Tafasitamab mediates killing of B-cell non-Hodgkin’s lymphoma in combination with γδ T cell or allogeneic NK cell therapy

Her, Jung Hyun; Pretscher, Dominik; Patra-Kneuer, Maria; Schanzer, Juergen; Cho, Sung Yoo; Hwang, Yu Kyeong; Hoeres, Timm; Boxhammer, Rainer; Heitmueller, Christina; Wilhelm, Martin; Steidl, Stefan; Endell, Jan

doi:10.1007/s00262-022-03165-w

Cited by 7 publications

(5 citation statements)

References 22 publications

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“…This study used previously described methods for expanding and cultivating human primary NK cells [29]. Briefly, RPMI-1640 medium (A1049101, Gibco, USA) was utilized to culture primary NK cells, which contained DNase I (A6283, Sigma-Aldrich, USA) and IL-2 (D4513, Sigma-Aldrich, USA).…”

Section: Nk-cell Expansion and Adoptive Transfermentioning

confidence: 99%

NR4A1 mediates NK‐cell dysfunction in hepatocellular carcinoma via the IFN‐γ/p‐STAT1/IRF1 pathway

Wang

et al. 2022

Immunology

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Hepatocellular carcinoma (HCC) is one of the most fatal tumours worldwide and has a high recurrence rate. Nevertheless, the mechanism of HCC genesis remains partly unexplored, while the efficiency of HCC treatments remains limited. The present study analysed the expression of nuclear receptor subfamily 4 group A member 1 (NR4A1) in tumour‐infiltrating natural killer (NK) cells derived from both human patients with HCC and tumour‐bearing mouse models, as well as the features of NR4A1high and NR4A1low NK cells. In addition, knockout of NR4A1 by CRISPR/Cas9 and adoptive transfer experiments were applied to verify the function of NR4A1 in both tumour‐infiltrating NK cells and anti‐PD‐1 therapy. The present study found that NR4A1 was significantly highly expressed in tumour‐infiltrating NK cells, which mediated the dysfunction of tumour‐infiltrating NK cells by regulating the IFN‐γ/p‐STAT1/IRF1 signalling pathway. Knockout of NR4A1 in NK cells not only restored the antitumour function of NK cells but also enhanced the efficacy of anti‐PD‐1 therapy. The present findings suggest a regulatory role of NR4A1 in the immune progress of NK cells against HCC, which may provide a new direction for immunotherapies of HCC.

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Section: Nk-cell Expansion and Adoptive Transfermentioning

confidence: 99%

NR4A1 mediates NK‐cell dysfunction in hepatocellular carcinoma via the IFN‐γ/p‐STAT1/IRF1 pathway

Wang

et al. 2022

Immunology

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“…Next, we found that the prognosis of patients was more closely related to γδT cells and macrophages by analyzing immune cells within different ICI subgroups and gene subgroups. A study carried out by Jung Hyun Her revealed that γδ T cells that express the FcγRIIIa receptor can be effector cells for tafasitamab, an Fc-modified monoclonal antibody, thus inducing antibody-dependent cellular cytotoxicity against a range of NHL cell lines ( 25 ). Further, some studies claimed that macrophage polarization in DLBCL was associated with CREBBP/EP300 mutations and in turn promotes tumor progression ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

CCL8 as a promising prognostic factor in diffuse large B-cell lymphoma via M2 macrophage interactions: A bioinformatic analysis of the tumor microenvironment

Lou

Zhao

et al. 2022

Front. Immunol.

