In Situ Flash Synthesis of Ultra-High-Performance Metal Oxide Anode through Shunting Current-Based Electrothermal Shock.

The synthesis of anode materials plays an important role in determining the production efficiency, cost, and performance of lithium-ion batteries (LIBs). However, a low-cost, high-speed, scalable manufacturing process of the anode with the desired structural feature for practical technology adoption remains elusive. In this study, we propose a novel method called in situ flash shunt-electrothermal shock (SETS) which is controllable, fast, and energy-saving for synthesizing metal oxide-based materials. By using the example of direct electrothermal decomposition of ZIF-67 precursor loaded onto copper foil support, we achieve rapid (0.1-0.3 s) pyrolysis and generate porous hollow cubic structure material consisting of carbon-coated ultrasmall (10-15 nm) subcrystalline CoO/Co nanoparticles with controllable morphology. It was shown that CoO/Co@N-C exhibits prominent electrochemical performance with a high reversible capacity up to 1503.7 mA h g-1 after 150 cycles at 0.2 A g-1and stable capacities up to 434.1 mA h g-1 after 400 cycles at a high current density of 6 A g-1. This fabrication technique integrates the synthesis of active materials and the formation of electrode sheets into one process, thus simplifying the preparation of electrodes. Due to the simplicity and scalability of this process, it can be envisaged to apply it to the synthesis of metal oxide-based materials and to achieve large-scale production in a nanomanufacturing process.

Preclinical optimization of a GPC2-targeting CAR T-cell therapy for neuroblastoma.

BACKGROUND: Although most patients with newly diagnosed high-risk neuroblastoma (NB) achieve remission after initial therapy, more than 50% experience late relapses caused by minimal residual disease (MRD) and succumb to their cancer. Therapeutic strategies to target MRD may benefit these children. We developed a new chimeric antigen receptor (CAR) targeting glypican-2 (GPC2) and conducted iterative preclinical engineering of the CAR structure to maximize its anti-tumor efficacy before clinical translation. METHODS: We evaluated different GPC2-CAR constructs by measuring the CAR activity in vitro. NOD-SCID mice engrafted orthotopically with human NB cell lines or patient-derived xenografts and treated with human CAR T cells served as in vivo models. Mechanistic studies were performed using single-cell RNA-sequencing. RESULTS: Applying stringent in vitro assays and orthotopic in vivo NB models, we demonstrated that our single-chain variable fragment, CT3, integrated into a CAR vector with a CD28 hinge, CD28 transmembrane, and 4-1BB co-stimulatory domain (CT3.28H.BBζ) elicits the best preclinical anti-NB activity compared with other tested CAR constructs. This enhanced activity was associated with an enrichment of CD8+ effector T cells in the tumor-microenvironment and upregulation of several effector molecules such as GNLY, GZMB, ZNF683, and HMGN2. Finally, we also showed that the CT3.28H.BBζ CAR we developed was more potent than a recently clinically tested GD2-targeted CAR to control NB growth in vivo. CONCLUSION: Given the robust preclinical activity of CT3.28H.BBζ, these results form a promising basis for further clinical testing in children with NB.

Murine allogeneic CAR T cells integrated before or early after posttransplant cyclophosphamide exert antitumor effects.

