Search

Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). With increasing approval of CAR T-cell products and advances in CAR T cell therapy, CAR T cells are expected to be used in a growing number of cases. However, CAR T-cell-associated toxicities can be severe or even fatal, thus compromising the survival benefit from this therapy. Standardizing and studying the clinical management of these toxicities are imperative. In contrast to other hematological malignancies, such as acute lymphoblastic leukemia and multiple myeloma, anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features, most notably local cytokine-release syndrome (CRS). However, previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL. Consequently, we developed this consensus for the prevention, recognition, and management of these toxicities, on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions. This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management, and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

Abstract In Northwestern China, more and more traditional cultivation system (TC) with no mulching and flood irrigation have been replaced by modern cultivation technology (MC) combining plastic film mulching with drip irrigation. Does plastic film mulching increase or reduce soil CO2 emission in arid areas? In order to study the effects of plastic mulching on soil CO2 efflux, a field study was conducted to compare soil CO2 concentration, soil CO2 efflux, soil temperature and moisture between the TC treatment and the MC treatment during a cotton growing season in Northwestern China. The seasonal patterns of soil profile temperature and soil moisture in the TC treatment were similar to that in the MC treatment. The mean value of soil profile temperature in the MC treatment was higher than that in the TC treatment. Except for soil moisture at 15 cm depth, the mean value of soil moisture at 5 cm and 10 cm depths in the MC treatment was higher than that in the TC treatment. The variation patterns of soil CO2 concentration and soil CO2 efflux in MC treatment were different to that in the TC treatment. Although the peak of soil CO2 concentration in the TC treatment was earlier than that in the MC treatment, the duration of soil CO2 concentration with high values in TC treatment was shorter than that in the MC treatment. Based on the model of Fick’s first diffusion law, soil surface CO2 efflux in the MC and TC treatments were determined. The surface CO2 efflux in the TC treatment calculated by Fick’s first diffusion law model was in good agreement with the value measured by chamber method. The seasonal curve of soil surface CO2 efflux in the MC treatment indicate the similar pattern with that in the TC treatment, and the rate of CO2 efflux was lower in the MC system. In the MC treatment, the seasonal variation of soil surface efflux was explained more by soil moisture than by soil temperature. However, in the TC treatment, the seasonal variation of soil surface efflux was explained more by soil temperature than by soil moisture. Over the completely experimental period, accumulated rates of soil CO2 efflux were 361 g C m−2 and 474 g C m−2 for the MC and TC system, respectively. We concluded that converting agricultural practices from traditional cultivation to the plastic mulching cultivation could reduce soil CO2 efflux by approximately 110 g C m−2 year−1 in agricultural land in arid areas of Northwestern China.

Abstract CD19-directed chimeric antigen receptor T cell (CART19) therapy is efficient and approved for relapsed/refractory diffuse large B cell lymphoma (DLBCL). To increase durable antitumor response, we previously designed tandem CART19/20 cells and shown longer progression-free survival. However, a proportion of CART19/20-treated patients will finally progress and require salvage therapies. In this study, we analyzed data from five patients with relapsed/refractory DLBCL who had disease progression or relapse following CART19/20 therapy and then treated with PD-1-blocking antibodies as salvage therapy. Two of five patients acquired complete remissions after anti-PD-1 therapy, including one patient remained ongoing remission for more than 21 months. One patient achieved a partial remission, and the other two had progressive diseases. No ≥ grade 3 treatment-related adverse events or cytokine release syndrome was observed. Immunohistochemistry of tumor specimens revealed higher PD-1/PD-L1 expression in responsive patients with anti-PD-1 therapy as compared to that in non-responders. After anti-PD-1 treatment, circulating T cells were activated in responders, and no significant expansion of CART19/20 cells was detected. Our data suggest that PD-1 blockade therapy can be active in patients with relapsed/refractory DLBCL after failure of CAR T cell therapy who had PD-L1 expression in tumor cells and high PD-1 level in tumor-infiltrated T cells.

Background Programmed death-1 (PD-1) blockade monotherapy induced durable remission in a subset of patients with relapsed/refractory classical Hodgkin lymphoma (cHL). We asked whether the anti-PD-1 agent, camrelizumab, combined with the DNA demethylating agent, decitabine, improves progression-free survival (PFS) in patients with relapsed/refractory cHL over camrelizumab alone.Methods This extended follow-up of an ongoing randomized phase II trial analyzed PFS among patients enrolled from January 2017 through July 2018. Sixty-one patients with relapsed/refractory cHL who were clinically naïve to PD-1 blockade and had received ≥2 previous therapies were randomized 1:2 to receive either camrelizumab (200 mg) monotherapy or camrelizumab (200 mg, day 8) combined with decitabine (10 mg/day, days 1–5) every 3 weeks.Results With a median follow-up of 34.5 months, complete remission was 79% (95% CI 63% to 90%) in the decitabine-plus-camrelizumab group versus 32% (95% CI 13% to 57%) in the camrelizumab group (p=0.001). Median duration of response was not reached in the decitabine-plus-camrelizumab group, with an estimated 63% (95% CI 46% to 75%) of patients maintaining a response at 24 months. Median PFS with decitabine-plus-camrelizumab therapy was 35.0 months (95% CI not reached) and 15.5 months (95% CI 8.4 to 22.7 months) with camrelizumab monotherapy (HR, 0.46; 95% CI 0.21 to 1.01; p=0.02). Female gender, lower tumor burden, and fewer previous therapies were favorable prognostic factors for durable remission with camrelizumab monotherapy. The PFS benefits of decitabine-plus-camrelizumab versus camrelizumab were observed in most subgroups, especially in patients with relative larger tumor burdens and those treated with ≥3 prior therapies. After decitabine-plus-camrelizumab treatment, the percentage increase of circulating peripheral central memory T-cells correlated with both improved clinical response and PFS, suggesting a putative biomarker of decitabine-plus-camrelizumab therapy for cHL.Conclusions Decitabine-plus-camrelizumab results in longer PFS compared with camrelizumab alone in patients with relapsed/refractory cHL.Trial registration numbers NCT02961101 and NCT03250962.

