POLE2 knockdown suppresses lymphoma progression via downregulating Wnt/ß-catenin signaling pathway.

Lymphoma is the most common malignant tumor arising from immune system. Recently, DNA polymerase epsilon subunit 2 (POLE2) was identified to be a tumor promotor in a variety of malignant tumors. However, the biological role of POLE2 in lymphoma is still largely unclear. In our present study, the expression patterns of POLE2 in lymphoma tissues were identified by immunohistochemistry (IHC) staining of human tissue microarray. Cell viability was determined by CCK-8 assay. Cell apoptosis and cycle distribution were evaluated by Annexin V and PI staining, respectively. Cell migration was analyzed by transwell assay. Tumor growth in vivo was observed by a xenograft model of mice. The potential signaling was explored by human phospho-kinase array and immunoblotting. POLE2 was significantly upregulated in human lymphoma tissues and cells. POLE2 knockdown attenuated the proliferation, migration capabilities of lymphoma cells, as well as induced cell apoptosis and cycle arrest. Moreover, POLE2 depletion impaired the tumor growth in mice. Furthermore, POLE2 knockdown apparently inhibited the activation of ß-Catenin and downregulated the expression of Wnt/ß-Catenin signaling-related proteins. POLE2 knockdown suppressed the proliferation and migration of lymphoma cells by inhibiting Wnt/ß-Catenin signaling pathway. POLE2 may serve as a novel therapeutic target for lymphoma.

Surface-Grafted Single-Atomic Pt-Nx Complex with a Precisely Regulating Coordination Sphere for Efficient Electron Acceptor-Inducing Interfacial Electron Transfer.

Based on the electron-withdrawing effect of the Pt(bpy)Cl2 molecule, a simple post-modification amide reaction was firstly used to graft it onto the surface of NH2-MIL-125, which performed as a highly efficient electron acceptor that induced the conversion of the photoinduced charge migration pathway from internal BDC→TiOx migration to external BDC→PtNx migration, significantly improving the efficiency of photoinduced electron transfer and separation. Furthermore, precisely regulating over the first coordination sphere of Pt single atoms was achieved using further post-modification with additional bipyridine to investigate the effect of Pt-Nx coordination numbers on reaction activity. The as-synthesized NML-PtN2 exhibited superior photocatalytic hydrogen evolution activity of 7.608 mmol g-1 h-1, a remarkable improvement of 225 and 2.26 times compared to pristine NH2-MIL-125 and NML-PtN4, respectively. In addition, the superior apparent quantum yield of 4.01 % (390 nm) and turnover frequency of 190.3 h-1 (0.78 wt % Pt SA; 129 times compared to Pt nanoparticles/NML) revealed the high solar utilization efficiency and hydrogen evolution activity of the material. And macroscopic color changes caused by the transition of carrier migration paths was first observed. It holds profound significance for the design of MOF-Molecule catalysts with efficient charge carrier separation and precise regulation of single-atom coordination sphere.

Bruton tyrosine kinase inhibitors preserve anti-CD19 chimeric antigen receptor T-cell functionality and reprogram tumor micro-environment in B-cell lymphoma.

BACKGROUND AIMS: Combination therapy is being actively explored to improve the efficacy and safety of anti-CD19 chimeric antigen receptor T-cell (CART19) therapy, among which Bruton tyrosine kinase inhibitors (BTKIs) are highly expected. BTKIs may modulate T-cell function and remodel the tumor micro-environment (TME), but the exact mechanisms involved and the steps required to transform different BTKIs into clinical applications need further investigation. METHODS: We examined the impacts of BTKIs on T-cell and CART19 phenotype and functionality in vitro and further explored the mechanisms. We evaluated the efficacy and safety of CART19 concurrent with BTKIs in vitro and in vivo. Moreover, we investigated the effects of BTKIs on TME in a syngeneic lymphoma model. RESULTS: Here we identified that the three BTKIs, ibrutinib, zanubrutinib and orelabrutinib, attenuated CART19 exhaustion mediated by tonic signaling, T-cell receptor (TCR) activation and antigen stimulation. Mechanistically, BTKIs markedly suppressed CD3-ζ phosphorylation of both chimeric antigen receptor and TCR and downregulated the expression of genes associated with T-cell activation signaling pathways. Moreover, BTKIs decreased interleukin 6 and tumor necrosis factor alpha release in vitro and in vivo. In a syngeneic lymphoma model, BTKIs reprogrammed macrophages to the M1 subtype and polarized T helper (Th) cells toward the Th1 subtype. CONCLUSIONS: Our data revealed that BTKIs preserved T-cell and CART19 functionality under persistent antigen exposure and further demonstrated that BTKI administration was a potential strategy for mitigating cytokine release syndrome after CART19 treatment. Our study lays the experimental foundation for the rational application of BTKIs combined with CART19 in clinical practice.