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BackgroundsPrior investigations of the tumor microenvironment (TME) of diffuse large B-cell lymphoma (DLBCL) have shown that immune and stromal cells are key contributing factors to patients’ outcome. However, challenges remain in finding reliable prognostic biomarkers based on cell infiltration. In this study, we attempted to shed some light on chemokine C–C motif chemokine ligand 8 (CCL8) in DLBCL via interaction with M2 macrophages.MethodsThe Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm was applied to evaluate immune and stromal scores from transcriptomic profiles of 443 DLBCL samples from The Cancer Genome Atlas (TCGA) and GSE10846 datasets. Immune cell infiltration (ICI) clusters were obtained based on different immune cell infiltrations of each sample, and gene clusters were derived through differentially expressed genes (DEGs) between the distinct ICI clusters. Five immune-related hub genes related to overall survival (OS) and clinical stages were obtained by COX regression analysis and protein–protein interaction (PPI) network construction then verified by quantitative real-time PCR (qPCR) and immunofluorescence staining in the FFPE tissues. The Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and TIMER websites were employed to explore the biological functions of CCL8-related DEGs. Uni- and multivariable Cox regression analyses were performed to analyze CCL8 as an independent prognostic risk factor in GSE10846 and were verified in other independent GEO cohorts.ResultsA higher stromal score was associated with favorable prognosis in DLBCL. Patients in the ICI B cluster and gene B clusters had a better follow-up status with a higher programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) expression. Most of ICI-related DEGs were enriched for immune-related signaling pathways. Five hub genes with a distinct prognosis association were identified, including CD163, which is a biomarker of M2 macrophages, and CCL8. Abundant M2 macrophages were discovered in the high-CCL8 expression group. The functional analysis indicated that CCL8 is a key component of immune-related processes and secretory granule groups. Cox regression analysis and data from other GSE datasets yielded additional evidence of the prognostic value of CCL8 in DLBCL.ConclusionsCCL8 has been implicated in macrophage recruitment in several solid tumors, and only a few reports have been published on the role of CCL8 in the pathogenesis of hematological malignancies. This article attempted to find out TME-related genes that associated with the survival in DLBCL patients. CCL8 was identified to be involved in immune activities. Importantly, a series of bioinformatics analysis indicated that CCL8 might become an effective target for DLBCL, which interacts with M2 macrophage and immune checkpoint. The potential related mechanisms need to be further elucidated.

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“…Tafasitamab and MG4101 allogeneic NK cells were co-administered in Raji and Ramos NHL xenograft models resulted in survival benefit over monotherapy with tafasitamab or MG4101, showing that adoptive cell transfer of ex vivo expanded allogeneic NK cells or autologous γδ T cells in combination with tafasitamab treatment may enhance the antitumor effect of tafasitamab. 25 …”

Section: Pharmacodynamicsmentioning

confidence: 99%

Tafasitamab for the treatment of patients with diffuse large B-cell lymphoma

Pirosa,

Stathis,

Zucca

2024

Human Vaccines & Immunotherapeutics

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Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) require additional treatments, especially those not eligible or not responding to high dose cytotoxic chemotherapy and stem cell transplantation. Over the last few years, several new treatments have been developed and approved for these patients, among them of particular relevance are those targeting CD19. Tafasitamab is a humanized monoclonal antibody targeting CD19, composed of a modified fragment crystallizable (Fc) region engineered with higher affinity for Fc gamma receptors (FcγR) receptors, leading to increased cytotoxicity through natural killer cells and macrophages (antibody-dependent cellular cytotoxicity and antibody-dependent cell-mediated phagocytosis). In this product review, we will discuss its mechanism of action, safety profile and efficacy results from clinical trials that led to its approval in combination with lenalidomide for patients with R/R DLBCL ineligible for high-dose chemotherapy and autologous transplantation.

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Tafasitamab mediates killing of B-cell non-Hodgkin’s lymphoma in combination with γδ T cell or allogeneic NK cell therapy

Cited by 7 publications

References 22 publications

NR4A1 mediates NK‐cell dysfunction in hepatocellular carcinoma via the IFN‐γ/p‐STAT1/IRF1 pathway

NR4A1 mediates NK‐cell dysfunction in hepatocellular carcinoma via the IFN‐γ/p‐STAT1/IRF1 pathway

CCL8 as a promising prognostic factor in diffuse large B-cell lymphoma via M2 macrophage interactions: A bioinformatic analysis of the tumor microenvironment

Tafasitamab for the treatment of patients with diffuse large B-cell lymphoma

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