Search

As an immunomodulatory agent with antitumor activity, lenalidomide has been evaluated for its value in diffuse large B-cell lymphoma (DLBCL). We performed a meta-analysis to gain a better understanding of the efficacy and safety of lenalidomide in DLBCL. PubMed, Cochrane Library, and Embase were searched up to March 2022 for potential studies. The pooled hazard ratio (HR) and relative risk (RR) with 95% confidence interval (CI) were estimated by the fixed/random effects model. Overall, 6 randomized controlled trials including 1938 patients were included. The complete response rate (CRR) of the group containing lenalidomide was 47.7% (95%CI 28.5–67.2%), which was higher than the 37.8% (95%CI 16.7–61.5%) of the control group without lenalidomide (RR = 1.11, 95%CI 1.03–1.20, P = 0.008). The overall estimation of survival showed a benefit for progression-free survival (PFS) (HR = 0.77, 95%CI 0.66–0.90, P = 0.001) but not overall survival (OS) or event-free survival (EFS). The lenalidomide group had a significant incidence of grade ≥ 3 hematological adverse events (AEs) involving neutropenia (RR = 1.56, 95%CI 1.15–2.11, P = 0.004) and febrile neutropenia (RR = 1.81, 95%CI 1.31–2.49, P

This study aims to explore the effect of the ITI (interferon alpha-1b, thalidomide, and interleukin-2) regimen on the AML1-ETO fusion gene in patients with t(8;21) acute myeloid leukemia (AML) who were in hematologic remission but positive for the AML1-ETO fusion gene. From September 2014 to November 2020; 20 patients with AML (15 from The Affiliated Cancer Hospital of Zhengzhou University, 4 from The First Affiliated Hospital; and College of Clinical Medicine of Henan University of Science and Technology, and 1 from Anyang District Hospital) with hematological remission but AML1-ETO fusion gene positivity were treated with different doses of the ITI regimen to monitor changes in AML1-ETO fusion gene levels. Twenty patients were treated with a routine dose of the ITI regimen, including 13 males and 7 females. The median patient age was 38 (14–70 years). The fusion gene was negative in 10 patients after 1 (0.5 ~ 8.6) month, significantly decreased in 4 patients after 2.8 (1 ~ 6) months, increased in 4 patients, and unchanged in 2 patients. The 4 patients with elevated levels of the fusion gene were treated with an increased dose of the ITI regimen, and all four patients became negative, for a total effective rate of 90%. The ITI regimen reduces AML1-ETO fusion gene levels in patients with AML who are in hematologic remission but are fusion gene–positive. Improvement was observed in patients’ response to a higher dose administration, and patients tolerated the treatment well.

Despite continuous improvements of AML therapy, the prognosis of AML patients remains unsatisfactory. Recently, lncRNAs have been reported to participate in the development of AML. Our data demonstrated that MMP15 and LINC00963 were upregulated and miR-608 was decreased in AML cells (THP-1, HL-60, HEL and MOLM-13) compared to HS-5 cells. RT-qPCR results showed that LINC00963 levels were higher in the serum and bone marrow of AML cases than in controls. Moreover, overexpression of LINC00963 promoted AML cell growth and EMT progression in both THP-1 and HL-60 cells. Furthermore, miR-608 levels were downregulated in the serum and bone marrow of AML cases compared with controls, and Pearson's correlation analysis indicated that LINC00963 was negatively correlated with miR-608 in the serum and bone marrow of AML samples. In addition, we demonstrated that LINC00963 sponged miR-608 expression and that MMP-15 was a target of miR-608 in AML cells. Finally, rescue experiments indicated that ectopic expression of LINC00963 accelerated cell growth and EMT development by modulating MMP-15. These data demonstrated that LINC00963 acted as an oncogene and may be a potential target for AML treatment.

Purpose To investigate the role of the CXCR4/CXCL12 axis in chemotherapy resistance in refractory/relapsed (R/R) ALL patients. Methods CXCR4 expression on ALL cells from newly diagnosed or R/R ALL patients were detected using flow cytometry. The CXCR4/CXCL12 signaling pathway was blocked by the CXCR4 inhibitor AMD3100 in a co-culture model of primary drug-resistant ALL cells and umbilical cord mesenchymal stem cells (UCMSCs). Surface CXCR4 expression, apoptosis rate, and apoptosis-related protein expression in primary ALL cells under various treatments were detected. Results Of the 37 ALL patients examined, CXCR4 expression was higher in R/R patients than that in those with newly diagnosed disease. Similarly, in in vitro co-cultures of drug-resistant ALL cells with UCMSCs, the expression of CXCR4 was increased in the presence of vincristine (VCR), but reduced when VCR was combined with the CXCR4 antagonist AMD3100. Additionally, the supernatants of ALL-UCMSC co-cultures contained high CXCL12 concentrations, which were upregulated by VCR and significantly decreased by the combination of VCR plus AMD3100. Furthermore, the apoptosis rate of ALL cells significantly decreased, Bax expression was downregulated, and Bcl-2 was upregulated when ALL was co-cultured with UCMSCs compared with ALL cells alone. With the addition of VCR, the apoptosis rate mildly increased, Bax was upregulated, and Bcl-2 was downregulated. Nevertheless, the above results were further intensified, particularly Bax expression, when VCR was combined with AMD3100. Conclusion The CXCR4 antagonist could effectively reverse MSC-mediated drug resistance by blocking the CXCR4/CXCL12 axis and sensitizing leukemic cells from R/R ALL patients to chemotherapy drugs.