Relapse limits the therapeutic efficacy both of chimeric antigen receptor (CAR) T cells and allogeneic hematopoietic cell transplantation (allo-HCT). Patients may undergo these therapies sequentially to prevent or treat relapsed malignancy. However, direct integration of the 2 therapies has been avoided over concerns for potential induction of graft-versus-host disease (GVHD) by allogeneic CAR T cells. We have shown in murine T-cell-replete MHC-haploidentical allo-HCT that suppressive mechanisms induced immediately after posttransplant cyclophosphamide (PTCy), given on days +3/+4, prevent GVHD induction by alloreactive T cells infused as early as day +5. Therefore, we hypothesized that allogeneic CAR T cells given in a similarly integrated manner in our murine MHC-haploidentical allo-HCT model may safely exert antitumor effects. Indeed, allogeneic anti-CD19 CAR T cells given early after (day +5) PTCy or even prior to (day 0) PTCy cleared leukemia without exacerbating the cytokine release syndrome occurring from the MHC-haploidentical allo-HCT or interfering with PTCy-mediated GVHD prevention. Meanwhile, CAR T-cell treatment on day +9 or day +14 was safe but less effective, suggesting a limited therapeutic window. CAR T cells infused before PTCy were not eliminated, but surviving CAR T cells continued to proliferate highly and expand despite PTCy. In comparison with infusion on day +5, CAR T-cell infusion on day 0 demonstrated superior clinical efficacy associated with earlier CAR T-cell expansion, higher phenotypic CAR T-cell activation, less CD4+CD25+Foxp3+ CAR T-cell recovery, and transcriptional changes suggesting increased activation of CD4+ CAR T cells and more cytotoxic CD8+ CAR T cells. This study provides mechanistic insight into PTCy's impact on graft-versus-tumor immunity and describes novel approaches to integrate CAR T cells and allo-HCT that may compensate for deficiencies of each individual approach.

Fabrication of an anion exchange membrane with textured structure for enhanced performance of direct borohydride fuel cells.

Developing electrolyte membranes with a simple preparation process and high performance is a top priority for the commercialization of fuel cells. Inspired by solar cell texturing to improve its conversion efficiency, this study prepares a textured membrane by increasing the roughness of a glass plate. The structures of the textured membrane and the flat membrane are characterized and compared. The membranes are assembled in fuel cells for performance testing. The surface area of the textured membrane is 1.27 times that of the flat membrane, which increases the size of the three-phase boundary in fuel cells. The maximum power density of the fuel cell using the textured membrane is 1.17 times of the cell using the flat membrane at 60 °C. The excellent performance of the cell using the textured membrane profit from the enlargement of the three-phase boundary. This work offers a simple way to develop outstanding-performance membranes by changing their surface roughness.

The value of contrast-enhanced ultrasound quantitative parameters in the prognosis prediction of hepatocellular carcinoma after thermal ablation: a retrospective cohort study.

Background: The postoperative recurrence rate is the main factor affecting the prognosis of hepatocellular carcinoma (HCC) patients, this study sought to investigate the value of contrast-enhanced ultrasound (CEUS) quantitative parameters in predicting the recurrence and the survival of HCC patients after thermal ablation. Methods: The data of 97 patients with pathologically diagnosed HCC who underwent thermal ablation were retrospectively included in this study. The patients had an average age of 46.6 years (range, 23-79 years), and 79 were male and 18 were female. CEUS follow-up was performed at 1- and 3-month after thermal ablation, then at 6-month intervals thereafter for 5 years. CEUS was performed before thermal ablation, and the results were analyzed quantitatively using CEUS perfusion software (VueBox®, Bracco, Italy). The ratios of the CEUS quantitative parameters between the HCC lesions and reference liver parenchyma were calculated. The parameters included the average contrast signal intensity (MeanLin), peak enhancement (PE), rising time (RT), fall time (FT), time to peak (TTP), mean transit time (mTT), perfusion index (PI), Wash-in Area Under the Curve (WiAUC), Wash-in Rate (WiR), Wash-in Perfusion Index (WiPI), Wash-out Area Under the Curve (WoAUC), Wash-out Rate (WoR), and WiAUC + WoAUC (WiWoAUC). The correlations between the preoperative CEUS quantitative parameter ratios, the blood laboratory indexes, postoperative recurrence, and survival were analyzed using log-rank tests and a Cox regression model. Results: The average follow-up duration period was 79 months (range, 5-145 months). The average recurrence time after ablation was 1-127 months, and the median disease-free survival time was 21 months. The 1-, 3- and 5-year survival rates were 96.9%, 92.3%, and 80.6%, respectively. The log-rank tests showed that tumor size, prothrombin time, and WiAUC, WoAUC, and WiWoAUC ratios were predictors of survival, and aspartate aminotransferase was a predictor of recurrence. The Cox regression analysis showed that tumor size [odds ratio (OR): 6.421; 95% CI: 1.434-28.761] and alanine transaminase (OR: 0.88; 95% CI: 0.010-0.742) were predictors of a poor prognosis. Conclusions: CEUS quantitative parameters before thermal ablation and blood laboratory indexes provide potential clinical value for predicting the postoperative recurrence and survival of HCC patients.

