In this open-label randomized clinical trial, HLA-identical sibling-matched hematopoietic stem cells (HSC) were transplanted (non-MSCs group, n ¼ 15) or cotransplanted with mesenchymal stem cells (MSCs) (MSCs group, n ¼ 10) in hematologic malignancy patients. The median number of MSCs infused was 3.4 Â 10 5 kg À1 (range, 0.3-15.3 Â 10 5 kg À1 ). MSCs infusions were well tolerated. The median time to neutrophil engraftment (absolute neutrophil count 40.5 Â 10 9 l À1 ) was 16 days for MSCs group and 15 days for non-MSCs group. The median time to platelet engraftment (platelet count 450 Â 10 9 l À1 ) was 30 and 27 days, respectively. Grades II-IV acute graft-versus-host disease (GVHD) was observed respectively, in one (11.1%) and eight (53.3%) evaluable patients. Chronic GVHD was found in one (14.3%) and four (28.6%) evaluable patients. The number of patients who relapsed were six (60.0%) and three (20.0%), and the 3-year disease-free survivals were 30.0 and 66.7%, respectively. Thus cotransplantation of MSCs and HSCs may prevent GVHD, but the relapse rate is obviously higher than the control group. We conclude that use of MSCs must be handled with extreme caution before a large-scale clinical trial is performed.

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Key Points• A salvage therapy for adults with refractory hemophagocytic lymphohistiocytosis.• Liposomal doxorubicin treatment combined with etoposide and methylprednisolone showed an encouraging overall response and was welltolerated.Hemophagocytic lymphohistiocytosis (HLH) is a refractory immune disorder with a significant risk of death. Although standard therapy has dramatically improved survival in HLH patients, approximately 30%, especially adults, show no response to current treatment strategies. This prospective study aimed to investigate the efficacy of liposomal doxorubicin treatment combined with etoposide and methylprednisolone (doxorubicin-etoposidemethylprednisolone; DEP) as a salvage therapy for adult refractory HLH. Adult patients who did not achieve at least partial response 2 weeks after initial standard HLH therapy were enrolled in this study between June 2013 and June 2014. Response to salvage therapy was assessed at 2 and 4 weeks after initiation of DEP therapy and patients were followed until death or until November 2014. Sixty-three refractory HLH patients were enrolled, including 29 cases of lymphoma-associated HLH, 22 cases of Epstein-Barr virus-associated HLH, and 4 cases of familial HLH. There were 8 cases with unknown underlying diseases. Seventeen cases (27.0%) achieved complete response and 31 cases (49.2%) achieved partial response. The overall response was 76.2% (48/63). Patients who showed no response to DEP died within 4 weeks after salvage therapy. Twenty-nine of the 48 patients who achieved partial or complete response survived to subsequent chemotherapy, allogenic hematopoietic stem cell transplantation, or splenectomy. Our study suggests that DEP regimen is an effective salvage regimen for adult refractory HLH, which can prolong patient survival as we continue to understand the responsible mechanisms and bridge the gap between HLH and its underlying diseases. This study was registered in the Chinese Clinical Trials Registry Platform

BACKGROUND. DC-based tumor vaccines have had limited clinical success thus far. SOCS1, a key inhibitor of inflammatory cytokine signaling, is an immune checkpoint regulator that limits DC immunopotency.METHODS. We generated a genetically modified DC (gmDC) vaccine to perform immunotherapy. The adenovirus (Ad-siSSF) delivers two tumor-associated antigens (TAAs), survivin and MUC1; secretory bacterial flagellin for DC maturation; and an RNA interference moiety to suppress SOCS1. A 2-stage phase I trial was performed for patients with relapsed acute leukemia after allogenic hematopoietic stem cell transplantation: in stage 1, we compared the safety and efficacy between gmDC treatment (23 patients) and standard donor lymphocyte infusion (25 patients); in stage 2, we tested the efficacy of the gmDC vaccine for 12 acute myeloid leukemia (AML) patients with early molecular relapse.RESULTS. gmDCs elicited potent TAA-specific CTL responses in vitro, and the immunostimulatory activity of gmDC vaccination was demonstrated in rhesus monkeys. A stage 1 study established that this combinatory gmDC vaccine is safe in acute leukemia patients and yielded improved survival rate. In stage 2, we observed a complete remission rate of 83% in 12 relapsed AML patients. Overall, no grade 3 or grade 4 graft-versus-host disease incidence was detected in any of the 35 patients enrolled.CONCLUSIONS. This study, with combinatory modifications in DCs, demonstrates the safety and efficacy of SOCS1-silenced DCs in treating relapsed acute leukemia.TRIAL REGISTRATION. ClinicalTrials.gov NCT01956630.FUNDING. National Institute of Health (R01CA90427); the Key New Drug Development and Manufacturing Program of the “Twelfth Five-Year Plan” of China (2011ZX09102-001-29); and Clinical Application Research of Beijing (Z131107002213148).

