ALBERT

Description: Abstract In this article, isocyanate was adopted to modify Y2O3 powder for the purpose of preparing transparent Y2O3 ceramics via gel casting. The modification could enhance the hydration resistance of Y2O3 powder through the steric hindrance effect. The coating mechanism can be proved by the infrared spectrum of the surface‐modified Y2O3 powder. Modification could not only prevent Y2O3 particles from reacting with water, but also prevents agglomeration between particles. The viscosity of the slurry with a solid content of 52.7 vol% is only 0.48 Pa·s at the shear rate of 100 s−1, which is suitable for preparing high‐density compacts by gel casting. The transmittance of the sample (1840°C × 8 h, 1 mm thickness) at 1100 nm reaches 75%. The microstructure of the sintered body is dense with the average grain size of 6.5 μm without obvious impurities nor pores. Five mol% ZrO2‐doped Y2O3 transparent ceramic fairing with the diameter of 5 cm without defects was successfully fabricated by gel casting (52.7 vol% solid volume) and vacuum sintering (1840°C × 8 h).

Description: Studying the interaction between demand forecasting and train stop planning is important, as it ensures the sustainable development of high-speed rail (HSR). Forecasting the demand for high-speed rail (HSR), which refers to modal choice or modal split in this paper, is the first step in high-speed rail (HSR) planning. Given the travel demand and the number of train trips on each route, the train stop planning problem (TSPP) of line planning involves determining the stations at which each train trip stops, i.e., the stop-schedule of each train trip, so that the demand can be satisfied. To integrate and formulate the two problems, i.e., the modal choice problem (MCP) and train stop planning problem (TSPP), a nonlinear model is presented with the objective of maximizing the total demand captured by a high-speed rail system. To solve the model, a heuristic iterative algorithm is developed. To study the relationship between the demand and the service, the Beijing–Shanghai high-speed rail (HSR) corridor in China is selected. The empirical analysis indicates that combining modal choice and train stop planning should be considered for the sustainable design of high-speed rail (HSR) train services. Furthermore, the model simulates the impact of the number of stops on its mode share by reflecting changes in travelers’ behaviors according to HSR train stop planning, and it also provides a theoretical basis for the evaluation of the adaptability of the service network to travel demand.

Description: Abstract Ultra‐highly transparent ZrO2‐doped Yb3+: Y2O3 ceramics were prepared by slip casting and vacuum pressureless sintering and the transmittance reached the highest value of 80.9% for the sample doped with 8.0 at% Yb3+. There are three main absorption peaks at 905, 950, and 976 nm, corresponding to the transition from the lowest level of field splitting of 2F7/2 crystal to every splitting energy levels of 2F5/2 crystal field. We analyzed the absorption and emission spectra of transparent Yb3+: Y2O3 from the energy level structure of Yb3+, and the transmission, absorption, and emission spectra were systematically studied. There are three main absorption peaks at 905, 950, and 976 nm and four emission peaks at 1076, 1031, 1013, and 977 nm, respectively. The emission peaks at 977 and 1013 nm broaden and vanish for 8.0 and 10.0 at% Yb3+‐doped Y2O3, which may be related to the change of Y2O3 crystal field caused by high concentration.

Description: Introduction: B cell maturation antigen (BCMA) has become a popular research target for multiple myeloma (MM) in chimeric antigen receptor (CAR)-T cell therapy. Up to now, many trials with anti-BCMA CAR-T cells has demonstrated inspiring outcome in patients with relapsed or refractory (R/R) MM. While, cytokine release syndrome (CRS) is a big challenge, it occurs in almost 76% of the patients, and can be fatal if not managed well. However, the pathophysiology of CRS is not so clear, and dynamic changes are ignored. Here, we deeply analyze the dynamic changes of various cytokines in different stages of CRS, trying to find the cytokines closely related to CRS and looking for the target proteins that might be used to control CRS. Methods: 28 patients with R/R MM were enrolled and got treatment with informed consent in Ruijin Hospital, First Affiliated Hospital of Nanjing Medical University and Changzheng Hospital from April 3, 2017 to October 8, 2019. All patients received anti-BCMA CAR-T cells infusions at doses of 0.05~2.78×106 CAR+ T cells/kg. Criteria previously reported by the CARTOX working group were adopted for the grading of CRS. Genomic DNA was isolated from whole blood for CAR-T cells detection by qPCR. 61 cytokines were assessed in the serum of 25 patients before infusions and at multiple time points after infusions within three weeks (Magnetic LuminexR Assay; R&D Systems). P values were determined using Mann-Whitney U test. Results: Within one month, CAR-T cells presented proliferation in all patients tested and the median peak value of CAR+T was 78148 copy number/μg DNA. All patients experienced CRS, which generally occurred at a median of 7 days (range 3-10) after infusions. And the median time of fever onset was 8 days after infusions. Of the 28 cases, 46% of patients had grade≥3 CRS. To better understand the dynamic changes in cytokine profile, we chose 6 different time points in each patient which represented baseline period (time before infusions), latent period (day 3~5 after infusions), fever period (day 6~9 after infusions), acute aggravation period (day 10~12 and day 13~15 after infusions), remission period (day 20~23 after infusions). Levels of many cytokines were increased remarkably after treatment. The peak fold-change (pFC) over the baseline was calculated for each cytokine in each patient, IL-6 ranked first with a median pFC of nearly 92 times, followed by Granzyme B, IL-10, G-CSF. And IL-6 was the most closely associated cytokine with Grade≥3 CRS (P=0.005) among all cytokines. For exploring the early initiation cytokines for CRS, FC over the baseline of all the cytokines were analyzed. Cytokines with a median FC of over 2 times at latent period were G-CSF, GM-CSF, Granzyme B and IL-1β, which were in sharp contrast to others for example IL-6. The levels of these cytokines in Grade≥3 CRS were higher than that of Grade≤2 CRS, especially at acute aggravation period with significant difference (Fig.1A~B). Meanwhile, high levels of IL-6 in which group the FC of G-CSF was over 1.9 at latent period may indicate that G-CSF had a warning effect on the rise of IL-6 (Fig.1C). Conclusions: We have conducted the largest protein chip screening for exploring CRS due to CAR-T cell therapy so far. As the CAR-T cells expanded in the body, patients began to experience stress and developed CRS in varying degree. IL-6 exhibited the largest median peak FC and highest correlation with severe CRS (Grade≥3 CRS), all of these laid the foundation for the use of tocilizumab (IL-6 receptor antagonist) to control CRS. We also speculated G-CSF may be used as an early CRS indicator or target for early intervention, but more in-depth mechanism exploration is needed to support and testify. Disclosures Xu: National Natural Science Foundation of China: Other: Grants; Shanghai Rising-Star Program: Other: Grants; Shanghai Excellent Youth Medical Talents Training Program: Other: Grants.