IL-10 plus the EASIX score predict bleeding events after anti-CD19 CAR T-cell therapy.

Chimeric antigen receptor (CAR) T-cell-associated coagulopathy can cause bleeding events. To explore risk factors for hemorrhage after CAR T-cell therapy, we retrospectively analyzed routine indicators in 56 patients with non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia who received anti-CD19 CAR T-cell therapy. Disturbance of coagulation occurred mainly within one month post infusion, especially on day 7 and 14. The cumulative incidence of bleeding events within one month was 32.8%, with the median onset of 7 (range, 0-28) days. All bleeding events were grade 1-3. Patients who experienced bleeding events within one month had longer prothrombin time, higher IL-6, higher IL-10, and lower platelets before lymphodepletion. There were also correlations among coagulation-, inflammatory-, and tumor burden-related markers. Multi-variate analysis showed IL-10 (> 7.98 pg/mL; adjusted odds ratio [OR], 13.84; 95% confidence interval [CI], 2.03-94.36; P = 0.007) and the endothelial activation and stress index (EASIX, defined as dehydrogenase [U/L] × creatinine [mg/dL] / platelets [×109 cells/L]; >7.65; adjusted OR, 7.06; 95% CI, 1.03-48.23; P = 0.046) were significant risk factors for bleeding events. IL-10 plus the EASIX defined three risk groups for bleeding events with cumulative incidence of 100% (hazard ratio [HR], 14.47; 95% CI, 2.78-75.29; P < 0.0001), 38.5% (HR, 3.68; 95% CI, 0.82-16.67; P = 0.089), and 11.8% (reference), respectively. Future studies are needed to verify the risk assessment models for bleeding events after CAR T-cell treatment in larger cohorts.

Comparison Research on Characterization and Evaluation Approaches for Paint Coated Corrosion Using Eddy Current Pulsed Thermography.

Paint coated corrosion detection and evaluation is a big challenge for steel performance and structure health. Eddy current pulsed thermography (ECPT) technique is investigated because it can reflect the corrosion physical properties through paint coating by the infrared signal. This paper proposes skewness method, which presents the feature of temperature curve's shape automatically, and compares it with principal component analysis (PCA), phase analysis, and kurtosis feature extraction methods for paint coated corrosion characterization and evaluation. The averaged skewness shows the best sensitivity for 0-6 months corrosion. The normalized second principal component (PC) presents good sensitivity and the best measurement scale for corroded time. Furthermore, the temperature curve analysis proves that the electrical conductivity dominates the induced heating and heat distribution. The corrosion height is utilized to explain why ECPT technique is valid within 10 months corroded time. ECPT technique is proved as a smart sensor system for paint coated corrosion detection and characterization.

Adverse effects in hematologic malignancies treated with chimeric antigen receptor (CAR) T cell therapy: a systematic review and Meta-analysis.

