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 (17.9%) experienced grade 4 treatment-emergent adverse events of interest (neutropenia, n = 4; infection, n = 1). Two deaths reported at the end of the study were unrelated to treatment with blinatumomab (disease progression, n = 1; infection, n = 1). 3/4 patients with PR and 4/4 patients with SD after R-chemotherapy achieved CR following blinatumomab. Consolidation with blinatumomab in patients with newly diagnosed, high-risk DLBCL who did not progress under R-chemotherapy was better tolerated than in previous studies where blinatumomab was used for treatment of patients with lymphoma

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. Restoration of IFN signaling in IFN-deficient melanoma cells induces senescence and suppresses melanoma progression. Additional data from human melanoma patients and mouse transplanted tumor models suggest the importance of non-cell-autonomous IFN signaling. Inactivation of the IFN pathway is mediated by the IFN receptor IFNAR1 downregulation that invariably occurs during melanoma development. Mice harboring an IFNAR1 mutant, which is partially resistant to downregulation, delay melanoma development, suppress metastatic disease, and better respond to BRAF or PD-1 inhibitors. These results suggest that IFN signaling is an important tumor-suppressive pathway that inhibits melanoma development and progression and argue for targeting IFNAR1 downregulation to prevent metastatic disease and improve the efficacy of molecularly target and immune-targeted melanoma therapies

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. In turn, IFN acts to amplify DNA-damage responses, activate the p53 pathway, promote senescence, and inhibit stem cell function in response to telomere shortening. Inactivation of the IFN pathway abrogates the development of diverse progeric phenotypes and extends the lifespan of Terc knockout mice. These data identify DNA-damage-response-induced IFN signaling as a critical mechanism that links accumulating DNA damage with senescence and premature aging

Triggering ubiquitination of IFNAR1 protects tissues from inflammatory injury

Abstract 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. Presented here results demonstrate that inability to stimulate IFNAR1 ubiquitination in the Ifnar1SA knock‐in mice renders them highly susceptible to numerous inflammatory syndromes including acute and chronic pancreatitis, and autoimmune and toxic hepatitis. Ifnar1SA mice (or their bone marrow‐receiving wild type animals) display persistent immune infiltration of inflamed tissues, extensive damage and gravely inadequate tissue regeneration. Pharmacologic stimulation of IFNAR1 ubiquitination is protective against from toxic hepatitis and fulminant generalized inflammation in wild type but not Ifnar1SA mice. These results suggest that endogenous mechanisms that trigger IFNAR1 ubiquitination for limiting the inflammation‐induced tissue damage can be purposely mimicked for therapeutic benefits

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

<div><p>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. We have evaluated these activities in the BRAF-dependent melanoma and provide evidence revealing a complex role for PERK in melanoma where a 50% reduction is permissive for Braf^V600E-dependent transformation, while complete inhibition is tumor suppressive. Consistently, PERK mutants identified in human melanoma are hypomorphic with dominant inhibitory function. Strikingly, we demonstrate that small molecule PERK inhibitors exhibit single agent efficacy against Braf^V600E-dependent tumors highlighting the clinical value of targeting PERK.</p></div

Deletion of one Perk allele cooperates with Braf^V600E to drive metastatic melanoma.

<p><b>A)</b> Kaplan-Mayer survival curve of TyrCre+/-;Braf^V600ECA/+;Perk+/- mice treated with 4-HT. <b>B)</b> Western blot of melanoma skin lysates from TyrCre+/-;Braf^V600ECA/+;Fbxo4;Perk +/+ or TyrCre+/-;Braf^V600ECA/+;Perk+/- or Perk-/- mice (blot anti-Perk, p-eIF2α, eIF2α). <b>C)</b> Melanoma from TyrCre+/-;Braf^V600ECA/+;Perk+/- mice analyzed by H&E. Scale bars = 50μm.</p

Bi-allelic Perk deletion abolishes Braf^V600ECA/+;Fbxo4+/- melanoma initiation, but Perk inhibition cannot recede tumor progression.

<p><b>A)</b> Kaplan-Mayer survival curve of Braf^V600ECA/+, Fbxo4 +/- and Perk +/+, +/- or -/- mice treated with 4-Hydroxytamoxifen (4-HT). <b>B)</b> Western blot of melanoma lysates from TyrCreCA/+; Braf^V600ECA/+; Fbxo4 +/-; Perk +/+, Perk+/- or Perk-/- mice <b>C)</b> IHC analysis of skin from TyrCre+/-;Braf^V600ECA/+;Fbxo4 +/-; Perk+/+ or Perk -/- mice; H&E or IHC with antibodies for S100, p-eIF2α, Chop, cyclin D1, p-Akt, CD31 and quantification of staining/staining index (SI) of IHC. Scale bars = 50μm. <b>D)</b> Tumor volume in TyrCre+/-;Braf^V600ECA/+;Pten-/- mice treated with LY-4; p-values analyzed by two-tailed Student t test. <b>E-F)</b> Western blot of melanoma skin lysates from TyrCre+/-; Braf^V600ECA/+;Pten-/- mice treated with LY-4.</p

Braf^V600ECA/+;Perk+/- tumors are dependent upon the remaining Perk allele.

<p><b>A)</b> LY4 PERK inhibitor inhibits stress-dependent PERK signaling in cultured melanoma cells. <b>B-C)</b> Measurement of melanoma tumor volume B) and tumor weight C) in TyrCre+/-;Braf^V600ECA/+;Perk +/- mice treated with LY-4; p-values analyzed by two-tailed Student t test. <b>D-F)</b> Western blot of melanoma skin lysates obtained from TyrCre+/-;Braf^V600ECA/+;Perk +/- mice treated with PERK inhibitor LY-4. <b>G)</b> Kaplan-Mayer survival curve of TyrCre+/-;Braf^V600ECA/+;Chop+/- or TyrCre+/-;Braf^V600ECA/+;Chop-/- mice expressed relative to control genotypes. <b>H)</b> Kaplan-Mayer survival curve for Braf^V600ECA/+;D1+/-;Perk+/- expressed relative to control genotypes.</p