T cell acute lymphoblastic leukemia (T-ALL) was a malignant lymphoma. Therefore, the development of novel therapeutic agents against T-ALL is imperative. Previous studies have shown that chrysophanol (CHL), an anthraquinone compound isolated from the Rheum palmatum L., exerts anti-proliferative and anti-metastatic effects in multiple malignant tumors. However, the effect of CHL on the progression of TALL is poorly understood. The aim of this study was to explore the role of CHL in the biological behavior of T-ALL cells and determine its underlying mechanism. Both T-ALL cell lines (Jurkat and TALL-104) were treated with CHL. The proliferation, apoptosis, migration, and invasion of T-ALL cells were determined by CCK-8, flow cytometry, wound healing, and Transwell assay, respectively. Western blot and RT-qPCR were applied to examine gene expression. The dual-luciferase reporter gene assay was employed to examine the regulation mechanism of miR-9 and PD-L1. A T-ALL xenograft model also was used to examine the effect of CHL on the tumor growth and metastasis in vivo. CHL treatment significantly inhibited the proliferation, migration, and invasion ability of both Jurkat and TALL-104 cells and induced cell apoptosis and the expression of miR-9. Moreover, miR-9 was proved to target PD-L1 by binding to its 3'-untranslated region (UTR). Mechanically, pretreated with PD-L1 inhibitor could augment the anti-proliferation and anti-metastatic effect of CHL, while miR-9-silenced alleviated this effect. Consistent with in vitro studies, CHL significantly suppressed the growth and metastasis of tumor in vivo. Our finding uncovers the antitumorigenic effect of CHL in T-ALL progression through upregulating the expression of miR-9 and suppressing PD-L1 expression, which may provide a new potential strategy for T-ALL clinical treatment.

Objectives: This study investigated the therapeutic effects of combined recombinant human interferon-α-1b (IFN-α1b), thalidomide, and recombinant interleukin-2 (IL-2) in treating acute myeloid leukemia (AML) in patients of various disease status and vulnerabilities. Methods: Patients with AML (n = 166) were treated with combined recombinant IFN-α1b, thalidomide, and recombinant IL-2 (ITI regimen). The rates of partial and complete remission, minimal residual disease (MRD) status, quality of life, and long-term survival were compared among 3 patient groups. Lymphocyte profiles and relevant cytokine levels determined from peripheral blood samples of patients (pre- and post-treatment) and healthy individuals were compared. (Registration number: ChiCTR-ONC-14004688; Registered 23 May 2014, www.chictr.org.cn)Results: Sixty patients with primary AML who were unable to receive chemotherapy, or with relapsed/refractory AML, showed a total response rate of 30% after undergoing the ITI regime, and maintained a good quality of life. Eighteen patients with morphologically complete remission and consistently positive MRD achieved a response rate of 72.2%: the MRD converted to negative or was mitigated in 9 and 4 patients, respectively; 5 patients did not respond. For 88 patients with initial complete remission and negative MRD, 11 failed to maintain the negative MRD, and the relapse rate was 12.5%. The ITI regime was associated with substantial anti-leukemic changes in peripheral blood lymphocyte profiles and cytokine levels. Conclusions: The ITI regimen may be an effective and affordable option for patients with AML who cannot tolerate conventional chemotherapy, including those with relapsed/refractory disease, or complete remission status but MRD-positive, or after initial complete remission.

Background To investigate the value of dynamic monitoring peripheral blood lymphocyte-to-monocyte (LMR) ratio in evaluating the treatment response and prognosis of patients with extranodal NK/T cell lymphoma (ENKTL). Methods A total of 148 patients with ENKTL were retrospectively analyzed in the Affiliated Tumor Hospital of Zhengzhou University between March 2012 and March 2018. The optimal cut-off value of LMR was determined using the receiver operating characteristic curve (ROC) method, then patients were divided into low LMR group and high LMR group. The LMR level was dynamically measured at various time points, and the relationships between LMR and therapeutic response, and survival were analyzed. Results The complete remission rate (CR) was 85.7% in patients with high LMR at diagnosis, which was remarkably higher than that of patients with low LMR at diagnosis (64.9%) (P = 0.009). The 5-year overall survival (OS) and progression-free survival (PFS) were 49.28% and 44.89% in the low LMR group, respectively; 5-year OS and PFS in the high LMR group were 84.50% and 67.12%, respectively, significantly longer (P values were P values P values were 0.001 and 0.016, respectively). Univariate and multivariate analysis demonstrated that low LMR was an independent risk factor for poor prognosis in ENKTL patients (P values were Conclusions Lymphocyte to monocyte ratio can be used as an indicator of treatment response, prognosis and recurrence in patients with ENKTL. Low LMR before and after treatment is a poor prognostic factor.

Objective: Chimeric antigen receptor-modified T (CAR-T) cells have shown impressive results against relapsed/refractory B cell malignancies. However, the traditional manufacture of CAR-T cells requires leukapheresis to isolate large amounts of peripheral blood T cells, thus making some patients ineligible for the procedure. Methods: We developed a simple method for CAR-T cell preparation requiring small volumes of peripheral blood. First, CD3+ T cells isolated from 50 mL peripheral blood from patients (B-cell malignancies) were stimulated with immobilized anti-CD3/RetroNectin in 6-well plates and then transduced with CAR-expressing lentiviral vector. After 4 d, the T cells were transferred to culture bags for large-scale CAR-T cell expansion. In vitro and animal experiments were performed to evaluate the activity of the manufactured CAR-T cells. Finally, 29 patients with B-cell acute lymphoblastic leukemia (B-ALL) and 9 patients with B-cell lymphoma were treated with the CAR-T cells. Results: The CAR-T cells were expanded to 1–3 × 108 cells in 8–10 d and successfully killed B cell-derived malignant tumor cells in vitro and in vivo. For patients with B-ALL, the complete remission rate was 93% 1 month after CAR-T cell infusion; after 12 months, the overall survival (OS) and leukemia-free survival rates were 69% and 31%, respectively. For patients with lymphoma, the objective response rate (including complete and partial remission) was 78% 2 months after CAR-T cell infusion, and after 12 months, the OS and progression-free survival rates were 71% and 43%, respectively. Cytokine-release syndrome (CRS) occurred in 65.51% and 55.56% of patients with B-ALL and B-cell lymphoma, respectively; severe CRS developed in 20.69% of patients with B-ALL and in no patients with lymphoma. Conclusions: Our novel method can generate sufficient numbers of CAR-T cells for clinical use from 50–100 mL peripheral blood, thus providing an alternative means of CAR-T cell generation for patients ineligible for leukapheresis.