BACKGROUND: Recently, chimeric antigen receptor-modified (CAR) T cell therapy for hematological malignancies has shown clinical efficacy. Hundreds of clinical trials have been registered and lots of studies have shown hematologic toxic effects were very common. The main purpose of this review is to systematically analyze hematologic toxicity in hematologic malignancies treated with CAR-T cell therapy. METHODS: We searched databases including PubMed, Web of Science, Embase and Cochrane up to January 2021. For safety analysis of overall hematologic toxicity, the rate of neutrophil, thrombocytopenia and anemia were calculated. Subgroup analysis was performed for age, pathological type, target antigen, co-stimulatory molecule, history of hematopoietic stem cell transplantation (HSCT) and prior therapy lines. The incidence rate of aspartate transferase (AST) increased, alanine transaminase (ALT) increased, serum creatine increased, APTT prolonged and fibrinogen decreased were also calculated. RESULTS: Overall, 52 studies involving 2004 patients were included in this meta-analysis. The incidence of any grade neutropenia, thrombocytopenia and anemia was 80% (95% CI: 68-89%), 61% (95% CI: 49-73%), and 68% (95%CI: 54-80%) respectively. The incidences of grade ≥ 3 neutropenia, thrombocytopenia and anemia were 60% (95% CI: 49-70%), 33% (95% CI: 27-40%), and 32% (95%CI: 25-40%) respectively. According to subgroup analysis and the corresponding Z test, hematological toxicity was more frequent in younger patients, in patients with ≥4 median lines of prior therapy and in anti-CD19 cases. The subgroup analysis of CD19 CAR-T cell constructs showed that 41BB resulted in less hematological toxicity than CD28. CONCLUSION: CAR-T cell therapy has dramatical efficacy in hematological malignancies, but the relevant adverse effects remain its obstacle. The most common ≥3 grade side effect is hematological toxicity, and some cases die from infections or severe hemorrhage in early period. In long-term follow-up, hematological toxicity is less life-threatening generally and most suffered patients recover to adequate levels after 3 months. To prevent life-threatening infections or bleeding events, clinicians should pay attention to intervention of hematological toxicity in the early process of CAR-T cell therapy.

Synthesis and Characterization of a Displacement-Type Ferroelectric-Ferroelectric Phase Transition Compound [(NH3)(CH2)3(NH3)]2[InBr6]Br·H2O.

Ferroelectric materials have aroused the researchers' great interest due to their wide applications. Here, a displacement-type ferroelectric-ferroelectric phase transition material [(NH3)(CH2)3(NH3)]2[InBr6]Br·H2O (1) with Tc = 143 K was successfully prepared. The ferroelectric phase transition is verified by the characterization techniques such as differential scanning calorimetry, single-crystal structure elucidation, dielectric and ferroelectric measurements. The single-crystal structure elucidation reveals that the displacement and distortion of [(NH3)(CH2)3(NH3)]2+ cations lead to the phase transition from Cmc21 to Pca21. The spontaneous polarizations at 293 and 133 K are 0.15 and 0.12 µC·cm-2, respectively. We expect that this work will help in further exploration of some new ferroelectric materials.

[Analysis of Response of IBS-SSS, AR, and IBS-QOL in IBS Clinical Effect Evaluation].

Objective To observe the response of common indices for clinical effect evaluation on irritable bowel syndrome (IBS), thereby providing reference for IBS related clinical indices in clinical trials of Chinese medicine (CM). Methods A randomized, double-blinded, placebo control trial was set up. Totally 58 diarrhea-predominant IBS (IBS-D) patients were randomly assigned to the test group (28 cases) and the control group (30 cases). Patients in the test group took Chang'an Recipe I (CR I), while those in the control group took CR I placebo. The therapeutic course for all was 8 weeks. Defeca- tion related symptoms was taken as significance in clinics. Principal component analysis was performed in symptoms index. IBS symptom severity score (IBS-SSS) and IBS quality of life (IBS-QOL) were taken as dependent variables. Main component value and the integral of hospital anxiety and depression scale a (HADa) and hospital anxiety and depression scale d (HADd) were taken as independent variables. Their linear correlation was analyzed. Adequate relief (AR) value was taken as dependent variable, while symptoms index was taken as independent variable. Their Logistic regression correlation was analyzed. Main component value A and B of symptoms index were taken as measurement index. A group with effi- cacy was selected from the test group or the control group, and response analyzed in patients of this group. Results There was statistical difference in main component value of A and B in the test group after treatment (P <0.05). So data of the test group were taken as referential standard, the responsibili- ties of IBS-SSS, AR, IBS-QOL were observed. (1) The score of IBS-SSS had a linear regression with defecation related symptoms and anxiety scores, and its responsibility was higher with an effect size of 1.59. (2) Response to each AR was linearly related to defecation related symptoms.(3) The score of IBS-QOL was not obviously correlated with defecation related symptoms, but with moderate response to anxiety state (an effect size of 0. 61). Domains of dysphoria and worries about health could reflect clinical changes with the effect size of 0. 50 and 0. 70 respectively. Conclusions IBS-SSS had better clinical response, which was suitable for IBS clinical effect evaluation. Response to each AR was related with defe- cation related symptoms. But attention should be paid to its clinical meaning. IBS-QOL had a moderate effect size. It was suggested to be used in long-term clinical research.

