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Survival in Epstein–Barr virus (EBV)-positive post-transplant lymphoproliferative disease following haematopoietic stem-cell transplant (HSCT) or solid organ transplant (SOT) is poor after failure of initial therapy, indicating an urgent need for therapies for this ultra-rare disease. With recent EU marketing authorisation, tabelecleucel is the first off-the-shelf, allogeneic, EBV-specific T-cell immunotherapy to receive approval for treatment of relapsed or refractory EBV-positive post-transplant lymphoproliferative disease. We aimed to determine the clinical benefit of tabelecleucel in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease following HSCT or SOT. In this global, multicentre, open-label, phase 3 trial, eligible patients (of any age) had biopsy-proven EBV-positive post-transplant lymphoproliferative disease, disease that was relapsed or refractory to rituximab after HSCT and rituximab with or without chemotherapy after SOT, and partially HLA-matched and appropriately HLA-restricted tabelecleucel available. Patients received tabelecleucel administered intravenously at 2 × 106 cells per kg on days 1, 8, and 15 in 35-day cycles and are assessed for up to 5 years for survival post-treatment initiation. The primary endpoint was objective response rate. All patients who received at least one dose of tabelecleucel were included in safety and efficacy analyses. This trial is registered with ClinicalTrials.gov , NCT03394365 , and is ongoing. From June 27, 2018, to Nov 5, 2021, 63 patients were enrolled, of whom 43 (24 [56%] male and 19 [44%] female) were included, 14 had prior HSCT, 29 had SOT. Seven (50%, 95% CI 23–77) of 14 participants in the HSCT group and 15 (52%, 33–71) of 29 participants in the SOT group had an objective response, with a median follow-up of 14·1 months (IQR 5·7–23·9) and 6·0 months (1·8–18·4), respectively. The most common grade 3 or 4 treatment-emergent adverse events were disease progression (in four [29%] of 14 in HSCT and eight [28%] of 29 in SOT) and decreased neutrophil count (in four [29%] of 14 in HSCT and four [14%] of 29 in SOT). Treatment-emergent serious adverse events were reported in 23 (53%) of 43 patients and fatal treatment-emergent adverse events in five (12%); no fatal treatment-emergent adverse event was treatment-related. There were no reports of tumour flare reaction, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, transmission of infectious diseases, marrow rejection, or infusion reactions. No events of graft-versus-host disease or SOT rejection were reported as related to tabelecleucel. Tabelecleucel provides clinical benefit in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease, for whom there are no other approved therapies, without evidence of safety concerns seen with other adoptive T-cell therapies. These data represent a potentially transformative and accessible treatment advance for patients with relapsed or refractory disease with few treatment options. Atara Biotherapeutics. [ABSTRACT FROM AUTHOR]

Summary Human natural killer (NK) cells develop in secondary lymphoid tissues (SLTs) through distinct stages. We identified two SLT lineage (Lin) − CD34 − CD117 +/− CD94 + CD16 − “stage 4” subsets according to expression of the C-type lectin-like surface-activating receptor, NKp80: NKp80 − (stage “4a”) and NKp80 + (stage “4b”). Whereas stage 4b cells expressed more of the transcription factors T-BET and EOMES, produced interferon-gamma, and were cytotoxic, stage 4a cells expressed more of the transcription factors RORγt and AHR and produced interleukin-22, similar to SLT Lin − CD34 − CD117 + CD94 − CD16 − “stage 3” cells, whose phenotype overlaps with that of group 3 innate lymphoid cells (ILC3s). Co-culture with dendritic cells or transplantation into immunodeficient mice produced mature NK cells from stage 3 and stage 4a populations. These data identify NKp80 as a marker of NK cell maturity in SLTs and support a model of human NK cell development through a stage 4a intermediate with ILC3-associated features. [ABSTRACT FROM AUTHOR]

