Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons (MNs) and has no effective treatment. Mutations in the fused in sarcoma (FUS) gene and abnormal aggregation of FUS protein have been reported in ALS. However, the mechanisms involved in ALS are poorly understood. Clinical drug trails have failed due to a lack of appropriate disease models, including a lack of access to MNs from ALS patients. Induced pluripotent stem (iPS) cells derived from patients with ALS provide an indispensable resource for in vitro mechanistic studies and for future patient-specific cell-based therapies. Previous reports demonstrated that viral-based ALS-iPS cells generated from fibroblasts harvested from Caucasian populations are ideal for basic research; however, ALS-iPS cells are precluded from cell-based therapeutic applications because of the risks associated with the integration of viral sequences into the genome and inconvenience associated with dermal biopsies. To establish a model for use in clinical applications, using episomal vectors, we generated an integration-free iPS cell line from peripheral blood mononuclear cells (PBMCs) harvested from a familial ALS (FALS) patient carrying the FUS-P525L mutation and a healthy control. Furthermore, we successfully differentiated ALS patient-specific iPS cells into MNs and subsequently detected cytoplasmic mislocalization and formation of FUS protein aggregates in MNs due to the FUS-P525L mutation. Our findings offer a cell-based disease model for use in further elucidating ALS pathogenesis and provide a tool for exploring gene repair coupled with cell replacement therapy.

Background: ENKTL is a highly aggressive NHL related to Epstein-Barr virus, with a higher incidence in Asia. Patients with r/r-ENKTL have a poor prognosis after failing asparaginase based regimen, and there is lack of effective treatment. Anti-PD-1 antibody represented a favorable treatment for rr-ENKTL. ORIENT-4 trial demonstrated Sintilimab was effective and well tolerated in r/r-ENKTL. The efficacy of Chidamide, an oral HDACi was reported on rr-ENKTL(CHIPEL trial, 2017 ASH). Here we present preliminary results of Sintilimab plus Chidamide for r/r-ENKTL. Methods: This trial enrolled eligible patients with histologically confirmed r/r-ENKTL failing from asparaginase-based regimen; ECOG performance status ≤ 2; adequate organ function and bone marrow function; and at least one measurable or evaluable lesion. This study consisited of a Phase Ib (dose escalation) portion followed by a Phase II expansion portion. In the Phase Ib, a standard "3+3" design was utilized to identify the MTD, DLT and recommended Phase II dosage (RP2D) of Chidamide plus Sintilimab. In the phase II portion, patients received 6 cycles of Sintilimab (200 mg) plus Chidamide (RP2D) every 3 weeks. Patients with complete response (CR) or partial response (PR) received up to 1 year. The primary endpoint was objective response rate (ORR) assessed by investigators per RECIL 2017 criteria. Key secondary endpoints included TTR, DOR,PFS,OS and safety. Adverse events (AEs) were defined according to CTCAE 5.0. Pretreatment formalin-fixed, paraffin-embedded (FFPE) tumor samples were obtained. Samples were tested using Dako PD-L1 22C3. PD-L1 protein expression was determined using tumor proportion score (TPS) and combined positive score (CPS). CPS ≥1 was considered positive. All patients' blood samples were collected for ctDNA assessment before treatment in each of cycles. ctDNA samples were analyzed by capture-based NGS targeting 475 lymphoma- and cancer- relevant genes. This trial was registered at ClinicalTrials.gov (NCT 03820596) Results: From March 2019 to May 2020, 41 patients were screened and 37 eligible patients were enrolled from 5 institutions. Median age 48 years (range, 20-72), 27 (73.0%) male, 26 (70.3%) patients with Stage IV of disease at screening, 20 (54.1%) patients with PINK-E score ≥ 3 points, 16 (43.2%) patients received ≥ 2 lines of prior systemic therapy. In Phase Ib , no MTD or DLT events were observed, RP2D of chidamide was 30 mg twice a week. Of 36 response evaluable patients, 21 (58.3%) achieved response including 16 (44.4%) patients with CR and 5 (13.9%) with PR(Figure 1). The median time to initial response was 6.0 weeks (5.0-12.4w). The median DOR time was 9.2+ months (1.3 -14.5+m) (Figure 2). The median follow-up time was 7.3 (0.9-16.1) months. Estimated 1-year OS rate was 79.1%, 1-year PFS rate was 66.0%. 19 (51.3%) patients remained on treatment,18 (48.7%) patients had discontinued from study treatment (16 for PD, 1 for AEs, 1 for personal reasons). The OS and PFS of patients with CR/PR is significantly superior to patients with SD/PD. Estimated 1-year OS rate for CR/PR and SD/PD was 95.0% and 51.9% (P<0.001), 1-year PFS rate was 95.0% and 31.2%, respectively (P<0.001). Among 27 patients with available FFPE tissue specimens, PD-L1 expression in more than 50% and 10% of tumor cells were observed in 12 (44.4%) and 8 patients (29.6%). The median value of CPS was 40.0, patients with PD-L1 CPS≥30 exhibited benefit more from treatment. Dynamics ctDNA assay is in progress, data in detail will be reported at the ASH conference. 21 (56.8%) patients reported treatment-related AEs (TRAEs). The most frequently observed (≥10%) TRAEs were neutropenia (51.4%), thrombocytopenia (45.9%), transaminase increased (29.7%), nausea (24.3%). The most frequent Grade (G) ≥3 TRAEs were neutropenia (16.2%) and thrombocytopenia (10.8%). Immune-related AEs were reported in 16 (43.2%) patients including a G4 exfoliative dermatitis, and the most common irAEs were G1 hypothyroidism and rash. No death was related to the study. Conclusion: Sintilimab plus Chidamide showed manageable safety profile and yielded effective antitumor activity, durable response in patients with r/r-ENKTL for the first time. It is a promising therapeutic option for this population, especially for those with CPS≥30. Epigenetic strategies synergize with anti-PD-1 antibody maybe enhanced antitumor responses to r/r-ENKTL, further investigation is warranted. Disclosures No relevant conflicts of interest to declare.