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Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) following chemotherapy is part of standard treatment protocol for patients with acute myeloid leukemia (AML). FUS-ERG+ AML is rare but has an extremely poor prognosis even with allo-HSCT in remission, possibly due to its a leukemia stem cell (LSC)-driven disease resulting in chemotherapy resistance and a novel therapy is urgently required. It has been reported that FUS-ERG-positive AML expresses CD123, a marker of LSC, in some cases. CD123-targeted CAR T cell (CART123) is promising immunotherapy, but how to improve the complete remission (CR) rate and rescue potential hematopoietic toxicity still need to explore.Case Presentation: We used donor-derived CART123 as part of conditioning regimen for haploidentical HSCT (haplo-HSCT) in a patient with FUS-ERG+ AML who relapsed after allogeneic transplantation within 3 months, resists to multi-agent chemotherapy and donor lymphocyte infusion (DLI) and remained non-remission, aiming to reduce these chemotherapy-resistant blasts and rescue potential hematopoietic toxicity. The blasts in BM were reduced within 2 weeks and coincided with CAR copies expansion after CART123 infusion. The patient achieved full donor chimerism, CR with incomplete blood count recovery, and myeloid implantation.Conclusion: Our results hints that CART123 reduces the chemotherapy-resistant AML blasts for FUS-ERG+ AML without affecting the full donor chimerism and myeloid implantation.

The survival rate of childhood acute lymphoblastic leukemia (ALL) is approaching 90%, while the prognosis of adults remains poor due to the limited therapeutic approaches. In order to identify new targets for ALL, we performed whole-exome sequencing on four adults with B-ALL and discovered a somatic JAK1 S646P mutation. Sanger sequencing of JAK1 was conducted on 53 ALL patients, and two cases exhibited A639G and P960S mutations separately. Functional studies demonstrated that only JAK1 S646P mutation could activate multiple signaling pathways, drive cytokine-independent cell growth, and promote proliferation of malignant cells in nude mice. Moreover, a high sensitivity to the JAK1/2 inhibitor ruxolitinib was observed in S646P mutant model. Exploration in a total of 209 ALL cases showed that JAK1 mutations occur at a frequency of 10.5% in T-ALL (2/19) and 1.6% in B-ALL (3/190). Collectively, our results suggested that JAK1 S646P is an activating mutation in vitro and in vivo. JAK-STAT pathway might represent a promising therapeutic target for ALL.

As an essential component of paraspeckles, nuclear paraspeckle assembly transcript 1 (NEAT1) localizes in the nucleus, promoting progression of various malignant solid tumors. Herein, an adverse effect of NEAT1 is reported, showing that the short isoform, NEAT1_1 suppresses acute myeloid leukemia (AML) development. NEAT1_1 is downregulated in leukemia stem cells (LSCs) and its decreased expression correlates with recurrence in AML patients. It is demonstrated that NEAT1_1 suppresses leukemogenesis and LSC function but is dispensable for normal hematopoiesis. Mechanistically, NEAT1_1 is released from the nucleus into the cytoplasm of AML cells, regulated by transcription factor C/EBP𝜷 and nuclear protein NAP1L1. Cytoplasmic NEAT1_1 interacts with Wnt component DVL2 and E3 ubiquitin ligase Trim56, facilitates Trim56-mediated DVL2 degradation, and thus suppresses Wnt signaling. Collectively, the findings show NEAT1_1 is translocated from the nucleus to the cytoplasm and acts as a tumor suppressor in AML.