Background The TP53 aberration[both del(17p) and TP53 mutations], a high-risk prognostic factor in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), is closely related to drug-resistance, rapid disease progression, and short-term survival. Although novel agents, such as ibrutinib, idelalisib, as well as venetoclax, have shown good responses, allogenic hematopoietic stem cell transplantation (allo-HSCT) has been considered the only approach offered with curative intent.Case presentation We reported a case of young high-risk CLL/SLL patient with Ritcher’s transformation received ibrutinib plus CAR-T cells after the BCL-2 inhibitor venetoclax resistance, and then bridging to allo-HSCT when she had a complete remission (CR). Unfortunately, the patients died on day + 99 after transplantation due to intestinal grade IV acute graft-versus-host-disease (aGVHD) which could not be reversed by intensified immunosuppressive agents, including high-dose glucocorticoid, anti-CD25 monoclonal antibody basiliximab, and small-molecular inhibitors ruxolitinib, ibrutinib, as well as fecal microbiota transplantation (FMT).Conclusion TP53 aberrations in CLL/SLL patients are prone to large cell transformation, and have a poor prognosis, especially in venetoclax-resistant patients. Ibrutinib combined with CAR-T cells offered a treatment option, but whether bridging allo-HSCT following CAR-T cells increased severe aGVHD remained unclear.

Background： CT103A, a fully human BCMA-specific chimeric antigen receptor (CAR) T-cell therapy product showed excellent safety and promising efficacy in heavily pretreated relapsed and refractory multiple myeloma (RRMM) patients in our previous report [Blood. 2021; 137 (21): 2890-2901]. The unique CAR structure containing fully human single-chain variable fragments (scFvs) may bypass the potential host anti-CAR immunogenicity and retain antitumor activity. Here we reported the safety and efficacy results of 71 patients in 1.0×10 6 CAR+ T cells/kg cohort from the ongoing phase1/2 study (ChiCTR1800018137/ ChiCTR2000033946). Notably, it was the first time that prior BCMA CAR-T exposed patients were eligible to participate in an anti-BCMA CAR-T cell trial. Methods： This phase 1/2 study of CT103A is single-arm designed and is conducted in 13 centers in China. The study enrolled RRMM patients who had received ≥ 3 lines of prior therapies containing at least a proteasome inhibitor and an immunomodulatory agent and were refractory to their last line of treatment. 1.0 × 10 6 CAR+ T cells/Kg was previously identified as recommended phase 2 dose (RP2D). Lymphodepletion with fludarabine and cyclophosphamide was performed for three consecutive days. After 1-day rest, patients received CT103A. The primary objectives of this study were to assess the safety and efficacy of CT103A at RP2D. The cellular pharmacokinetic profile of CT103A in peripheral blood was investigated by measuring CAR transgene levels using droplet digital polymerase chain reaction (ddPCR) and CAR-T cells by flow cytometry. Minimal residual disease (MRD) negativity was evaluated in bone marrow aspirate by standardized Euroflow 8-color flow cytometry with a minimum sensitivity of 10 -5 nucleated cells. Immunogenicity was assessed by MSD-based antidrug antibody (ADA) assay. Results: As of the July 15, 2021, 71 patients [59.2% male; median age 58.0 years (range 41-71)] with RRMM received CT103A (9 in phase 1a; 17 in phase 1b; 45 in phase 2). The median follow-up time was 147 days (range 31 to 1029). The treated patients had received a median of 4 (range 3-13) lines of prior therapy. 28.2% and 18.3% were previously treated with auto-HSCT and anti-CD38 antibody respectively. Notably, 18.3% had previously received CAR-T therapy. What's more, 7% of the patients had the extramedullary disease at baseline, and 76.1% had high-risk cytogenetics. The most common ≥ grade 3 treatment-related AEs were hematological toxicities. 93.0% of the patients experienced CRS, among which only 2.8% were grade 3. All CRS cases were rapidly relieved after conventional CRS intervention, including tocilizumab and steroids. The median time to CRS onset was 6 days (range 1-12) with a median duration of 4 days (range 1-27). Only one (1.4%) patient experienced grade 2 ICANS which manifested as a transiently decreased level of consciousness and soon recovered without intervention. All 71 patients were evaluable for at least one month of efficacy assessment. The median time to first response was 15 days (range 11-124). A 94.4% ORR was observed, with 50.7% ≥ CR, 26.8% VGPR, and 16.9% PR. Among them, 50 patients who have completed follow-up of 3 months achieved 96.0% ORR, with 54.0% ≥ CR, 28% VGPR, and 14% PR. For 13 patients who have previously been treated with CAR-T therapy, ORR was 76.9%, with ≥ CR rate of 38.5%，VGPR of 15.4%, and PR of 23.1%. Of the 69 patients with evaluable bone marrow aspirate, 92.8% achieved MRD-negativity with a median time to MRD-negative of 17 days (range 13-180), and among them, 75.0% (95%CI 53.1-87.6%) achieved sustained MRD negativity over six months. The expansion of CT103A reached the peak at a median of 12 days (range 5 to 29). CT103A was still detectable in 88.5% (23/26) patients at 6 months and 87.5% (14/16) patients at 12 months after infusion. The first enrolled patient remains in sCR for 34 months with significant persistence of CT103A transgene. In addition, only 2 of 71 patients were detected positive for anti-drug antibody, which was reported to be a high-risk factor for disease relapse/progression after CAR-T therapy. Conclusion: The impressive efficacy of CT103A, including time to response, overall response rate, and durability, was corroborated by robust expansion and prolonged persistence of CT103A. The expansion and clinical benefits of CT103A did not seem to be influenced by prior murine BCMA CAR-T. Disclosures No relevant conflicts of interest to declare.