Epigenetic regulation by the type II protein arginine methyltransferase, PRMT5, plays an essential role in the control of cancer cell proliferation and tumorigenesis. In this report, we investigate the relationship between PRMT5 and WNT/β- CATENIN as well as AKT/GSK3β proliferative signaling in three different types of non-Hodgkin's lymphoma cell lines, clinical samples, and mouse primary lymphoma cells. We show that PRMT5 stimulates WNT/β-CATENIN signaling through direct epigenetic silencing of pathway antagonists, AXIN2 and WIF1, and indirect activation of AKT/GSK3β signaling.PRMT5 inhibition with either shRNA-mediated knockdown or a specific small molecule PRMT5 inhibitor, CMP-5, not only leads to derepression ofWNTantagonists and decreased levels of active phospho-AKT (Thr-450 and Ser-473) and inactive phospho- GSK3β (Ser-9) but also results in decreased transcription of WNT/β-CATENIN target genes, CYCLIN D1, c-MYC, and SURVIVIN, and enhanced lymphoma cell death. Furthermore, PRMT5inhibition leads to reduced recruitment of co-activators CBP, p300, and MLL1, as well as enhanced recruitment of co-repressors HDAC2 and LSD1 to the WNT/β-CATENIN target gene promoters. These results indicate that PRMT5 governs expression of prosurvival genes by promoting WNT/β- CATENIN and AKT/GSK3β proliferative signaling and that its inhibition induces lymphoma cell death, which warrants further clinical evaluation. [ABSTRACT FROM AUTHOR]

Arginine methylation governs important cellular processes that impact growth and proliferation, as well as differentiation and development. Through their ability to catalyze symmetric or asymmetric methylation of histone and non-histone proteins, members of the protein arginine methyltransferase (PRMT) family regulate chromatin structure and expression of a wide spectrum of target genes. Unlike other PRMTs, PRMT5 works in concert with a variety of cellular proteins including ATP-dependent chromatin remodelers and co-repressors to induce epigenetic silencing. Recent work also implicates PRMT5 in the control of growth-promoting and pro-survival pathways, which demonstrates its versatility as an enzyme involved in both epigenetic regulation of anti-cancer target genes and organelle biogenesis. These studies not only provide insight into the molecular mechanisms by which PRMT5 contributes to growth control, but also justify therapeutic targeting of PRMT5. [Copyright &y& Elsevier]