Inhibition of Potato Fusarium Wilt by Bacillus subtilis ZWZ-19 and Trichoderma asperellum PT-29: A Comparative Analysis of Non-Targeted Metabolomics.

Potato Fusarium Wilt is a soil-borne fungal disease that can seriously harm potatoes throughout their growth period and occurs at different degrees in major potato-producing areas in China. To reduce the use of chemical agents and improve the effect of biocontrol agents, the inhibitory effects of the fermentation broth of Bacillus subtilis ZWZ-19 (B) and Trichoderma asperellum PT-29 (T) on Fusarium oxysporum were compared under single-culture and co-culture conditions. Furthermore, metabolomic analysis of the fermentation broths was conducted. The results showed that the inhibitory effect of the co-culture fermentation broth with an inoculation ratio of 1:1 (B1T1) was better than that of the separately cultured fermentation broths and had the best control effect in a potted experiment. Using LC-MS analysis, 134 metabolites were determined and classified into different types of amino acids. Furthermore, 10 metabolic pathways had the most significant variations, and 12 were related to amino acid metabolism in the KEGG analysis. A correlation analysis of the 79 differential metabolites generated through the comprehensive comparison between B, T, and B1T1 was conducted, and the results showed that highly abundant amino acids in B1T1 were correlated with amino acids in B, but not in T.

Bispecific CS1-BCMA CAR-T cells are clinically active in relapsed or refractory multiple myeloma.

Multiple myeloma (MM) bears heterogeneous cells that poses a challenge for single-target immunotherapies. Here we constructed bispecific CS1-BCMA CAR-T cells aiming to augment BCMA targeting with CS1. Sixteen patients with relapsed or refractory (RR) MM received CS1-BCMA CAR-T infusion. Six patients (38%) had cytokine release syndrome, which was of grade 1-2 in 31%. No neurological toxicities were observed. The most common severe adverse events were hematological, including leukopenia (100%), neutropenia (94%), lymphopenia (100%) and thrombocytopenia (31%). Three patients with solitary extramedullary disease (sEMD) did not respond. At a median follow-up of 246 days, 13 patients (81%) had an overall response and attained minimal residual disease-negativity, and six (38%) reached a stringent complete response (sCR). Among the 13 responders, 1-year overall survival and progression-free survival were 72.73% and 56.26%, respectively. Four patients maintained sCR with a median duration of 17 months. Four patients experienced BCMA+ and CS1+ relapse or progression. One patient responded after anti-BCMA CAR-T treatment failure. Lenalidomide maintenance after CAR-T infusion and the resistance mechanism of sEMD were preliminarily explored in three patients. CAR-T cells persisted at a median of 406 days. Soluble BCMA could serve as an ideal biomarker for efficacy monitoring. CS1-BCMA CAR-T cells were clinically active with good safety profiles in patients with RRMM. Clinical trial registration: This study was registered on ClinicalTrials.gov, number NCT04662099.

Targeting autophagy overcomes cancer-intrinsic resistance to CAR-T immunotherapy in B-cell malignancies.

