Single agent subcutaneous blinatumomab for advanced acute lymphoblastic leukemia.

Blinatumomab is a BiTE® (bispecific T-cell engager) molecule that redirects CD3 T-cells to engage and lyse CD19 target cells. Here we demonstrate that subcutaneous (SC) blinatumomab can provide high efficacy and greater convenience of administration. In the expansion phase of a multi-institutional phase 1b trial (ClinicalTrials.

Spatial characterization and quantification of CD40 expression across cancer types.

Background: CD40, a TNF receptor family member, is expressed by a variety of immune cells and is involved in the activation of both adaptive and innate immune responses. Here, we used quantitative immunofluorescence (QIF) to evaluate CD40 expression on the tumor epithelium of solid tumors in large patient cohorts of lung, ovarian, and pancreatic cancers.

Methods: Tissue samples from nine different solid tumors (bladder, breast, colon, gastric, head and neck, non-small cell lung cancer (NSCLC), ovarian, pancreatic and renal cell carcinoma), constructed in tissue microarray format, were initially assessed for CD40 expression by QIF.

Open-label, phase 2 study of blinatumomab after frontline R-chemotherapy in adults with newly diagnosed, high-risk DLBCL.

This open-label, multicenter, single-arm, phase 2 study assessed the safety and efficacy of blinatumomab consolidation therapy in adult patients with newly diagnosed, high-risk diffuse large B-cell lymphoma (DLBCL; International Prognostic Index 3-5 and/or double-/triple-hit or double MYC/BCL-2 expressors) who achieved complete response (CR), partial response (PR), or stable disease (SD) following run-in with 6 cycles of R-chemotherapy (NCT03023878). Of the 47 patients enrolled, 28 received blinatumomab. Five patients (17.

An Interferon-Driven Oxysterol-Based Defense against Tumor-Derived Extracellular Vesicles.

Tumor-derived extracellular vesicles (TEV) "educate" healthy cells to promote metastases. We found that melanoma TEV downregulated type I interferon (IFN) receptor and expression of IFN-inducible cholesterol 25-hydroxylase (CH25H). CH25H produces 25-hydroxycholesterol, which inhibited TEV uptake.

Tumor-immune profiling of murine syngeneic tumor models as a framework to guide mechanistic studies and predict therapy response in distinct tumor microenvironments.

Mouse syngeneic tumor models are widely used tools to demonstrate activity of novel anti-cancer immunotherapies. Despite their widespread use, a comprehensive view of their tumor-immune compositions and their relevance to human tumors has only begun to emerge. We propose each model possesses a unique tumor-immune infiltrate profile that can be probed with immunotherapies to inform on anti-tumor mechanisms and treatment strategies in human tumors with similar profiles.

PERK Is a Haploinsufficient Tumor Suppressor: Gene Dose Determines Tumor-Suppressive Versus Tumor Promoting Properties of PERK in Melanoma.

The unfolded protein response (UPR) regulates cell fate following exposure of cells to endoplasmic reticulum stresses. PERK, a UPR protein kinase, regulates protein synthesis and while linked with cell survival, exhibits activities associated with both tumor progression and tumor suppression. For example, while cells lacking PERK are sensitive to UPR-dependent cell death, acute activation of PERK triggers both apoptosis and cell cycle arrest, which would be expected to contribute tumor suppressive activity.

A Potent Antitumor Efficacy of Novel Recombinant Type I Interferon.

Antiproliferative, antiviral, and immunomodulatory activities of endogenous type I IFNs (IFN1) prompt the design of recombinant IFN1 for therapeutic purposes. However, most of the designed IFNs exhibited suboptimal therapeutic efficacies against solid tumors. Here, we report evaluation of the and antitumorigenic activities of a novel recombinant IFN termed sIFN-I.

Suppression of Type I Interferon Signaling Overcomes Oncogene-Induced Senescence and Mediates Melanoma Development and Progression.

Oncogene activation induces DNA damage responses and cell senescence. We report a key role of type I interferons (IFNs) in oncogene-induced senescence. IFN signaling-deficient melanocytes expressing activated Braf do not exhibit senescence and develop aggressive melanomas.

Type I Interferons Control Proliferation and Function of the Intestinal Epithelium.

Wnt pathway-driven proliferation and renewal of the intestinal epithelium must be tightly controlled to prevent development of cancer and barrier dysfunction. Although type I interferons (IFN) produced in the gut under the influence of microbiota are known for their antiproliferative effects, the role of these cytokines in regulating intestinal epithelial cell renewal is largely unknown. Here we report a novel role for IFN in the context of intestinal knockout of casein kinase 1α (CK1α), which controls the ubiquitination and degradation of both β-catenin and the IFNAR1 chain of the IFN receptor.

Type 1 interferons contribute to the clearance of senescent cell.

The major known function of cytokines that belong to type I interferons (IFN, including IFNα and IFNβ) is to mount the defense against viruses. This function also protects the genetic information of host cells from alterations in the genome elicited by some of these viruses. Furthermore, recent studies demonstrated that IFN also restrict proliferation of damaged cells by inducing cell senescence.

DNA-damage-induced type I interferon promotes senescence and inhibits stem cell function.

Expression of type I interferons (IFNs) can be induced by DNA-damaging agents, but the mechanisms and significance of this regulation are not completely understood. We found that the transcription factor IRF3, activated in an ATM-IKKα/β-dependent manner, stimulates cell-autonomous IFN-β expression in response to double-stranded DNA breaks. Cells and tissues with accumulating DNA damage produce endogenous IFN-β and stimulate IFN signaling in vitro and in vivo.

Type I interferon controls propagation of long interspersed element-1.

Type I interferons (IFN) including IFNα and IFNβ are critical for the cellular defense against viruses. Here we report that increased levels of IFNβ were found in testes from mice deficient in MOV10L1, a germ cell-specific RNA helicase that plays a key role in limiting the propagation of retrotransposons including Long Interspersed Element-1 (LINE-1). Additional experiments revealed that activation of LINE-1 retrotransposons increases the expression of IFNβ and of IFN-stimulated genes.

Triggering ubiquitination of IFNAR1 protects tissues from inflammatory injury.

Type 1 interferons (IFN) protect the host against viruses by engaging a cognate receptor (consisting of IFNAR1/IFNAR2 chains) and inducing downstream signaling and gene expression. However, inflammatory stimuli can trigger IFNAR1 ubiquitination and downregulation thereby attenuating IFN effects in vitro. The significance of this paradoxical regulation is unknown.