Self-Assembly of a Graphene Oxide Liquid Crystal for Water Treatment.

Adsorbents, especially those with high removal efficiency, long life, and multi-purpose capabilities, are the most crucial components in an adsorption system. By taking advantage of the liquid-like mobility and crystal-like ordering of liquid crystal materials, a liquid crystal induction method is developed and applied to construct three-dimensional graphene-based adsorbents featuring excellent shape adaptability, a distinctive pore structure, and abundant surface functional groups. When the monoliths are used for water restoration, the large amount of residual oxygen-containing groups is more susceptible to electrophilic attack, thus contributing to cation adsorption (up to 705.4 mg g-1 for methylene blue), while the connected microvoids between the aligned graphene oxide sheets facilitate mass transfer, e.g., the high adsorption capacity for organic pollutants (196.2 g g-1 for ethylene glycol) and the high evaporation rate for water (4.01 kg m-2 h-1). This work gives a practical method for producing high-performance graphene-based functional materials for those applications that are sensitive to surface and mass transfer properties.

Selection and validation of reference genes for RT-qPCR analysis of different organs at various development stages in Caragana intermedia.

Reverse transcription quantitative PCR (RT-qPCR) is a technique widely used to investigate the expression of genes. An appropriate reference gene (RG) is essential for RT-qPCR analysis to obtain accurate and reliable results. Caragana intermedia plays an important role in afforestation as a bush. However, due to the lack of appropriate RGs, the research on development-related genes is limited. In this study, the selection for suitable RGs of different organs at various development stages to normalize the results of RT-qPCR about development-related genes was performed. To test the expression stability across all samples, we used the software algorithms such as geNorm, NormFinder, BestKeeper, and RefFinder to evaluate all the candidate RGs. Our results showed that CiEF1α was the most stable RG with little fluctuation among all samples. In addition, CiGAPDH in roots, CiSKIP1 in stems and leaves, and CiEF1α in different organs were selected as the most stable RGs. To confirm the applicability of the most stable RGs, the relative expression of CiWRKY17 was normalized using different candidate RGs. Taken together, our research laid a foundation for the study of development-related genes in C. intermedia.

The complete chloroplast genome sequence of Lilium concolor var. pulchellum.

Lilium concolor var. pulchellum is a perennial herbaceous plant with high ornamental and edible value; it is a critical breeding parent of Asiatic hybrids. In this study, we reported the complete chloroplast genome of L. concolor var. pulchellum. The total size of the genome is 152,126 bp with a GC content of 37.0%. It has a conserved quadripartite structure comprising 136 genes, including 38 tRNA genes, 8 rRNA genes, 83 protein-coding genes, and 7 pseudogenes. Phylogenetic analysis strongly supported a close relation between L. concolor var. pulchellum and L. callosum. The complete plastome sequence of L. concolor var. pulchellum could provide useful information for phyletic evolution of the genus Lilium.

An optimized bicistronic chimeric antigen receptor against GPC2 or CD276 overcomes heterogeneous expression in neuroblastoma.