T cell acute lymphoblastic leukemia (T-ALL) was a malignant lymphoma. Therefore, the development of novel therapeutic agents against T-ALL is imperative. Previous studies have shown that chrysophanol (CHL), an anthraquinone compound isolated from the Rheum palmatum L., exerts anti-proliferative and anti-metastatic effects in multiple malignant tumors. However, the effect of CHL on the progression of TALL is poorly understood. The aim of this study was to explore the role of CHL in the biological behavior of T-ALL cells and determine its underlying mechanism. Both T-ALL cell lines (Jurkat and TALL-104) were treated with CHL. The proliferation, apoptosis, migration, and invasion of T-ALL cells were determined by CCK-8, flow cytometry, wound healing, and Transwell assay, respectively. Western blot and RT-qPCR were applied to examine gene expression. The dual-luciferase reporter gene assay was employed to examine the regulation mechanism of miR-9 and PD-L1. A T-ALL xenograft model also was used to examine the effect of CHL on the tumor growth and metastasis in vivo. CHL treatment significantly inhibited the proliferation, migration, and invasion ability of both Jurkat and TALL-104 cells and induced cell apoptosis and the expression of miR-9. Moreover, miR-9 was proved to target PD-L1 by binding to its 3'-untranslated region (UTR). Mechanically, pretreated with PD-L1 inhibitor could augment the anti-proliferation and anti-metastatic effect of CHL, while miR-9-silenced alleviated this effect. Consistent with in vitro studies, CHL significantly suppressed the growth and metastasis of tumor in vivo. Our finding uncovers the antitumorigenic effect of CHL in T-ALL progression through upregulating the expression of miR-9 and suppressing PD-L1 expression, which may provide a new potential strategy for T-ALL clinical treatment.

8025 Background: Relapsed/refractory (RR) multiple myeloma (MM), RRMM, remains as an incurable disease and has a 5-year survival rate of nearly 50%. To address the unmet medical need, an autologous CAR-T cell therapy was developed previously with a humanized single-domain antibody (sdAb) targeting BCMA as the antigen binding domain, 4-1BB and CD3ζ as cytoplasmic domain. Methods: An investigator-initiated clinical trial (IIT) was conducted in China to assess the safety and efficacy of the sdAb-based CAR-T. The trail was started in June 2018 and the last patient infused in June 2019. As of 1 February 2021, 34 were treated and followed up. The patients had received multiple lines of prior treatment (including bortezomib, lenalidomide, and others). Following a lymphodepleting regimen of cyclophosphamide (300-600 mg/m2, d-5, -4) and fludarabine (25-30 mg/m2, d-5 to d-3), patients were infused with 2.5-10.0 × 106 CAR+ cells/kg body weight. CAR-T was infused immediately after preparation and quality control performed in all patients except one, who was infused a 10.0 × 106 CAR+ cells/kg dose of frozen cells. Efficacy was assessed based on the IMWG criteria, toxicity was graded by CTCAE 4.02, and CRS grading was based on the grading system by CARTOX working group. Results: All 34 patients had the tumor burden of plasma cells in bone marrow, or M protein or free light chains (FLCs) in serum, 7 patients were accompanied with extramedullary diseases. The efficacy shows the best ORR is 88.2% (30/34), sCR rate is 55.9% (19/34). The mPFS was 12.1 months, several patients shows continuous sCR after 2 years. No obvious correlation between efficacy and dosage were found in three dose groups of 2.5×106 CAR+ cells/kg (6 pts), 5.0×106 CAR+ cells/kg (23 pts) or 10.0×106 CAR+ cells/kg (5 pts). The observed adverse events include thrombocytopenia (≥grade 3, 38.2%), neutropenia (≥grade 3, 44.1%), leukopenia (≥grade 3, 32.4%), lymphopeniPa (≥grade 3, 26.5%), and anemia (≥grade 3, 20.6%). CRS was monitored occurring in 29 patients (any grade, 85.3%, ≥grade 3, 2.9%). Conclusions: Our result demonstrates that the CART employing one humanized sdAb targeting BCMA is safe and efficacious for clinical application. The phase I clinical trial has been initiated in China for searching the RP2D using the cryopreserved CAR-T cells. Clinical trial information: NCT03661554.

T cell acute lymphoblastic leukemia (T-ALL) was a malignant lymphoma. Therefore, the development of novel therapeutic agents against T-ALL is imperative. Previous studies have shown that chrysophanol (CHL), an anthraquinone compound isolated from the Rheum palmatum L., exerts anti-proliferative and anti-metastatic effects in multiple malignant tumors. However, the effect of CHL on the progression of TALL is poorly understood. The aim of this study was to explore the role of CHL in the biological behavior of T-ALL cells and determine its underlying mechanism. Both T-ALL cell lines (Jurkat and TALL-104) were treated with CHL. The proliferation, apoptosis, migration, and invasion of T-ALL cells were determined by CCK-8, flow cytometry, wound healing, and Transwell assay, respectively. Western blot and RT-qPCR were applied to examine gene expression. The dual-luciferase reporter gene assay was employed to examine the regulation mechanism of miR-9 and PD-L1. A T-ALL xenograft model also was used to examine the effect of CHL on the tumor growth and metastasis in vivo. CHL treatment significantly inhibited the proliferation, migration, and invasion ability of both Jurkat and TALL-104 cells and induced cell apoptosis and the expression of miR-9. Moreover, miR-9 was proved to target PD-L1 by binding to its 3′-untranslated region (UTR). Mechanically, pretreated with PD-L1 inhibitor could augment the anti-proliferation and anti-metastatic effect of CHL, while miR-9-silenced alleviated this effect. Consistent with in vitro studies, CHL significantly suppressed the growth and metastasis of tumor in vivo. Our finding uncovers the antitumorigenic effect of CHL in T-ALL progression through upregulating the expression of miR-9 and suppressing PD-L1 expression, which may provide a new potential strategy for T-ALL clinical treatment.

