First-in-human in vivo genome editing via AAV-zinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B.

Zinc-finger nuclease (ZFN)-based in vivo genome editing is a novel treatment that can potentially provide lifelong protein replacement with single intravenous administration. Three first-in-human open-label ascending single-dose phase 1/2 studies were performed in parallel (starting November 2017) primarily to assess safety and tolerability of ZFN in vivo editing therapy in mucopolysaccharidosis I (MPS I) (n = 3), MPS II (n = 9), and hemophilia B (n = 1). Treatment was well tolerated with no serious treatment-related adverse events.

Correction: Blood transcriptional profiling reveals IL-1 and integrin signaling pathways associated with clinical response to extracorporeal photopheresis in patients with leukemic cutaneous T-cell lymphoma.

[This corrects the article DOI: 10.18632/oncotarget.26900.

Blood transcriptional profiling reveals IL-1 and integrin signaling pathways associated with clinical response to extracorporeal photopheresis in patients with leukemic cutaneous T-cell lymphoma.

Extracorporeal photopheresis (ECP) is a frontline therapy for patients with leukemic cutaneous T-cell lymphoma (L-CTCL), but its mechanisms of action are not fully understood. This study was to explore the molecular mechanisms underlying clinical response versus non-response in patients with L-CTCL. We performed blood transcriptional profiling of ten L-CTCL patients at Day 2 and 1 month post- ECP compared to pre-ECP baseline using Agilent Whole Human Genome Microarray technology.

The effect of extracorporeal photopheresis alone or in combination therapy on circulating CD4(+) Foxp3(+) CD25(-) T cells in patients with leukemic cutaneous T-cell lymphoma.

Purpose: Extracorporeal photopheresis (ECP) alone or in combination therapy is effective for treatment of leukemic cutaneous T-cell lymphoma (L-CTCL), but its mechanism(s) of action remain unclear. This study was designed to investigate the effect of ECP on regulatory T cells and CD8(+) T cells in L-CTCL patients.

Experimental Design: Peripheral blood from 18 L-CTCL patients at baseline, Day 2, 1 month, 3 month, and 6 month post-ECP therapy was analyzed by flow cytometry for CD4(+) CD25(+/high) , CD4(+) Foxp3(+) CD25(+/-) , CD3(+) CD8(+) , CD3(+) CD8(+) CD69(+) , and CD3(+) CD8(+) IFN-γ(+) T cells.

Extracorporeal photopheresis in the treatment of graft-versus-host disease: evidence and opinion.

Despite significant advances in prevention and treatment strategies, graft-versus-host disease remains the most significant cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cellular transplantation. Corticosteroids remain the standard frontline therapy for graft-versus-host disease; however, a considerable number of patients will not respond adequately and others will be significantly affected by adverse effects. Extracorporeal photopheresis is one of several secondary therapies which have shown promise in the clinical setting.

Sézary syndrome cells overexpress syndecan-4 bearing distinct heparan sulfate moieties that suppress T-cell activation by binding DC-HIL and trapping TGF-beta on the cell surface.

Because syndecan-4 (SD-4) on effector and memory T cells inhibits T-cell activation by binding dendritic cell-associated heparan sulfate proteoglycan-integrin ligand (DC-HIL) on antigen presenting cells and because malignant cells of the cutaneous T-cell lymphoma (CTCL) subset, Sézary syndrome (SS), exhibit memory T-cell phenotype, we posited SS cells to express SD-4. Indeed, malignant T cells from patients with SS and from CTCL cell lines constitutively expressed SD-4 at high levels, in contrast to T cells from healthy volunteers and patients with other inflammatory skin diseases and to non-CTCL cell lines that did not. SS cells also bound to DC-HIL at a level higher than normal T cells activated in vitro, resulting in their inhibited proliferation to anti-CD3 antibody.

Induction of T-cell responses against cutaneous T-cell lymphomas ex vivo by autologous dendritic cells transfected with amplified tumor mRNA.

Sézary syndrome (SzS), the leukemic variant of cutaneous T-cell lymphomas, is incurable. Dendritic cells (DCs) transfected with tumor mRNA can stimulate antitumor immunity in certain cancer patients. In this study, we determined whether mRNAs from Sézary cells could be used for loading DCs and stimulating antitumor immunity.