Chimeric antigen receptor (CAR) T cell therapies targeting single antigens have performed poorly in clinical trials for solid tumors due to heterogenous expression of tumor-associated antigens (TAAs), limited T cell persistence, and T cell exhaustion. Here, we aimed to identify optimal CARs against glypican 2 (GPC2) or CD276 (B7-H3), which were highly but heterogeneously expressed in neuroblastoma (NB), a lethal extracranial solid tumor of childhood. First, we examined CAR T cell expansion in the presence of targets by digital droplet PCR. Next, using pooled competitive optimization of CAR by cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq), termed P-COCC, we simultaneously analyzed protein and transcriptome expression of CAR T cells to identify high-activity CARs. Finally, we performed cytotoxicity assays to identify the most effective CAR against each target and combined the CARs into a bicistronic "OR" CAR (BiCisCAR). BiCisCAR T cells effectively eliminated tumor cells expressing GPC2 or CD276. Furthermore, the BiCisCAR T cells demonstrated prolonged persistence and resistance to exhaustion when compared with CARs targeting a single antigen. This study illustrated that targeting multiple TAAs with BiCisCAR may overcome heterogenous expression of target antigens in solid tumors and identified a potent, clinically relevant CAR against NB. Moreover, our multimodal approach integrating competitive expansion, P-COCC, and cytotoxicity assays is an effective strategy to identify potent CARs among a pool of candidates.

CD19/22 CAR T cells in children and young adults with B-ALL: phase 1 results and development of a novel bicistronic CAR.

Remission durability following single-antigen targeted chimeric antigen receptor (CAR) T-cells is limited by antigen modulation, which may be overcome with combinatorial targeting. Building upon our experiences targeting CD19 and CD22 in B-cell acute lymphoblastic leukemia (B-ALL), we report on our phase 1 dose-escalation study of a novel murine stem cell virus (MSCV)-CD19/CD22-4-1BB bivalent CAR T-cell (CD19.22.BBζ) for children and young adults (CAYA) with B-cell malignancies. Primary objectives included toxicity and dose finding. Secondary objectives included response rates and relapse-free survival (RFS). Biologic correlatives included laboratory investigations, CAR T-cell expansion and cytokine profiling. Twenty patients, ages 5.4 to 34.6 years, with B-ALL received CD19.22.BBζ. The complete response (CR) rate was 60% (12 of 20) in the full cohort and 71.4% (10 of 14) in CAR-naïve patients. Ten (50%) developed cytokine release syndrome (CRS), with 3 (15%) having ≥ grade 3 CRS and only 1 experiencing neurotoxicity (grade 3). The 6- and 12-month RFS in those achieving CR was 80.8% (95% confidence interval [CI]: 42.4%-94.9%) and 57.7% (95% CI: 22.1%-81.9%), respectively. Limited CAR T-cell expansion and persistence of MSCV-CD19.22.BBζ compared with EF1α-CD22.BBζ prompted laboratory investigations comparing EF1α vs MSCV promoters, which did not reveal major differences. Limited CD22 targeting with CD19.22.BBζ, as evaluated by ex vivo cytokine secretion and leukemia eradication in humanized mice, led to development of a novel bicistronic CD19.28ζ/CD22.BBζ construct with enhanced cytokine production against CD22. With demonstrated safety and efficacy of CD19.22.BBζ in a heavily pretreated CAYA B-ALL cohort, further optimization of combinatorial antigen targeting serves to overcome identified limitations (www.clinicaltrials.gov #NCT03448393).

Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct design.