Background & Aim The Chimeric antigen receptor T cells (CART) targeting BCMA has the promised effects to treat the relapsed/refractory (RR) multiple myeloma (MM), RRMM. We developed CART cells (CART-BCMA) using one single-domain antibody as the binding domain for BCMA. The anti-BCMA single-domain antibody was derived from the alpaca with the affinity of 1.14nM, then was humanized, and was used to construct the CAR molecule, which use the 4-1BB and CD3ζ intracellular regions as T cell activation domain. Methods, Results & Conclusion A single-arm clinical study was conducted to assess the safety and efficacy of CART-BCMA. The enrolled RRMM patients had received at least 3 lines of prior treatment. Patients were subjected to a lymphodepletion regimen with Cy (300-600 mg/m2, d-5, -4) and Flu (30 mg/m2, d-5 to d-3) before CART infusion at the dose of 2-10 × 106 CAR+ cells/kg (body weight). The efficacy was assessed based on the IMWG Criteria, and the toxicity was graded by CTCAE 4.02. As of November 30, 2019, 34 patients were infused with autologous CART-BCMA cells and had at least 5 months of follow-up. Many patients have M protein in serum, some patients have extramedullary diseases. The different dose shows a similar efficacy (Table 1), the best ORR is 88.2% (30/34), CR/sCR rate is 52.9% (18/34). Many patients showed no or grade 1/2 CRS, one patient showed the grade 3 CRS. Other ≥grade 3 adverse events (AE) include neutropenia (38.2%), leukopenia (29.4%), thrombocytopenia (38.2%), anemia (23.5%).Our result demonstrates the promising efficacy of anti-BCMA CAR-T using the humanized single domain antibody, and supports further development of this anti-RRMM cellular immunotherapy. Clinical trial information: NCT03661554.

With the domain of aero technics, aviation mental fatigue research has been aimed at preventing the tragedy caused by fatigue flights. There are specific effects of the mental fatigue on behavioral performance in pilots, characterized as a decrease of reaction rate and distractibility of attention. Fourteen subjects completed an experiment with visual search tasks and simulated flight task. The eye movement data were recorded by the eye tracker with 120 Hz of the sampling rate. The results of the questionnaire showed that the fatigue value in the fatigue periods was higher compared with the awake periods. Moreover, the results of eye movement features showed that the PERCLOS and blinking frequency amplitude increases monotonically with increasing fatigue value during the task. Lastly, the conclusion can be made that the measurement of eye movement pattern can be used to assess and forecast pilots mental fatigue status.

Background: Simultaneous multiple myeloma (MM) and pulmonary adenocarcinoma is a rare occurrence, and thus, treatment is a challenge. This study reports on 1 such case of MM with concurrent lung cancer, where an accurate diagnosis was made and the patient underwent treatment for both cancers. Case summary: A 68-year-old man presented with 2 months of progressive lower back pain. Visualization with magnetic resonance imaging (MRI) revealed multiple collapsed vertebrae from T12 to S3, as well as an altered signal intensity at the T3 vertebra. The patient was diagnosed with MM upon examination. A chest computed tomography (CT) scan revealed a round mass in the left lower lobe of the lungs, and a CT-guided needle biopsy uncovered a moderately differentiated adenocarcinoma. There were no additional notable findings in the left lung using positron emission tomography computed tomography (PET-CT). Therefore, a diagnosis of MM with pulmonary adenocarcinoma was made. Surgery was performed to excise the lung cancer. Bortezomib was used as first-line induction therapy against both tumors and lenalidomide was used for maintenance. The patient went into complete remission. Using this combined chemotherapy, the patient has survived for over 3 years since a diagnosis was made despite relapsing twice after the first year. Conclusion: This report clearly delineates the diagnosis and treatment of a rare case of synchronous MM and pulmonary adenocarcinoma, as well as depicts a potentially positive outcome for the patient. It also overviews some diagnostic and therapeutic implications for clinicians.

The Bruton’s tyrosine kinase inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of malignant B cells in CLL, are not fully characterized. Using next-generation sequencing technology, we characterized the diversity of TCRβ-chains in peripheral blood T cells from 15 CLL patients before and after 1 y of ibrutinib therapy. We noted elevated CD4+ and CD8+ T cell numbers and a restricted TCRβ repertoire in all pretreatment samples. After 1 y of ibrutinib therapy, elevated peripheral blood T cell numbers and T cell–related cytokine levels had normalized, and T cell repertoire diversity increased significantly. Dominant TCRβ clones in pretreatment samples declined or became undetectable, and the number of productive unique clones increased significantly during ibrutinib therapy, with the emergence of large numbers of low-frequency TCRβ clones. Importantly, broader TCR repertoire diversity was associated with clinical efficacy and lower rates of infections during ibrutinib therapy. These data demonstrate that ibrutinib therapy increases diversification of the T cell compartment in CLL patients, which contributes to cellular immune reconstitution.

Several chemotherapy regimens have been used as second-line therapies for relapsed and refractory diffuse large B-cell lymphoma (DLBCL). None have emerged as a preferred regimen. This retrospective study aimed to identify a regimen with high efficacy and low toxicity for patients with relapsed and refractory DLBCL. Fifty-eight patients diagnosed with relapsed or refractory DLBCL were included in the study. Patients were treated with cyclophosphamide, vindesine, cytarabine, dexamethasone and bleomycin (COAD-B). The overall response rate (ORR) was 70.7%, and the median remission duration was 13 months (3-48 months). The 1-, 2- and 4-year overall survival rates were 62.4%, 45.7% and 34.6%, respectively. The 1-, 2- and 4-year progression-free survival rates were 50.0%, 36.7% and 20.7%, respectively. The responses of patients with relapsed DLBCL to COAD-B were significantly better than those of patients with refractory DLBCL (p = 0.005). The main adverse reaction of patients was myelosuppression. Our data indicate that COAD-B should be used in treatment of patients with relapsed DLBCL.

