Interferon-alpha-based immunotherapies in the treatment of B cell-derived hematologic neoplasms in today’s treat-to-target era

Zhang, Li; Tai, Yu‐Tzu; Ho, Matthew; Qiu, Lugui; Anderson, Kenneth C.

doi:10.1186/s40164-017-0081-6

Cited by 33 publications

(38 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…37 In the 1980s, IFN-α was used as monotherapy in MM, with an overall response rate of 15-20%. 38 In this study, we found that a series of INF-stimulated genes were upregulated in MM cells by DOT1L inhibitors, which may contribute to the drugs’ anti-myeloma effects. The mechanism underlying the activation of immune response genes and INF signaling is unclear.…”

Section: Discussionmentioning

confidence: 67%

DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling

et al. 2018

View full text Add to dashboard Cite

Epigenetic alterations play an important role in the pathogenesis in multiple myeloma, but their biological and clinical relevance is not fully understood. Here, we show that DOT1L, which catalyzes methylation of histone H3 lysine 79, is required for myeloma cell survival. DOT1L expression levels were higher in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma than in normal plasma cells. Treatment with a DOT1L inhibitor induced cell cycle arrest and apoptosis in myeloma cells, and strongly suppressed cell proliferation in vitro. The anti-myeloma effect of DOT1L inhibition was confirmed in a mouse xenograft model. Chromatin immunoprecipitation-sequencing and microarray analysis revealed that DOT1L inhibition downregulated histone H3 lysine 79 dimethylation and expression of IRF4-MYC signaling genes in myeloma cells. In addition, DOT1L inhibition upregulated genes associated with immune responses and interferon signaling. Myeloma cells with histone modifier mutations or lower IRF4/MYC expression were less sensitive to DOT1L inhibition, but with prolonged treatment anti-proliferative effects were achieved in these cells. Our data suggest that DOT1L plays an essential role in the development of multiple myeloma and that DOT1L inhibition may provide new therapies for myeloma treatment.

show abstract

Section: Discussionmentioning

confidence: 67%

DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Some of the strongest and most consistent enrichments included the interferon signaling pathway and the antigen presentation pathway, both of which were enriched after EPZ-6438 single agent treatment and the combination and have been shown to be directly modulated by EZH2 [ 48 ]. The interferon pathway has long been considered a target for therapeutic activation in MM [ 53 ]. Enrichment of this pathway was centered on the upregulation of STAT1 and most of its downstream promotor targets.…”

Section: Resultsmentioning

confidence: 99%

EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes

2018

View full text Add to dashboard Cite

Multiple myeloma (MM) remains a largely incurable hematologic cancer due to an inability to broadly target inevitable drug-resistant relapse. Epigenetic abnormalities are abundantly present in multiple myeloma and have increasingly demonstrated critical roles for tumor development and relapse to standard therapies. Accumulating evidence suggests that the histone methyltransferase EZH2 is aberrantly active in MM. We tested the efficacy of EZH2 specific inhibitors in a large panel of human MM cell lines (HMCLs) and found that only a subset of HMCLs demonstrate single agent sensitivity despite ubiquitous global H3K27 demethylation. Pre-treatment with EZH2 inhibitors greatly enhanced the sensitivity of HMCLs to the pan-HDAC inhibitor panobinostat in nearly all cases regardless of single agent EZH2 inhibitor sensitivity. Transcriptomic profiling revealed large-scale transcriptomic alteration by EZH2 inhibition highly enriched for cancer-related pathways. Combination treatment greatly increased the scale of gene expression change with a large portion of differentially expressed genes being unique to the combination. Transcriptomic analysis demonstrated that combination treatment further perturbed oncogenic pathways and signaling nodes consistent with an antiproliferative/pro-apoptotic state. We conclude that combined inhibition of HDAC and EZH2 inhibitors is a promising therapeutic strategy to broadly target the epigenetic landscape of aggressive MM.

show abstract

“…Currently, the structure of a CAR contains an antigen-recognition domain, a transmembrane domain, a costimulatory segment, and a signaling domain [ 1 , 24 – 26 ]. A single-chain fragment of variable region (scFv) replaces the conventional T cell antigen recognition domain.…”

Section: Introductionmentioning

confidence: 99%

Cytokine release syndrome: grading, modeling, and new therapy

2018

View full text Add to dashboard Cite

Genetically modified T cells that express a chimeric antigen receptor (CAR) are opening a new frontier in cancer immunotherapy. CAR T cells currently are in clinical trials for many cancer types. Cytokine release syndrome (CRS) and neurotoxicities (CAR-related encephalopathy syndrome, CRES) are major adverse events limiting wide deployment of the CAR T cell treatment. Major efforts are ongoing to characterize the pathogenesis and etiology of CRS and CRES. Mouse models have been established to facilitate the study of pathogenesis of the major toxicities of CAR T cells. Myeloid cells including macrophages and monocytes, not the CAR T cells, were found to be the major cells mediating CRS and CRES by releasing IL-1 and IL-6 among other cytokines. Blocking IL-1 or depletion of monocytes abolished both CRS and CRES, whereas IL-6 blocker can ameliorate CRS but not CRES. Therefore, both IL-1 and IL-6 are major cytokines for CRS, though IL-1 is responsible for CRES. It was also demonstrated in the mouse models that blocking CRS does not interfere with the CAR T cell antitumor functions. We summarized new developments in the grading, modeling, and possible new therapeutic approaches for CRS and CRES in this review.

show abstract

Interferon-alpha-based immunotherapies in the treatment of B cell-derived hematologic neoplasms in today’s treat-to-target era

Cited by 33 publications

References 55 publications

DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling

DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling

EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes

Cytokine release syndrome: grading, modeling, and new therapy

Contact Info

Product

Resources

About