To study the effects of different guide vane numbers on the unsteady performance of pump as turbine based on the Navier–Stokes equation and standard k-epsilon turbulence model, computation fluid dynamics technology was used to simulate the flow field in pump as turbine. The turbulent kinetic energy, unsteady radial forces, and power losses were also clarified. The results show that for turbines with a guide vane, the distribution of turbulent kinetic energy is more uniform than before, and the radial force vector distribution is more symmetrical within four quadrants. The time-domain distribution of radial force is more periodic, the number of fluctuation periods is equal to the guide vane numbers, and the dominant frequency of the radial force is equal to the blade frequency. For different guide vane numbers, the effects on the unsteady performance of pump as turbine are different. When the guide vane number is equal to 9, the distribution of turbulence kinetic energy is optimal. In addition, at an optimal flow rate, both the time domains of the radial force and the power losses of the impeller are minimal, so to the geometric parameters of the hydraulic turbine are definite, the optimal guide vane number exists.

Pump as turbine is a device for energy conversion. To master the characteristics of energy transformation, especially within impeller, plays important roles for further optimum design of pump as turbine. In order to analyze the energy-changing features in detail using computational fluid dynamics, the impeller is divided into six regions by the radius. Under different operating conditions, the variations of power in the different radial cross-section of the impeller, the input net energy in different regions of the impeller, and the energy from the fluid to the impeller were demonstrated. The results show that the pressure energy of fluid is primary for impeller work, instead of the kinetic energy; the front and middle regions of the impeller (about the area of (0.6–1.0) D 2 ) are important parts for energy conversion; in the rear area of the impeller, it acquires little energy from fluid relatively, what’s more, the fluid not only does not work to impeller, but also consumes the impeller mechanical energy under the large flow conditions. So this research may point out the direction for optimization design of the impeller blade.

The engineering of T lymphocytes to express chimeric antigen receptors (CARs) aims to establish T cell-mediated tumor immunity rapidly. In this study, we conducted a pilot clinical trial of autologous or donor- derived T cells genetically modified to express a CAR targeting the B-cell antigen CD19 harboring 4-1BB and the CD3ζ moiety. All enrolled patients had relapsed or chemotherapy-refractory B-cell lineage acute lymphocytic leukemia (B-ALL). Of the nine patients, six had definite extramedullary involvement, and the rate of overall survival at 18 weeks was 56%. One of the two patients who received conditioning chemotherapy achieved a three-month durable complete response with partial regression of extramedullary lesions. Four of seven patients who did not receive conditioning chemotherapy achieved dramatic regression or a mixed response in the haematopoietic system and extramedullary tissues for two to nine months. Grade 2–3 graft-versus-host disease (GVHD) was observed in two patients who received substantial donor-derived anti-CD19 CART (chimeric antigen receptor-modified T) cells 3–4 weeks after cell infusions. These results show for the first time that donor-derived anti-CD19 CART cells can cause GVHD and regression of extramedullary B-ALL. This study is registered at www.clinicaltrials.gov as NCT01864889.

Aberrant DNA methylation is one of the main drivers of tumor initiation and progression. The reversibility of methylation modulation makes it an attractive target for novel anticancer therapies. Clinical studies have demonstrated that high-dose decitabine, a hypomethylating agent, results in some clinical benefits in patients with refractory advanced tumors; however, they are extremely toxic. Low doses of decitabine minimize toxicity while potentially improving the targeted effects of DNA hypomethylation. Based on these mechanisms, low-dose decitabine combined with chemoimmunotherapy may be a new treatment option for patients with refractory advanced tumors. We proposed the regimen of low-dose decitabine-based chemoimmunotherapy for patients with refractory advanced solid tumors. A favorable adverse event profile was observed in our trial that was highlighted by the finding that most of these adverse events were grades 1-2. Besides, the activity of our cohort was optimistic and the clinical benefit rate was up to 60%, and the median PFS was prolonged compared with PFS to previous treatment. We also identified a significant correlation between the PFS to previous treatment and clinical response. The low-dose DAC decitabine-based chemoimmunotherapy might be a promising protocol for improving the specificity and efficiency of patients with refractory advanced solid tumors. This trial is registered in the ClinicalTrials.gov database (identifier NCT01799083).