Background Acute myeloid leukaemia (AML) is a malignancy derived from haematopoietic stem cells in which maturation and apoptosis are blocked and proliferation is uncontrolled during differentiation. With the optimization of chemotherapy regimens, the emergence of new drugs and the development of haematopoietic stem cell transplantation technology, the complete remission (CR) rate and long-term survival of AML patients have significantly improved, but 20-40% of patients still have difficulty achieving a CR. Furthermore, approximately 60% of patients eventually relapse after a CR. Patients who are unable to obtain a CR and who relapse after remission are more likely to develop refractory AML. For patients with refractory/relapsed AML, there is no standard rescue therapy, and general chemotherapy drugs have limited efficacy. It is of great significance to explore new salvage treatment options. Venetoclax (ABT-199) is an effective oral inhibitor of Bcl-2. ABT-199 has been used to treat various in vitro and in vivo tumour models, including AML models, and these experiments have shown its effectiveness as a single agent. However, its efficacy is very limited in refractory/relapsed AML, Mcl-1 play important roles in ABT-199 resistance. As an ancient pro-apoptotic drug, arsenic trioxide (ATO) has been shown to induce apoptosis in vivo and in vitro. ATO can downregulate the expression of Mcl-1, thereby inducing apoptosis. objective To explore not only the synergistic pro-apoptotic effects of the Bcl-2 inhibitor ABT-199 and ATO on AML cell lines and AML primary cells, but also the clinical effects on refractory/relapsing AML patients. Methods 1. Bcl-2 and Mcl-1 mRNA and protein levels in AML cell lines (MOLM13, MV4-11, THP-1, OCI-AML3, U937) were detected by real-time PCR and Western blot, respectively; 2.Apoptosis rates of AML cell lines after treatment with different concentrations of ABT-199 or ATO alone or in combination were measured by flow cytometry; 3. The transcriptomes of THP-1 and OCI-AML3 cells before and after treatment with ABT-199 or ATO alone or in combination were analysed; 4. Western blot, co-immunoprecipitation, cell cycle assay ABT-199, ATO effect on oci-AML3 cells; 5. ABT-199 combined with ATO in the treatment of patients with relapsed and refractory AML, the specific program is: ABT-199 100mg d1, 200mg d2, 400mg d3-28, oral 30 minutes after breakfast, ATO 6mg/m2, d1-28, daily intravenous infusion for 6 hours, review the effect of bone marrow aspiration on the 28th day. Results 1.MOLM13, MV4-11, THP-1, OCI-AML3 and U937 cells expressed both Bcl-2 and Mcl-1. The sensitivity of AML cell lines to ABT-199 was positively correlated with the Bcl-2 protein expression level; 2.In AML cell lines whether ABT-sensitive or ABT-resistant and primary AML cells, ABT-199 and ATO synergistically promoted apoptosis in a time- and concentration-dependent manner; 3. ABT-199 up-regulated the expression of Mcl-1 in ABT-resistant OCI-AML3 cells, ATO down-regulated the expression of p-AKT, p-GSK3β, and Mcl-1, and the expression of Mcl-1 decreased after the combination of the two drugs. Bim and Mcl-1 protein binding decreased after treatment OCI-AML3 cells with the combination of the two drugs for 24h; 4. ATO promotes DNA damage, and the effect is further enhanced when combinated with ABT-199; 5. A total of 7 patients with relapse were treated with ABT-ATO combined regimen. Four of the 7 patients had multiple relapses and 3 patients had short-term recurrence after remission, with an average age of 49 years. On the 28th day, the bone marrow was reviewed. Two of them achieved CRi, one case with Leukemia-free state (MLFS), two cases with PR, one case with SD, and one case with PD. Conclusion We demenstrated ATO could reverse AML resistance to ABT-199 and the synergistic effects of the combination of ATO and ABT-199, which may provide a new and probably more effective treatment strategy for refractory/relapsed AML . Key Words Bcl-2 inhibitor; ABT-199; arsenic trioxide; Mcl-1; AKT; apoptosis Disclosures No relevant conflicts of interest to declare.

The aim of the present study was to compare the efficacy of an L-asparaginase-based regimen and a CHOP regimen followed by radiotherapy as first-line treatments for newly diagnosed nasal type extranodal natural killer cell/T-cell lymphoma (ENKTL). A total of 69 patients received the CHOP regimen as the first-line treatment and 112 patients received the L-asparaginase-based regimen. All patients received radical radiotherapy following two cycles of chemotherapy. The overall response rates of the L-asparaginase-based and CHOP treatment groups were 90.18 and 72.46%, respectively (P=0.002). The one, two, and five-year overall survival (OS) rates and progression-free survival (PFS) rates of the L-asparaginase group were 96.0, 88.3, 65.1, 94.2, 79.8 and 50.0%, respectively. The one, two, and five-year OS and PFS rates of the CHOP group were 82.6, 61.9, 25.8, 63.8, 44.0 and 21.0%, respectively (P

To evaluate the value of grand glass opacity(GGO) on CT as a diagnostic sign of pulmonary fungal infection.The clinical data of 143 patients treated in department of hematology from January 2007 to June 2015 were analyzed retrospectively, and GGO or other attendant signs were observed.The cases of fungal infection secondary to acute leukemia(AL), myelodysplastic syndromes(MDS), non-Hodgkin's lymphoma(NHL), multiple myeloma(MM), Hodgkin's lymphoma(HL) were 83, 23, 18, 10, 9, respectively, including 23 patients with hematopoietic stem cell transplantation.Ninety percent(128/143) of patients with GGO changes was accompanied with the presence of neutropenia.GGO was mostly accompanied by funicular inflammatory infiltrating shadows or nodules.The cases of possible invasive pulmonary fungal infections(IPFI), probable IPFI, proven IPFI, undefined IPFI were 56, 15, 4, 26, respectively.The total effective cases after anti-fungal therapy was 92.Ground glass opacity as sign of pulmonary infection of CT mostly occurred in neutropenia and is more common in patients with acute leukemia or hematopoietic stem cell transplantation.GGO is a diagnostic sign of pulmonary fungal infection and it's indicating that anti-fungal medicine should be considered.