BACKGROUND: Chimeric antigen receptor T (CAR-T) therapy has substantially revolutionized the clinical outcomes of patients with hematologic malignancies, but the cancer-intrinsic mechanisms underlying resistance to CAR-T cells remain yet to be fully understood. This study aims to explore the molecular determinants of cancer cell sensitivity to CAR-T cell-mediated killing and to provide a better understanding of the underlying mechanisms and potential modulation to improve clinical efficacy. METHODS: The human whole-genome CRISPR/Cas9-based knockout screening was conducted to identify key genes that enable cancer cells to evade CD19 CAR-T-cell-mediated killing. The in vitro cytotoxicity assays and evaluation of tumor tissue and bone marrow specimens were further conducted to confirm the role of the key genes in cancer cell susceptibility to CAR-T cells. In addition, the specific mechanisms influencing CAR-T cell-mediated cancer clearance were elucidated in mouse and cellular models. RESULTS: The CRISPR/Cas9-based knockout screening showed that the enrichment of autophagy-related genes (ATG3, BECN1, and RB1CC1) provided protection of cancer cells from CD19 CAR-T cell-mediated cytotoxicity. These findings were further validated by in vitro cytotoxicity assays in cells with genetic and pharmacological inhibition of autophagy. Notably, higher expression of the three autophagy-related proteins in tumor samples was correlated with poorer responsiveness and worse survival in patients with relapsed/refractory B-cell lymphoma after CD19 CAR-T therapy. Bulk RNA sequencing analysis of bone marrow samples from B-cell leukemia patients also suggested the clinical relevance of autophagy to the therapeutic response and relapse after CD19 CAR-T cell therapy. Pharmacological inhibition of autophagy and knockout of RB1CC1 could dramatically sensitize tumor cells to CD19 CAR-T cell-mediated killing in mouse models of both B-cell leukemia and lymphoma. Moreover, our study revealed that cancer-intrinsic autophagy mediates evasion of CAR-T cells via the TNF-α-TNFR1 axis-mediated apoptosis and STAT1/IRF1-induced chemokine signaling activation. CONCLUSIONS: These findings confirm that autophagy signaling in B-cell malignancies is essential for the effective cytotoxic function of CAR-T cells and thereby pave the way for the development of autophagy-targeting strategies to improve the clinical efficacy of CAR-T cell immunotherapy.

[Intervention of chronic hepatitis B liver fibrosis patients in different stages by syndrome typing and different activating blood removing stasis methods: a clinical study].

OBJECTIVE: To observe the clinical efficacy of treating chronic hepatitis B liver fibrosis (CHBLF) in different stages by syndrome typing and different activating blood removing stasis methods (ABRSM). METHODS: Totally 100 CHBLF patients of vital qi deficiency blood stasis syndrome (VQDBSS) treated at the Department of Liver Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences from July 2008 to December 2011, were randomly assigned to the treatment group and the control group, 50 in each group. Those in the treatment group were treated by self-formulated decoctions for activating blood nourishing blood (ABNB), activating blood removing stasis (ABRS), and activating blood softening hard mass (ABSHM) according to their stages of disease conditions (mild, moderate, and severe). Those in the control group were treated with Compound Biejia Ruangan Tablet (CBRT). Integrals of Chinese medical syndromes, liver functions [mainly including alanine aminotransferase (ALT), albumin/globulin (A/ G)], ultrasonographic examinations of liver (mainly including echoes of liver, width of spleens, width of portal vein), four indicators of serum hepatic fibrosis [including serum hyaluronic acid (HA), laminin (LN), type IV collagen (IV-C), type III collagen peptide (P-III-P)] were statistically analyzed. The therapeutic course was 6 months for all. RESULTS: Compared with before treatment in the same group, the integrals of Chinese medical syndromes both decreased after treatment in the two groups (P < 0.05). The width of spleens decreased in the treatment group more obviously after treatment than before treatment (P < 0.05). Compared with the control group, the integrals of Chinese medical syndromes and the width of spleens were more obviously improved in the treatment group, showing statistical difference (P < 0.05). Compared with before treatment in the same group, levels of ALT, HA, and LN significantly decreased, and the level of A/G significantly increased after treatment in the two groups, showing statistical difference (P < 0.05). Compared with the control group, the A/G level, HA, and LN were more obviously improved in the treatment group, showing statistical difference (P < 0.05). The total effective rate was 76% in the treatment group and 46% in the control group, showing statistical difference (P < 0.05). CONCLUSIONS: Treating CH-BLF in different stages by ABRSM got better effect than using CBRT alone. It could favorably improve clinical symptoms of CHBLF patients and their serum biochemical indicators.