BACKGROUND: Successful development of chimeric antigen receptor (CAR) T cell immunotherapy for children and adults with relapsed/refractory acute myeloid leukemia (AML) is highly desired given their poor clinical prognosis and frequent inability to achieve cure with conventional chemotherapy. Initial experiences with CD19 CAR T cell immunotherapy for patients with B-cell malignancies highlighted the critical impact of intracellular costimulatory domain selection (CD28 vs 4-1BB (CD137)) on CAR T cell expansion and in vivo persistence that may impact clinical outcomes. However, the impact of costimulatory domains on the efficacy of myeloid antigen-directed CAR T cell immunotherapy remains unknown. METHODS: In this preclinical study, we developed six CAR constructs targeting CD33, a highly expressed and validated AML target, comprised of one of three single-chain variable fragments with CD3ζ and either CD28 or 4-1BB costimulatory domains. We systematically compared the preclinical in vitro and in vivo efficacy of T cells lentivirally transduced with CD33 CAR constructs (CD33CARTs) against human AML. RESULTS: We observed potent in vitro cytokine production and cytotoxicity of CD33CARTs incubated with human CD33+ AML cell lines, as well as robust in vivo antileukemia activity in cell line and childhood AML patient-derived xenograft (PDX) models. Gemtuzumab-based CD33CARTs were unexpectedly toxic in vivo in animal models despite observed in vitro anti-leukemia activity. CD28-based CD33CARTs consistently induced more robust inhibition of leukemia proliferation in AML cell line and PDX models than did 4-1BB-based CD33CARTs. A 'best-in-class' lintuzumab-CD28/CD3ζ CAR construct was thus selected for clinical translation. CONCLUSIONS: CD33 is a critical antigen for potential immunotherapeutic targeting in patients with AML. Based on this rigorous preclinical evaluation, our validated clinical grade lintuzumab-CD28/CD3ζ CD33CART immunotherapy is now under evaluation in a first-in-child/first-in-human phase 1 clinical trial for children and adolescents/young adults with relapsed/refractory AML. TRIAL REGISTRATION NUMBER: clinicaltrials.gov; NCT03971799.

CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial.

Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19- or CD19lo disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial ( NCT03233854 ) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n = 17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n = 21), 62% of patients responded with 29% CR. Relapses were CD19-/lo in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22-/lo disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.

Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis.

Metastasis is the leading cause of cancer-related deaths, and greater knowledge of the metastatic microenvironment is necessary to effectively target this process. Microenvironmental changes occur at distant sites prior to clinically detectable metastatic disease; however, the key niche regulatory signals during metastatic progression remain poorly characterized. Here, we identify a core immune suppression gene signature in pre-metastatic niche formation that is expressed predominantly by myeloid cells. We target this immune suppression program by utilizing genetically engineered myeloid cells (GEMys) to deliver IL-12 to modulate the metastatic microenvironment. Our data demonstrate that IL12-GEMy treatment reverses immune suppression in the pre-metastatic niche by activating antigen presentation and T cell activation, resulting in reduced metastatic and primary tumor burden and improved survival of tumor-bearing mice. We demonstrate that IL12-GEMys can functionally modulate the core program of immune suppression in the pre-metastatic niche to successfully rebalance the dysregulated metastatic microenvironment in cancer.

Perforin-deficient CAR T cells recapitulate late-onset inflammatory toxicities observed in patients.

Late-onset inflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) occur after chimeric antigen receptor T cell (CAR T cell) infusion and represent a therapeutic challenge. Given the established link between perforin deficiency and primary HLH, we investigated the role of perforin in anti-CD19 CAR T cell efficacy and HLH-like toxicities in a syngeneic murine model. Perforin contributed to both CD8+ and CD4+ CAR T cell cytotoxicity but was not required for in vitro or in vivo leukemia clearance. Upon CAR-mediated in vitro activation, perforin-deficient CAR T cells produced higher amounts of proinflammatory cytokines compared with WT CAR T cells. Following in vivo clearance of leukemia, perforin-deficient CAR T cells reexpanded, resulting in splenomegaly with disruption of normal splenic architecture and the presence of hemophagocytes, which are findings reminiscent of HLH. Notably, a substantial fraction of patients who received anti-CD22 CAR T cells also experienced biphasic inflammation, with the second phase occurring after the resolution of cytokine release syndrome, resembling clinical manifestations of HLH. Elevated inflammatory cytokines such as IL-1ß and IL-18 and concurrent late CAR T cell expansion characterized the HLH-like syndromes occurring in the murine model and in humans. Thus, a murine model of perforin-deficient CAR T cells recapitulated late-onset inflammatory toxicities occurring in human CAR T cell recipients, providing therapeutically relevant mechanistic insights.

Inhibitory effect of 5-FU loaded ultrasound microbubbles on tumor growth and angiogenesis.