Chimeric antigen receptor T cells (CART) targeting CD19 have shown substantial activity against leukemia and lymphoma, which motivated developing CART cell therapy for Multiple myeloma (MM). B cell maturation antigen (BCMA) is the target molecule in MM. Several kinds of CART targeting BCMA have been created from 2016. Among these, the Bluebird Bio uses the humanized murine BCMA scFv to make CART, the Nanjing Legend company uses the single-domain antibody targeting BCMA to make CART. The single-domain antibody refers to the heavy chain antibody naturally present in camel species, which has no light chain. All VHh (Variable region of Heavy chain in heavy chain antibody) domains from the immunized alpaca were cloned into the phage-display library, then specific VHhs were screened out by solid-phase ELISA. Not like scFv using the linker region to connect the VH and VL to obtain the single chain region, the VHh itself is one single chain, which make it very suitable for making the recognition domain of CART. In order to increase the avidity, the Nanjing Legend company uses two tandem VHhs for binding BCMA. However, the single domain antibody has the capacity to bind the target molecule with very high affinity, one VHh should be able to bind BCMA tightly. To this aim, using our platform of single-domain antibody discovery and CART development, we successfully obtain the CART targeting BCMA (CART-BCMA) just using one VHh for recognizing the BCMA on tumor cells. Firstly, we immunized the alpaca using the extracellular domain of BCMA, then the B cell RNA were extracted, and the VHh phage-display library were constructed and screened. Finally we got the 6 single-domain antibodies through solid-phase ELISA screening. After gene sequencing and humanization of VHh, we constructed 6 lentiviral vectors with CAR gene including different VHh sequence connecting with CD8 hinge and transmembrane region, CD137 intracellular region, and CD3ζ intracellular region. We used 293T to package the lentivirus, and infected the healthy T cells to make 6 kinds of CART-BCMA cells. With in vitro killing assay, we found the #3 CART-BCMA is the best (83% killing rate at the E:T ratio of 4:1). Simultaneously, we used the Biocore to test the binding affinity of single-domain antibodies, the #3 antibody's affinity is 1.14nM, which indicated only one #3 VHh domain already have enough binding ability for CART to recognize the BCMA positive tumor cells. Next, we did further experiment to demonstrate the function of #3 CART-BCMA. We used the MM tumor cell line MM.1S (expressing high BCMA), myeloid tumor cell line K562 (no BCMA expression) as the target, the results show that CART-BCMA kill the MM.1S cells in 42% rate at the low E:T ratio of 0.5:1, but the CART-BCMA cells can't kill K562 cells even in high 4:1 E:T ratio. Accordingly, the cytokine level of IFN-γ or TNF-α is elevated dramatically in CART-BCMA wells. In animal experiment, the 1.5x106 MM.1S-Luc were injected into one NSG mouse. 40 mice were separated into 5 groups for PBS, 10x106 Mock T, 1.0x106 CART, 5.0x106 CART, 10x106 CART treatment. The results show that three CART groups of 1.0x106, 5.0x106, 10x106 CART are effective. Using the purified lentivirus, we found the lentivirus can infect the T cells at the MOI of 3, the CAR positive rate is over 50% by FACS, this implied that the CAR gene can be easily expressed on T cell membrane. For T cell infection, CAR-BCMA lentivirus need less amount compared to traditional CAR virus derived from scFv. We performed the clinical pilot study to investigate CART-BCMA's safety and effect on MM patients pre-conditioned with Fludarabine/cyclophosphamide. Until the time of abstract submission, 4 patients were enrolled, and got the dose of 5x106/kg (Pt1), dose of 10x106/kg (Pt2 and Pt3, split dose of 50% and 50% in two days), dose of 10x106/kg (Pt4) CART-BCMA cells. Pt1 has the CR response, and has the fever after 14 days. Pt2 has the PR response with no CRS. Pt3 has the PR response with grade 2 CRS. Pt4 has the PR response with grade 3 CRS and neurotoxicity (see table). In summary, we developed one CART-BCMA for MM treatment, which has the BCMA antigen recognition domain derived from the alpaca. Especially, the lentivirus carrying the CAR-BCMA gene can infect the T cells at the low MOI of 3, which will save the amount of lentivirus. The clinical pilot study showed that 4 patients received the CART-BCMA has the objective response (1 CR, 3 PR), further follow-up and enrollment is being performed. Table. Table. Disclosures Zhou: Health and Family Planning Commission of Henan Province: Patents & Royalties: Scientific and technological innovative talents "51282" Project leaders; Affiliated Cancer Hospital of Zhengzhou University: Employment; Natural Science Foundation of China: Research Funding; Henan Cancer Hospital: Consultancy, Employment. Zhang:The Shenzhen Pregene Biopharma Company, Ltd.: Employment. Du:The Shenzhen Pregene Biopharma Company, Ltd.: Employment. Li:The Shenzhen Pregene Biopharma Company, Ltd.: Employment.