• PRT543 is a potent and selective oral inhibitor of PRMT5. • PRT543 catalyzes symmetric arginine dimethylation of protein substrates. • In this phase I dose-expansion trial, patients with R/M ACC received PRT543. • PRT543 was generally well tolerated and yielded tumour regression in some patients. • Median progression-free survival was 5.9 months (95% CI: 3.8–8.3) • Further investigation of PRMT5 inhibitors for R/M ACC treatment is warranted. Currently, no systemic treatments are approved for patients with recurrent and/or metastatic (R/M) adenoid cystic carcinoma (ACC). PRT543, a protein arginine methyltransferase 5 inhibitor that downregulates NOTCH1 and MYB signalling in tumours, is a potential candidate for R/M ACC treatment. We report the safety, tolerability and preliminary efficacy of PRT543 in a dose-expansion cohort of patients with R/M ACC. This phase I multicentre, open-label, sequential-cohort, dose-escalation and dose-expansion study (NCT03886831) enrolled patients with advanced solid tumours and select haematologic malignancies. Dose-escalation study design and results were reported previously. In the dose expansion, patients with R/M ACC received recommended phase II doses of 35 or 45 mg PRT543 orally on days 1–5 of each week. Primary objectives were to establish the safety and tolerability of PRT543. Secondary objectives included efficacy. Between February 2019 and May 2022, 56 patients with ACC were enrolled across 23 US sites and received either 35 mg (n = 28) or 45 mg (n = 28) of PRT543. Overall, 23% of patients experienced a grade 3 treatment-related adverse event, most commonly anaemia (16%) and thrombocytopaenia (9%). No grade 4/5 treatment-emergent adverse events were reported. Median progression-free survival was 5.9 months (95% CI: 3.8–8.3). The clinical benefit rate was 57% (95% CI: 43–70). Overall response rate (per Response Evaluation Criteria in Solid Tumours v1.1) was 2%, with 70% of patients having stable disease. In this analysis, PRT543 was tolerable, and the observed efficacy was limited in patients with R/M ACC. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase-5 (PRMT5) is overexpressed in aggressive B-cell non-Hodgkin's lymphomas, including mantle cell lymphoma and diffuse large B-cell lymphoma, and supports constitutive expression of CYCLIN D1 and c-MYC. Here, we combined ChIP analysis with next-generation sequencing to identify microRNA (miRNA) genes that are targeted by PRMT5 in aggressive lymphoma cell lines. We identified enrichment of histone 3 dimethylation at Arg-8 (H3(Me2)R8) in the promoter regions of miR33b, miR96, and miR503. PRMT5 knockdown de-repressed transcription of all three miRNAs, accompanied by loss of recruitment of epigenetic repressor complexes containing PRMT5 and either histone deacetylase 2 (HDAC2) or HDAC3, enhanced binding of co-activator complexes containing p300 or CREB-binding protein (CBP), and increased acetylation of specific histones, including H2BK12, H3K9, H3K14, and H4K8 at the miRNA promoters. Re-expression of individual miRNAs in B-cell lymphoma cells down-regulated expression of PRMT5, CYCLIN D1, and c-MYC, which are all predicted targets of these miRNAs, and reduced lymphoma cell survival. Luciferase reporter assays with WT and mutant 3'UTRs of CYCLIN D1 and c-MYC mRNAs revealed that binding sites for miR33b, miR96, and miR503 are critical for translational regulation of the transcripts of these two genes. Our findings link altered PRMT5 expression to transcriptional silencing of tumor-suppressing miRNAs in lymphoma cells and reinforce PRMT5's relevance for promoting lymphoma cell growth and survival. [ABSTRACT FROM AUTHOR]

Myelopathy of the dorsal columns is a rare complication of intrathecal (IT) chemotherapy that occurs most frequently with IT methotrexate and cytarabine. This diagnosis is made with a combination of magnetic resonance imaging, somatosensory evoked potentials, and elevated cerebrospinal fluid (CSF) protein levels, particularly myelin basic protein. A 73-year-old man with blastic plasmacytoid dendritic cell neoplasm and known central nervous system involvement underwent standard treatment, including 5 doses of IT cytosine arabinoside. Following this, he had documented CSF clearance of disease. One year later, he developed progressive lower extremity weakness, numbness, and bowel/bladder dysfunction. Magnetic resonance imaging and repeat CSF analysis demonstrated recurrence, and he underwent further IT administration of methotrexate and cytarabine. CSF clearance of malignant cells was again established. However, weakness progressed to quadriplegia; loss of bowel/bladder control; and severe sensory loss, particularly vibration and proprioception. Repeat magnetic resonance imaging demonstrated high signal intensity in bilateral posterior columns. A lower thoracic spine dorsal column biopsy revealed cord destruction and diffuse macrophage infiltration with profound destruction of the neuropil. Although dorsal column myelopathy has previously been described in association with IT chemotherapy, this has solely been diagnosed on the basis of clinical examination, electrodiagnostic criteria, radiographic findings, and CSF analysis. This case provides a pathologic evaluation of an antemortem obtained specimen revealing diffuse macrophage infiltration and profound destruction of the neuropil. Whereas the mechanism underlying spinal cord toxicity following IT chemotherapy remains largely unknown, this case demonstrates a potentially macrophage-mediated process. [ABSTRACT FROM AUTHOR]