[Effect of ronggan mixture on immunoregulation and hepatocyte apoptosis-related factors in concanavalin A induced acute immunological liver injury mice].

OBJECTIVE: To explore the effect of Ronggan Mixture (RM) on immunoregulation and hepatocyte apoptosis-related factors in concanavalin A (Con A) induced acute immunological liver injury mice. METHODS: Totally 60 hepatitis B virus (HBV) transgenic mice were randomly divided into 6 groups, i.e., the blank control group, the model group, the RM group, the Herba Artemisiae Scopariae (HAS) group, the Yinchenhao Decoction (YD) group, and the Bifendate group, 10 mice in each group. The acute immunological liver injury model was established by tail vein injection of ConA. Fourteen days before modeling, normal saline was administered to mice in the blank control group and the model group. RM, YD, HAS decoction, and Bifendate solution was respectively given to mice in the RM group, the YD group, the HAS group, and the Bifendate group. The medication was performed once daily. One h after the last gastrogavage, phosphate buffer solution (PBS) was injected to mice in the blank control group from the tail vein. Modeling was conducted by injecting Con A at 3 microg/g body weight from the tail vein. Mice were sacrificed 8 h after modeling. Blood or tissue samples were collected to detect lab indicators such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), tumor necrosis factor alpha (TNF-alpha), interferon gamma (INF-gamma), IL-4, IL-10, Fas, FasL, Bax, and bcl-2. RESULTS: There was significant difference in all lab indicators between the normal group and the blank control group (P < 0.05, P < 0.01). Compared with the model group, ALT and AST levels were significantly lower in the RM group and the Bifendate group (P < 0.01); TBil significantly decreased in the RM group (P < 0.01). The expression level of TNF-alpha decreased in the RM group (P <0.05). The expression level of IFN-gamma decreased in the RM group and the YD group (P < 0.05). The expression level of IL-4 could be elevated in all medicated groups (P < 0.05). RM could elevate the expression level of IL-10 (P < 0.05). The expression level of Fas in the liver tissue decreased in the RM group and the YD group (P < 0.05). The expression level of FasL decreased and the expression of bcl-2 gene increased in the RM group (both P < 0.05). The expression level of Bax was down-regulated in the RM group and the YD group (P < 0.05). The ratio of bcl-2/Bax was up-regulated in the RM group (P < 0.05). Meanwhile, RM showed better effect in decreasing expressions of ALT and AST than HAS (P < 0.05). The effect of increasing IL-10 expression levels was better in the RM group than in the YD group (P < 0.01). The effect of decreasing expressions of Fas and FasL was better in the RM group than in the HAS group, the YD group, and the Bifendate group (P < 0.05). The effect of enhancing the expression of IL-10 in the liver tissue was better in the RM group than in the HAS group (P < 0. 05). CONCLUSION: RM had protective effect on Con A induced acute immunological liver injury mice, which might be achieved by changing the immunological balance of Thl/Th2 factors (decreasing expressions of TNF-alpha and IFN-gamma, elevating expressions of IL-10 and IL-4) and regulating hepatocyte apoptosis-related factors (down-regulating gene expressions of Fas, FasL, and Bax; up-regulating bcl-2 gene expression, and up-regulating the bcl-2/Bax ratio).

A Theory-based Deep-Learning Approach to Detecting Disinformation in Financial Social Media.

The spreading of disinformation in social media threatens cybersecurity and undermines market efficiency. Detecting disinformation is challenging due to large volumes of social media content and a rapidly changing environment. This research developed and validated a theory-based, novel deep-learning approach (called TRNN) to disinformation detection. Grounded in social and psychological theories, TRNN uses deep-learning and data-centric augmentation to enhance disinformation detection in financial social media. Temporal and contextual information is encoded as specific knowledge about human-validated disinformation, which was identified from our unique collection of 745,139 financial social media messages about four U.S. high-tech company stocks and their fine-grained trading data. TRNN uses multiple series of long short-term memory (LSTM) recurrent neurons to learn dynamic and hidden patterns to support disinformation detection. Our experimental findings show that TRNN significantly outperformed widely-used machine learning techniques in terms of precision, recall, F-score and accuracy, achieving consistently better classification performance in disinformation detection. A case study of Apple Inc.'s stock price movement demonstrates the potential usability of TRNN for secure knowledge management. The research contributes to developing novel approach and model, producing new information systems artifacts and dataset, and providing empirical findings of detecting online disinformation.