No abstract

Background: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma (PTCL) that has a poor 5-year overall survival rate due to its lack of precise therapeutic targets. Identifying potential prognostic markers of AITL may provide information regarding the development of precision medicine. Methods: RNA sequence data from PTCL and patient clinic traits were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA) were performed to identify DEGs between the different PTCL subtypes and investigate the relationship underlying co-expression modules and clinic traits. Gene ontology (GO) and protein–protein interaction (PPI) network analyses based on DAVID and the STRING website, respectively, were utilized to deeply excavate hub genes. Results: After removing the outliers from the GSE65823, GSE58445, GSE19069, and GSE6338 datasets using the results from an unsupervised cluster heatmap, 50 AITL samples and 55 anaplastic large cell lymphoma (ALCL) samples were screened. A total of 677 upregulated DEGs and 237 downregulated DEGs were identified in AITL and used to construct a PPI network complex. Using WGCNA, 12 identified co-expression modules were constructed from the 5468 genes with the top 10% of variance, and 192 genes from the Turquoise and Brown modules were with a Gene Significance (GS) cut-off threshold >0.6. Eleven hub genes (CDH1, LAT, LPAR1, CXCL13, CD27, ICAM2, CD3E, CCL19, CTLA-4, CXCR5, and C3) were identified. Only CTLA-4 overexpressed was found to be a poor prognostic factor according to survival analysis. Gene set enrichment analysis (GSEA) identified and validated the intersection of key pathways (T cell receptor, primary immunodeficiency, and chemokine signaling pathways). Conclusion: Our findings provide the framework for the identification of AITL co-expression gene modules and identify key pathways and driving genes that may be novel treatment targets and helpful for the development of a prognostic evaluation index.