The anti-neovascularization treatment is one of the effective strategies for tumor molecular target therapy. At present, the target and effect of the anti-neovascularization treatment is limited, and it is urgent to establish a new vascular targeting strategy to effectively treat tumors. In this work, we used high intensity focused ultrasound (HIFU) combined with targeted microbubbles to establish a molecular targeted ultrasound response microbubble for neovascular cells. Furthermore, the effects of drug loaded microbubbles on neovascularization and tumor cells were studied. The tumor vascular targeted and ultrasound-responsive microbubbles of 5-FU@DLL4-MBs were prepared by the thin-film dispersion method. The size and zeta potential of 5-FU@DLL4-MBs was about 1248 nm and -9.1 mV. 5-FU@DLL4-MBs released 5-FU showed an ultrasound-responsive manner, and had better vascular-targeting ability. Furthermore, the 5-FU@DLL4-MBs showed the strongest cytotoxic effect on HUVECs or HepG-2 cells and can be effectively internalized into the HUVECs cells. Thus, 5-FU@DLL4-MBs combined with HIFU can be considered as a potential method for antitumor angiogenesis in the future.

Bilayer Anion-Exchange Membrane with Low Borohydride Crossover and Improved Fuel Efficiency for Direct Borohdyride Fuel Cell.

The development of membranes with low fuel crossover and high fuel efficiency is a key issue in direct borohydride fuel cells (DBFCs). In previous work, we produced a poly(vinyl alcohol) (PVA)-anion-exchange resin (AER) membrane with a low fuel crossover and a low fuel efficiency by introducing Co ions. In this work, a bilayer membrane was designed to improve the fuel efficiency and cell performance. The bilayer membrane was prepared by casting a PVA-AER wet gel onto the partially desiccated Co-PVA-AER gel. The bilayer membrane showed a borohydride permeability of 1.34 × 10-6 cm2·s-1, which was even lower than that of the Co-PVA-AER membrane (1.98 ×10-6 cm2·s-1) and the PVA-AER membrane (2.80 × 10-6 cm2·s-1). The DBFC using the bilayer membrane exhibited a higher fuel efficiency (37.4%) and output power (1.73 Wh) than the DBFCs using the Co-PVA-AER membrane (33.3%, 1.27 Wh) and the PVA-AER membrane (34.3%, 1.2 Wh). Furthermore, the DBFC using the bilayer membrane achieved a peak power density of 327 mW·cm-2, which was 2.14 times of that of the DBFC using the PVA-AER membrane (153 mW·cm-2). The drastic improvement benefited from the bilayer design, which introduced an interphase to suppress fuel crossover and avoided unnecessary borohydride hydrolysis.

CD4/CD8 T-Cell Selection Affects Chimeric Antigen Receptor (CAR) T-Cell Potency and Toxicity: Updated Results From a Phase I Anti-CD22 CAR T-Cell Trial.

PURPOSE: Patients with B-cell acute lymphoblastic leukemia who experience relapse after or are resistant to CD19-targeted immunotherapies have limited treatment options. Targeting CD22, an alternative B-cell antigen, represents an alternate strategy. We report outcomes on the largest patient cohort treated with CD22 chimeric antigen receptor (CAR) T cells. PATIENTS AND METHODS: We conducted a single-center, phase I, 3 + 3 dose-escalation trial with a large expansion cohort that tested CD22-targeted CAR T cells for children and young adults with relapsed/refractory CD22+ malignancies. Primary objectives were to assess the safety, toxicity, and feasibility. Secondary objectives included efficacy, CD22 CAR T-cell persistence, and cytokine profiling. RESULTS: Fifty-eight participants were infused; 51 (87.9%) after prior CD19-targeted therapy. Cytokine release syndrome occurred in 50 participants (86.2%) and was grade 1-2 in 45 (90%). Symptoms of neurotoxicity were minimal and transient. Hemophagocytic lymphohistiocytosis-like manifestations were seen in 19/58 (32.8%) of subjects, prompting utilization of anakinra. CD4/CD8 T-cell selection of the apheresis product improved CAR T-cell manufacturing feasibility as well as heightened inflammatory toxicities, leading to dose de-escalation. The complete remission rate was 70%. The median overall survival was 13.4 months (95% CI, 7.7 to 20.3 months). Among those who achieved a complete response, the median relapse-free survival was 6.0 months (95% CI, 4.1 to 6.5 months). Thirteen participants proceeded to stem-cell transplantation. CONCLUSION: In the largest experience of CD22 CAR T-cells to our knowledge, we provide novel information on the impact of manufacturing changes on clinical outcomes and report on unique CD22 CAR T-cell toxicities and toxicity mitigation strategies. The remission induction rate supports further development of CD22 CAR T cells as a therapeutic option in patients resistant to CD19-targeted immunotherapy.

