Seeing Structural Mechanisms of Optimized Piezoelectric and Thermoelectric Bulk Materials through Structural Defect Engineering

Aberration-corrected scanning transmission electron microscopy (AC-STEM) has evolved into the most powerful characterization and manufacturing platform for all materials, especially functional materials with complex structural characteristics that respond dynamically to external fields. It has become possible to directly observe and tune all kinds of defects, including those at the crucial atomic scale. In-depth understanding and technically tailoring structural defects will be of great significance for revealing the structure-performance relation of existing high-property materials, as well as for foreseeing paths to the design of high-performance materials. Insights would be gained from piezoelectrics and thermoelectrics, two representative functional materials. A general strategy is highlighted for optimizing these functional materials’ properties, namely defect engineering at the atomic scale.

Development of a Low-Cost Wire Arc Additive Manufacturing System

Due to their unique advantages over traditional manufacturing processes, metal additive manufacturing (AM) technologies have received a great deal of attention over the last few years. Using current powder-bed fusion AM technologies, metal components are very expensive to manufacture, and machines are complex to build and maintain. Wire arc additive manufacturing (WAAM) is a new method of producing metallic components with high efficiency at an affordable cost, which combines welding and 3D printing. In this work, gas tungsten arc welding (GTAW) is incorporated into a gantry system to create a new metal additive manufacturing platform. Design and build of a simple, affordable, and effective WAAM system is explained and the most frequently seen problems are discussed with their suggested solutions. Effect of process parameters on the quality of two additively manufactured alloys including plain carbon steel and Inconel 718 were studied. System design and troubleshooting for the wire arc AM system is presented and discussed.

Identification and Development of PHE885: A Novel and Highly Potent Fully Human Anti-BCMA CAR-T Manufactured with a Novel T-Charge TM Platform for the Treatment of Multiple Myeloma

Background : Chimeric antigen receptor T cell (CAR-T) therapies for multiple myeloma (MM) targeting B cell maturation antigen (BCMA) have demonstrated promising efficacy; however, many patients with relapsed/refractory (r/r) MM will ultimately relapse. To improve on existing BCMA CAR-Ts, two critical attributes of the CAR-T product were investigated: 1) the potency of the BCMA CAR construct, and 2) a rapid manufacturing process that would both preserve the stemness of T cells to ensure longer duration of response and provide timely access for patients with rapidly progressing, aggressive disease. Through extensive panning and discriminating CAR-T functional assays to assess performance, we have identified a superior anti-BCMA CAR construct that when combined with an innovative T-Charge™ manufacturing platform, produces a highly potent product. Methods and Results : We have developed a novel anti-BCMA CAR-T product for the treatment of MM. Our anti-BCMA CAR consists of an extracellular single chain variable fragment (scFv) targeting BCMA, fused to the CD8α hinge and transmembrane domains, followed by CD137 (4-1BB) co-stimulatory and CD3ζ chain signaling domains. Selection of our development candidate was based on a screening of seventeen anti-BCMA CARs, each comprising a distinct scFv derived from phage display libraries and hybridoma with a wide range of affinities and epitopes. One candidate clone from the fully human B cell library was identified after rigorous assessment of transduction efficiency, CAR expression, antigen specificity/selectivity and CAR-T cell function against a MM cell line, both in vitro and in vivo. This scFv also demonstrates high specificity to human BCMA by Retrogenix platform using a commercial human plasma membrane protein array assay. CAR expression and functionality of the CAR constructs were compared in the CAR-T cells generated with two different cell processes: a traditional manufacturing (TM) in which CAR-T cells are expanded in vitro for 9-10 days and a novel T-Charge TM process, which is an expansionless CAR-T manufacturing process that takes <2days to generate functional CAR-Ts. PHE885 generated with the novel T-Charge TM manufacturing platform, retains naïve/ stem cell memory T cell (T scm) (CD45RO -/CCR7 +) while the traditionally manufactured cell product carrying the same scFv (TM_PHE885) mainly contains central-memory T cells (CD45RO +/CCR7 +). In addition to its unique phenotype, PHE885 secretes up to 25 fold more target specific IL-2 and ~7 fold more IFN gamma in vitro, when comparing to the TM products either using the same lentiviral vector (TM_PHE885) or a clinically validated anti-BCMA vector (MCM998). In an immunodeficient NOD-scid IL2R gamma null (NSG) mouse model of MM, PHE885 induced tumor regression at a very low dose in a dose-dependent manner, and was up to 5 fold more efficacious in eradicating tumors compared to the two TM products. This enhanced efficacy was accompanied by higher cellular expansion in vivo (up to 3 fold higher C max and AUC 0-21d). The ability of PHE885 to control the tumor at lower doses with a greater expansion profile confirms the robustness and potency of the PHE885 cells. Furthermore, unlike the TM products, PHE885 induced earlier graft-versus-host disease at medium and high tested doses in this mouse model, suggesting the stemness of the product is most likely the driver of stronger T cell expansion. Conclusions : PHE885 was discovered and designed to enhance potency and drive persistence of CAR-T through the combination of a novel CAR construct carrying a fully human anti-BCMA scFv fused to 4-1BB/CD3ζ signaling domains and a novel T-Charge TM manufacturing platform, which enables rapid and reliable patient access. The novel T-Charge TM platform allows PHE885 to preserve a significantly higher proportion of naïve/ T scm cells, enabling PHE885 to effectively engraft, expand and reject tumors at a dose of 5 fold lower than TM CAR-T cells. Based on these results, a Phase 1, open-label trial assessing PHE885 in patients with r/r MM (NCT04318327) was initiated. Initial data from the dose escalation portion of the Phase 1 study will be presented separately. Figure 1 Figure 1. Disclosures Bu: Novartis: Current Employment, Patents & Royalties: Co-inventor on patent applications. Bennett: BMS: Current Employment; Novartis: Ended employment in the past 24 months, Other: PB was a full-time employee of Novartis at the time of the study. Barton: BMS: Current Employment; Novartis: Other: NB was a full-time employee of Novartis at the time of the study. Bradshaw: Novartis: Other: LB was a full-time employee of Novartis at the time of the study; AstraZeneca: Current Employment. Pinon-Ortiz: NIBR: Current Employment, Current holder of stock options in a privately-held company. Li: Novartis: Current Employment. Vaidya: NIBR: Current Employment. Zhu: Novartis: Current equity holder in publicly-traded company; NIBR: Current Employment. Mansfield: Novartis: Current Employment. Granda: Novartis: Current Employment, Patents & Royalties: No royalties as company-held patents. Guimaraes: Novartis: Current Employment, Patents & Royalties: Co-inventor on patent applications. Treanor: Novartis: Current Employment, Current holder of individual stocks in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties: no royalties as company-held patents. Brogdon: Novartis Institutes for Biomedical Research: Current Employment.

