulated IFNγ signaling for ICB outcome.

2022-03-07 | PXD030580 | Pride

Blockade or Deletion of IFNγ Reduces Macrophage Activation without Compromising CAR T-cell Function in Hematologic Malignancies.

Project description:Chimeric antigen receptor (CAR) T cells induce impressive responses in patients with hematologic malignancies but can also trigger cytokine release syndrome (CRS), a systemic toxicity caused by activated CAR T cells and innate immune cells. Although IFNγ production serves as a potency assay for CAR T cells, its biologic role in conferring responses in hematologic malignancies is not established. Here we show that pharmacologic blockade or genetic knockout of IFNγ reduced immune checkpoint protein expression with no detrimental effect on antitumor efficacy against hematologic malignancies in vitro or in vivo. Furthermore, IFNγ blockade reduced macrophage activation to a greater extent than currently used cytokine antagonists in immune cells from healthy donors and serum from patients with CAR T-cell-treated lymphoma who developed CRS. Collectively, these data show that IFNγ is not required for CAR T-cell efficacy against hematologic malignancies, and blocking IFNγ could simultaneously mitigate cytokine-related toxicities while preserving persistence and antitumor efficacy.SignificanceBlocking IFNγ in CAR T cells does not impair their cytotoxicity against hematologic tumor cells and paradoxically enhances their proliferation and reduces macrophage-mediated cytokines and chemokines associated with CRS. These findings suggest that IFNγ blockade may improve CAR T-cell function while reducing treatment-related toxicity in hematologic malignancies. See related content by McNerney et al., p. 90 (17). This article is highlighted in the In This Issue feature, p. 85.

| S-EPMC9414118 | biostudies-literature

PrePhage safety

Project description:PrePhage safety

| PRJNA1126634 | ENA

Chromatin accessibility in naive and primed HeLa cells upon IFNγ treatment

Project description:chromatin accessibility (ATAC-seq) experiment. HeLa cells were primed with IFNγ for 24 hours, followed by IFNγ washout. After 48h, naïve and primed cells were induced by IFNγ for 1h and 3h. Cells were harvested at indicated time points and processed for ATAC-seq.

2023-05-06 | E-MTAB-12624 | biostudies-arrayexpress

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