Allogenic and autologous anti-CD7 CAR-T cell therapies in relapsed or refractory T-cell malignancies.

Chimeric antigen receptor-T (CAR-T) therapy remains to be investigated in T-cell malignancies. CD7 is an ideal target for T-cell malignancies but is also expressed on normal T cells, which may cause CAR-T cell fratricide. Donor-derived anti-CD7 CAR-T cells using endoplasmic reticulum retention have shown efficacy in patients with T-cell acute lymphoblastic leukemia (ALL). Here we launched a phase I trial to explore differences between autologous and allogeneic anti-CD7 CAR-T therapies in T-cell ALL and lymphoma. Ten patients were treated and 5 received autologous CAR-T therapies. No dose-limiting toxicity or neurotoxicity was observed. Grade 1-2 cytokine release syndrome occurred in 7 patients, and grade 3 in 1 patient. Grade 1-2 graft-versus-host diseases were observed in 2 patients. Seven patients had bone marrow infiltration, and 100% of them achieved complete remission with negative minimal residual disease within one month. Two-fifths of patients achieved extramedullary or extranodular remission. The median follow-up was 6 (range, 2.7-14) months and bridging transplantation was not administrated. Patients treated with allogeneic CAR-T cells had higher remission rate, less recurrence and more durable CAR-T survival than those receiving autologous products. Allogeneic CAR-T cells appeared to be a better option for patients with T-cell malignancies.

Novel CD19-specific γ/δ TCR-T cells in relapsed or refractory diffuse large B-cell lymphoma.

BACKGROUND: T cell receptor (TCR)-T cells possess similar effector function, but milder and more durable signal activation compared with chimeric antigen receptor-T cells. TCR-T cell therapy is another active field of cellular immunotherapy for cancer. METHODS: We previously developed a human anti-CD19 antibody (ET190L1) and generated novel CD19-specific γ/δ TCR-T cells, ET019003, by fusing the Fab fragment of ET190L1 with γ/δ TCR constant chain plus adding an ET190L1-scFv/CD28 co-stimulatory molecule. ET019003 cells were tested in preclinical studies followed by a phase 1 clinical trial. RESULTS: ET019003 cells produced less cytokines but retained comparable antitumor potency than ET190L1-CAR-T cells in vivo and in vitro. In the first-in-human trial, eight patients with relapsed or refractory DLBCL were treated. CRS of grade 1 was observed in three (37.5%) patients; ICANS of grade 3 was noted in one (12.5%) patient. Elevation of serum cytokines after ET019003 infusion was almost modest. With a median follow-up of 34 (range 6-38) months, seven (87.5%) patients attained clinical responses and six (75%) achieved complete responses (CR). OS, PFS and DOR at 3 years were 75.0%, 62.5%, and 71.4%, respectively. Notably, patient 1 with primary CNS lymphoma did not experience CRS or ICANS and got an ongoing CR for over 3 years after infusion, with detectable ET019003 cells in CSF. ET019003 showed striking in vivo expansion and persisted in 50% of patients at 12 months. Three patients received a second infusion, one for consolidation therapy after CR and two for salvage therapy after disease progression, but no response was observed. ET019003 expansion was striking in the first infusion, but poor in the second infusion. CONCLUSIONS: CD19-specific γ/δ TCR-T cells, ET019003, had a good safety profile and could induce rapid responses and durable CR in patients with relapsed or refractory DLBCL, even primary CNS lymphoma, presenting a novel and potent therapeutic option for these patients. TRIAL REGISTRATION: NCT04014894.

Timing of Tocilizumab Administration Under the Guidance of IL-6 in CAR-T Therapy for R/R Acute Lymphoblastic Leukemia.