This study examined the clinical efficacy and safety of thalidomide combined with interferons for the treatment of recurrent/refractory non-Hodgkin's lymphoma. We retrospectively analysed the clinical data of 42 patients with recurrent or refractory non-Hodgkin's lymphoma (NHL) who were treated with a regimen of thalidomide combined and interferon α-1b (IFNα-1b) at Henan Tumour Hospital from July 2007 to January 2017. Specifically, the patients initially received 100 mg thalidomide in tablet form once daily at bedtime. If the patient tolerated the drug, the dose was increased to 200 mg. Recombinant human interferon α-1b was subcutaneously injected at a dosage of 60 μg every other day over a period of four weeks. The efficacy was monitored throughout each treatment cycle, adverse reactions were evaluated, and the progress of the disease was assessed during follow-up visits. Relevant indicators, such as the overall response rate (ORR), the overall survival (OS), the progression-free survival (PFS) for all patients, and the safety of the regimen, were analysed. Forty-two patients were treated with a regimen of thalidomide combined with interferons for at least 1 period. The efficacy of the treatment was evaluated for each patient. The objective response rate (CR + PR) was 73.8%. The median overall survival time was 28 months and the median progression-free survival (PFS) time was 21 months. According to the standards of lymphoid malignancies classified by the WHO in 2001, 36 patients were diagnosed with B-cell lymphoma, 24 of whom suffered from recurrent or refractory mantle cell lymphoma (MCL). The combination of thalidomide and interferons improved the conditions of 16 MCL patients, 8 of whom experienced CR and 8 of whom experienced PR. The median OS was 28 months, and the median PFS was 19 months for the patients with MCL. The primary adverse effects of the regimen were drug-induced fever and joint pain caused by the IFN and neurotoxicity and constipation caused by the thalidomide. The adverse reactions ranged in severity from degree I~II and could be alleviated by symptomatic treatment. Serious adverse reactions, such as anaphylactic shock, deep vein thrombosis and bradycardia, did not occur. Disclosures No relevant conflicts of interest to declare.

To explore the clinical and survival significance of CD20 positive adult patients with B-lineage acute lymphoblastic leukemia (B-ALL).The clinical features and survival of 168 adult patients with B-ALL diagnosed and treated in our department from May 2007 to July 2011 were analyzed retrospectively, 58 expressed CD20 and 110 not.The sex, distribution of age, anemia, thrombocytopenia, infiltration of liver, spleen and lymph nodes, the expression of myeloid lineage marker, incidence of Ph chromosome, complete remission within 4 weeks showed no significant differences in CD20 positive and negative groups (P0.05); median white blood cell count at diagnosis and the rate of patients with high white blood cell count in CD20 positive group were 19.2×10⁹/L and 37.9% respectively, which were significantly higher than those of 6.93 × 10⁹/L and 20.9% in CD20 negative group (P0.05); cumulative incidence of relapse between two groups showed significant difference (P0.05); multivariable analysis for overall survival and progress-free survival identified CD20 positivity as independent predictor.The expression of CD20 in adult patients with B-ALL appeared to be associated with high white blood cell count and poor prognosis.

The purpose of this study is to explore the torque size of the joints of the ankle, knee, and hip under the static posture of car driving when an external force is exerted to the low limb joint. Twenty five anthropometric parameters of ten participants were sampled. The personalized digital model of ten participants was set up with sampled anthropometric data in the senior digital modeling of JACK. By simulating the driving posture and using the static strength prediction module of JACK, external force was imposed on front foot to calculate moment of low limb joint when the degree of ankle joint and knee joint was changed. The results indicated that the moment of knee joint and ankle joint produced by external force gradually decrease with the increase of ankle joint angle and the rate of decrease was faster and faster. The moment of hip joint gradually decreased with the increase of ankle joint angle and the decrease amplitude was uniform and linear trend. The moment of ankle joint monotonously increase with the increase of knee joint angle and the increase rate was slower and slower. The moment of knee joint first decreased and then increased with the increase of knee joint angle and the moment of knee was minimum when the angle of knee joint is 110°. The moment of hip joint gradually increased and made a linear increase with the increase of knee joint angle. The results calculated by JACK were compared to the data measured by Primus RS system and their results were consistent. Conclusions can be made from the result: the drivers can properly increase their ankle joint angle or decrease their knee joint angle, so as to reduce the low limb joints torque produced by external force imposed on foot because of braking; it is suggested that 108° to 113°of knee joint angle is the best.

BACKGROUND AND OBJECTIVE:T cell-mediated immunity plays an important role in enhancing antitumor response.This study aimed to investigate the changes in the T-lymphocyte subpopulation and to characterize the differential expression pattern of corresponding regulatory genes in peripheral blood mononuclear cells (PBMCs) from diffuse large B cell lymphoma (DLBCL) patients before and after chemotherapy. METHODS:A total of 56 DLBCL patients were recruited for analysis of T-cell subset distribution in the peripheral blood using flow cytometry; serum interferon (IFN)-γ and interleukin (IL)-4 levels using enzyme-linked immunosorbent assays; and early growth response protein 1 (EGR-1), T-bet, GATA-binding protein 3 (GATA-3), and transforming growth factor (TGF)-β mRNA levels using quantitative reverse-transcription polymerase chain reaction. Twenty-six healthy subjects served as controls. RESULTS:The percentage of CD3(+)CD4(+)T lymphocytes in peripheral blood from DLBCL patients was significantly decreased, whereas the percentages of CD3(+)CD8(+)T and CD4(+)CD25(+)T cells were significantly increased compared to those in controls (p < 0.05). Serum levels of IFN-γ and IL-4 were also significantly lower in DLBCL patients than those in controls (p < 0.05), and the levels of EGR-1, T-bet, and GATA-3 mRNA in PBMCs were lower (2.69 ± 1.48, 9.43 ± 2.14, and 20.83 ± 9.05 fold, respectively) in DLBCL patients than those in controls. Furthermore, there was a positive association between the levels of EGR-1 and T-bet mRNA (p = 0.001). However, the level of TGF-β mRNA was significantly increased in DLBCL patients, which was inversely associated with the T-bet mRNA level (p = 0.008), but positively associated with the percentage of T regulatory cells in PBMCs (p = 0.011). After three cycles of chemotherapy, the distribution of T-lymphocyte subsets in DLBCL patients were changed, and the levels of EGR-1, T-bet, and GATA-3 mRNA were significantly increased (p < 0.05) compared to those before chemotherapy. CONCLUSIONS:These results demonstrate the changes in T-lymphocyte subpopulations and the altered expression 34 pattern of the corresponding regulatory genes in PBMCs from DLBCL patients after chemotherapy, which are associated with the response of patients to treatment. The preferential expression of the T-bet gene after chemotherapy was closely correlated with the increased expression of the EGR-1 gene and decreased expression of the TGF-β gene.