Background: PRMT5, PRC2, and cyclin D1 are overexpressed in non-Hodgkin lymphoma (NHL). Results: PRMT5 expression inversely correlates with levels of hypophospho-RB1 and RBL2. Conclusion: PRMT5 inhibition reactivates RB1 and RBL2 and silences PRC2 and cyclin D1. Significance: PRMT5 inhibition results in NHL growth arrest and cell death. [ABSTRACT FROM AUTHOR]

Abstract: Alvocidib has demonstrated efficacy in high-risk chronic lymphocytic leukemia (CLL) patients. In this phase I study, we combined cyclophosphamide, alvocidib and rituximab (CAR) in a schema designed to mitigate tumor lysis syndrome (TLS) seen previously with alvocidib. Nine nucleoside analog-naïve, high-risk patients received escalating doses of CAR therapy. Dose limiting toxicity was not experienced. No instances of TLS were observed. Patient responses included three complete remissions and four partial remissions. CAR was tolerable and active in high-risk CLL patients without TLS toxicity. With continued monitoring of toxicities, a phase Ib/II study of this combination as frontline therapy is warranted. [Copyright &y& Elsevier]

Summary: The biologic and clinical significance of KIT overexpression that associates with KIT gain-of-function mutations occurring in subsets of acute myeloid leukemia (AML) (i.e., core binding factor AML) is unknown. Here, we show that KIT mutations lead to MYC-dependent miR-29b repression and increased levels of the miR-29b target Sp1 in KIT-driven leukemia. Sp1 enhances its own expression by participating in a NFκB/HDAC complex that further represses miR-29b transcription. Upregulated Sp1 then binds NFκB and transactivates KIT. Therefore, activated KIT ultimately induces its own transcription. Our results provide evidence that the mechanisms of Sp1/NFκB/HDAC/miR-29b-dependent KIT overexpression contribute to leukemia growth and can be successfully targeted by pharmacological disruption of the Sp1/NFκB/HDAC complex or synthetic miR-29b treatment in KIT-driven AML. [Copyright &y& Elsevier]

Abstract: Sézary Syndrome (SS) is an aggressive T-cell malignancy often presenting in advanced age and associated with poor prognosis. There is no standard therapy and because of co-morbidities, elderly patients are particularly challenging to treat. Alemtuzumab is an anti-CD52 monoclonal antibody that has activity in SS but is profoundly immunosuppressive, leading to great hesitation about its use in older patients. We treated five octogenarian patients with SS with subcutaneous (SQ) alemtuzumab, at relapse or as initial therapy, for 5–9 weeks. With the exception of transient grade 1–2 hematological toxicity and asymptomatic cytomegalovirus (CMV) (two patients) and Epstein-Barr virus (EBV) (one patient) reactivation, no other toxicities were observed. The clinical and hematological complete response (CR) rate was 100%. Three patients achieved durable responses (8+ to 17+ months). Alemtuzumab was safely administered and showed significant activity in very elderly SS patients. [Copyright &y& Elsevier]

Mantle-cell lymphoma (MCL) remains incurable despite numerous therapeutic advances. OSU-2S, a novel nonimmunosuppressive FTY720 (Fingolimod) derivative, exhibits potent cytotoxicity in MCL cell lines and primary cells. OSU-2S increased the surface expression of CD74, a therapeutic antibody target in MCL cells. OSU-2S, in combination with anti-CD74 antibody milatuzumab, enhanced cytotoxicity in MCL. Moreover, MCL tumor antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) targeted immunonanoparticle-carrying OSU-2S (2A2-OSU-2S-ILP)-mediated selective cytotoxicity of MCL in vitro, as well as activity in a xenografted mouse model of MCL in vivo. The newly developed OSU-2S delivery using ROR1-directed immunonanoparticles provide selective targeting of OSU-2S to MCL and other ROR1 + malignancies, sparing normal B cells. [ABSTRACT FROM AUTHOR]