Chimeric antigen receptor T (CAR-T) cells targeting CD19 have achieved great clinical responses in patients with relapsed or refractory (R/R) acute B lymphoblastic leukemia. However, severe adverse events such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome restrict it to further application. Tocilizumab is the corner stone for the treatment of severe CRS. It has been used to treat mild CRS in recent years, whereas some statistical supports clarifying the suitable timing of its administration are lacking. Sixty-seven patients with B-cell acute lymphoblastic leukemia (B-ALL) were treated with CD19-CART and enrolled in the study, of which 33 patients received Tocilizumab. Application of Tocilizumab in patients with grade 2 CRS in American Society for Transplantation and Cellular Therapy (ASTCT) criteria can significantly shorten the duration of CRS without affecting side effects and long-term efficacy. However, a number of patients still developed severe CRS with early use of Tocilizumab, indicating the significance of the introduction of clinical laboratories to assist medications. Statistically, patients with less than fourfold increase in IL-6 levels had a higher incidence of severe CRS after receiving Tocilizumab (37.5% versus. 0%, p=0.0125), which provided a basis for refining CRS intervention strategies under the guidance of IL-6. Clinical Trial Registration: www.clinicaltrials.gov, NCT02965092 and NCT04008251.

Two In-based organic-inorganic hybrid compounds with reversible phase transition derived from the order-disorder changes of cations or anions.

Solid-state phase transition materials have received extraordinary interest due to their rich physical properties, such as thermal, dielectric, and ferroelectric properties. Here, two In-based organic-inorganic hybrid compounds, (C6H5CH2CH2NH3)3[InBr5(H2O)] (1) and [(C3H7)4N][InCl4] (2), both display reversible phase transition and dielectric response. Differential scanning calorimetry measurements indicate that the phase transition temperatures (Tc) of 1 and 2 are 167 K and 351 K, respectively. Moreover, structural analyses disclose that the phase transition of 1 can be attributed to the order-disorder changes of phenethylammonium organic cations whereas the phase transition of 2 is caused by the order-disorder changes of [InCl4]- anions. The phase transitions of In-based organic-inorganic hybrid compounds can be driven by the order-disorder changes of cations or anions. Therefore, the system of In-based organic-inorganic hybrid compounds is very suitable for exploring organic-inorganic hybrid phase transition materials.

T Cell Exhaustion and CAR-T Immunotherapy in Hematological Malignancies.

T cell exhaustion has been recognized to play an immunosuppressive role in malignant diseases. Persistent tumor antigen stimulation, the presence of inhibitory immune cells and cytokines in tumor microenvironment (TME), upregulated expression of inhibitory receptors, changes in T cell-related transcription factors, and metabolic factors can all result in T cell exhaustion. Strategies dedicated to preventing or reversing T cell exhaustion are required to reduce the morbidity from cancer and enhance the effectiveness of adoptive cellular immunotherapy. Here, we summarize the current findings of T cell exhaustion in hematological malignancies and chimeric antigen receptor T (CAR-T) immunotherapy, as well as the value of novel technologies, to inverse such dysfunction. Our emerging understanding of T cell exhaustion may be utilized to develop personalized strategies to restore antitumor immunity.

Identification and Validation of a Novel Immune-Related Four-lncRNA Signature for Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is a major subtype of lung cancer, the prognosis of patients with which is associated with both lncRNAs and cancer immunity. In this study, we collected gene expression data of 585 LUAD patients from The Cancer Genome Atlas (TCGA) database and 605 subjects from the Gene Expression Omnibus (GEO) database. LUAD patients were divided into high and low immune-cell-infiltrated groups according to the single sample gene set enrichment analysis (ssGSEA) algorithm to identify differentially expressed genes (DEGs). Based on the 49 immune-related DE lncRNAs, a four-lncRNA prognostic signature was constructed by applying least absolute shrinkage and selection operator (LASSO) regression, univariate Cox regression, and stepwise multivariate Cox regression in sequence. Kaplan-Meier curve, ROC analysis, and the testing GEO datasets verified the effectiveness of the signature in predicting overall survival (OS). Univariate Cox regression and multivariate Cox regression suggested that the signature was an independent prognostic factor. The correlation analysis revealed that the infiltration immune cell subtypes were related to these lncRNAs.