Why is AAV FVIII gene therapy not approved by the US Food and Drug Administration yet?

The prospect of a clinical strategy using an adeno-associated virus (AAV) vector for expression of therapeutic levels of factor VIII (FVIII) has been highly desirable. This was initially anticipated by promising data from clinical studies on AAV5-FVIII in men with severe hemophilia A. However, long-term follow-up showed a unique efficacy concern on the sustainability and durability derived from a continuous decline in the FVIII transgene levels starting 1 year after vector injection through year 5. Additional follow-up of early-phase studies and outcomes of an ongoing phase 3 study will likely provide evidence on the feasibility of this approach. Here, the potential underlying mechanisms of the FVIII declining levels, together with the revision of several unique early and late onset findings, are discussed. The lack of long-term preclinical studies in large animal models prevents the firm conclusion that FVIII levels decline was unexpected. It is possible that the combination of vector manufacturing platform and dose, accompanied with ectopic expression of supraphysiologic levels of FVIII at short-term follow-up, may all contribute to the sustainability and durability of the transgene levels. Notably, vector readministration to further improve the FVIII levels is not feasible at this time. Thus, the need of a one-and-done AAV strategy to achieve sustain FVIII levels of expression is sine qua non to impact favorably the disease phenotype.

Green Supplier Selection Under Cloud Manufacturing Environment: A Hybrid MCDM Model

In the cloud manufacturing environment, the interaction and cooperation between enterprises become more convenient. The most optimal green supplier selection through cloud manufacturing platform can improve the production quality and sustainable development efficiency of enterprises. However, as alternative suppliers are all over the world, there is a risk that the selected supplier is not ideal. Therefore, in this paper, a hybrid supplier selection model based on TODIM method is proposed to choose the optimal green supplier under cloud manufacturing platform. Considering the characteristics of suppliers in the cloud manufacturing environment and green criteria, the comprehensive green supplier evaluation index system is constructed. The creative application of heterogeneous evaluation information including crisp numbers, interval numbers, and probabilistic linguistic values, can express the evaluation information of different subjects comprehensively. In order to consider human judgment and the importance of information provided by raw data, the criteria weights are determined by integrating fuzzy BWM (Best-worst method) weights and objective entropy weights. Then, with the full consideration of decision maker’s risk attitude, the TODIM method is used to process heterogeneous evaluation information and calculate the priority of the green suppliers. The proposed method is novel, and allows multi-subjects to participate in the assessment process and considers the risk attitude of decision-makers in the green supplier selection process. An empirical study of green supplier selection in the cloud manufacturing environment is conducted. Sensitivity analysis and comparative analysis indicate that the proposed selection model for green supplier is reliable and effective.

Contorting transformations: Uneven impacts of the U.S.–Mexico automotive industrial complex

Contrary to the triumphalist rhetoric that describes the automotive industry as a lever for both regional development in North America and industrial upgrading in Mexico, this article argues that the formation of the Mexico–U.S. automotive complex has instead been consolidated on the basis of longstanding processes of uneven regional development. To make this argument, the paper examines how global economic restructuring, trade policies, domestic economic development processes, transnational firm decision making and the maintenance of the geopolitical border have reproduced extreme wage differences between the United States and Mexico, resulting in the creation of a regional automotive sector that is both highly integrated and highly unequal. In this scenario, both nations are home to profoundly different industrial landscapes: the U.S. hosts the highest value-added links of the production chain, monopolizing processes of innovation and scientific and technological knowledge production, while in contrast, Mexico manufactures the most labour intense and lowest value-added links of the automotive production chain. From this perspective, the Mexican economy can be essentially understood as an export manufacturing platform which derives its ‘competitiveness’ from the aggressive industry maintenance of low wages.