Low-temperature pseudomorphic transformation of polyhedral MIL-88A to lithium ferrite (LiFe3O5) in aqueous LiOH medium toward high Li storage.

The ability to develop novel nanomaterials, and to precisely manufacture their functional structures at the nano- and microscales would benefit many emerging device applications. Herein, as a first example, we describe the exploration of feasibility for the morphological replacement of an iron-based MOF bearing trimeric FeIII-O clusters, MIL-88A preform, with a polyhedral architecture of around 0.4 × 1.2 µm by a lithium ferrite (LiFe3O5) phase via solid-liquid pseudomorphic transformation reactions in biologically and environmentally favourable aqueous lithium hydroxide (LiOH). The reaction proceeds at 170 °C, and the overall reaction can be described as Fe3O(H2O)2(FMA)3(OH)·nH2O (MIL-88A) + 7OH- + Li+ → LiFe3O5 + 3FMA2- + (n + 6) H2O (FMA = fumarate). It was proposed that through the coordination substitution of a MOF ligand by OH-, follow-up dehydration and dehydroxylation, and final H+/Li+ ionic exchange, the monolithiated iron oxides formed thermodynamically at comparatively low temperatures, which transcribe the global nanostructure morphologies of the polyhedral MOF preforms with the hexagonal symmetry, but were composed of interconnected LiFe3O5 particles (about 16 nm) that crystallize in a typical magnetite-type cubic (Fd3[combining macron]m) structure. Given the characteristic texture and structure of the Li-Fe oxide replica, cubic LiFe3O5 was preferentially employed as a new type of electrode material in rechargeable lithium cells. Notably, from the electrochemical evaluation, this metal oxide system exhibits decent anodic performances by undergoing a nine-electron conversion reaction, showing a substantially high specific capacity with an average potential of 0.8 V versus lithium metal, a long service life (700 cycles), and exceptional high-rate capability (up to 2.0 A g-1). The synthetic paradigms demonstrated that the MIL-88A to LiFe3O5 conversion may be transferable to other advanced inorganic-based electrodes from the parent metal compound such as LiFeO2, LiMn2O4 or LiCoO2 toward sustainable energy fields.

Chimeric Antigen Receptors Incorporating D Domains Targeting CD123 Direct Potent Mono- and Bi-specific Antitumor Activity of T Cells.

Chimeric antigen receptor (CAR) T cell therapies have demonstrated impressive initial response rates in hematologic malignancies. However, relapse rates are significant, and robust efficacies in other indications, such as solid tumors, will likely require novel therapeutic strategies and CAR designs. To that end, we sought to develop simple, highly selective targeting domains (D domains) that could be incorporated into complex, multifunctional therapeutics. Herein, we describe the identification and characterization of D domains specific for CD123, a therapeutic target for hematologic malignancies, including acute myelogenous leukemia (AML). CARs comprised of these D domains mediate potent T cell activation and cytolysis of CD123-expressing target cells and induce complete durable remission in two AML xenograft models. We describe a strategy of engineering less immunogenic D domains through the identification and removal of putative T cell epitopes and investigate the binding kinetics and affinity requirements of the resultant D domain CARs. Finally, we extended the utility of D domains by generating functional, bi-specific CARs comprised of a CD123-specific D domain and a CD19-specific scFv. The properties of D domains suggest that this class of targeting domain may facilitate the development of multi-functional CARs where conventional, scFv-based designs may be suboptimal.