Description: Background: LCAR-B38M is a structurally differentiated CAR-T cell therapy containing 2 BCMA-targeting single-domain antibodies designed to confer avidity. LEGEND-2 (NCT03090659) is an exploratory study using LCAR-B38M CAR-T cells for the treatment of patients (pts) with relapsed or refractory (R/R) multiple myeloma (MM). Key eligibility criteria included R/R MM ³3 prior lines of therapy. Earlier results from LEGEND-2 showed encouraging overall efficacy and manageable safety (N=74). Here, we present updated results of LCAR-B38M in 17 R/R MM pts published in PNAS (Xu J et al. Proc Natl Acad Sci USA. 2019;116:9543-9551), with a median follow-up of 22 months, from 3 sites: Jiangsu Provincial People's Hospital, Nanjing (JS); Ruijin Hospital, Shanghai (RJ); and Changzheng Hospital, Shanghai (CZ). Methods: Different sites adopted different lymphodepletion and dosing regimens. Eight pts (age, 18-75 years) with R/R MM received a lymphodepletion regimen of cyclophosphamide (Cy) 250 mg/m2 + fludarabine (Flu) 25 mg/m2, intravenously daily for 3 days (RJ and CZ), while 9 pts received Cy 300 mg/m2 intravenously daily for 3 days (JS). CAR-T cells were administered via 3 infusions (day 0, 3, and 6; n=8, RJ and CZ) or 1 infusion (day 0; n=9, JS) 5 days after lymphodepletion. Response was assessed per the International Myeloma Working Group criteria, adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03, and cytokine release syndrome was graded using CARTOX criteria (Neelapu SS et al. Nat Rev Clin Oncol. 2018;15:47-62). Results: Overall, 17 pts were enrolled. The mean dose was 0.7x106 (range, 0.2-1.5x106) CAR+ T cells/kg. The most common adverse events observed were cytokine release syndrome (100%; grade 1/2 [n=10]; grade 3 [n=6]; grade 5 [n=1]); cytopenia (82%; grade 1/2 [n=4]; grade 3 [n=5]; grade 4 [n=5]); and liver toxicity: 100%; elevated alanine aminotransferase (41%; grade 1/2 [n=7]; grade ≥3 [n=0]), elevated aspartate aminotransferase (94%, grade 1/2 [n=11]; grade 3 [n=5]), and elevated bilirubin (6%, grade 3 [n=1]). Tumor lysis syndrome was reported in 3 pts (18%) and no neurotoxicity was reported. The overall best response rate (partial response or better) was 88% (95% confidence interval [CI], 64-99). Complete response (CR) was achieved by 14 pts (82%; 62-99), and very good partial response by 1 pt (6%; 6-18). All of the 14 pts with CR were minimal residual disease negative (MRD-neg, by 8-color flow cytometry). The median time to first response was 1.0 months. At the July 20, 2019 data cutoff (median follow-up, 22 months [95% confidence interval, 16-23]), 6 (38%) pts remain progression-free. The median progression-free survival (PFS) for all-treated pts was 12 months (12-NE); median PFS for MRD-neg pts with CR was 18 months (13-NE). The median overall survival has not yet been reached (NE [12-NE]). At 18 months, 65% (39-90) of all-treated pts and 79% (54-99) of MRD-neg pts with CR were still living. In a post-hoc analysis, PFS was longer in pts at the RJ and CZ sites than in those at the JS site. Relapse occurred in 8/9 pts at the JS site, while relapse or progressive disease occurred in 2/7 evaluable pts at the RJ and CZ sites. In addition, 5/7 (71%) RJ/CZ pts remained stable in sCR (median follow-up, 745 days). Key differences between these sites included lymphodepletion regimens and the number of CAR-T infusions. Conclusions: LCAR-B38M has a safety profile consistent with other BCMA-targeted CAR-T cell therapy. This exploratory study has provided key evidence that LCAR-B38M may be a highly effective therapy for pts with R/R MM. It demonstrated deep and durable responses, particularly following Cy/Flu lymphodepletion. Although the sample size is too small to draw firm conclusions and multiple other factors may contribute, these outcomes suggest that different lymphodepletion regimens may contribute to differences in long-term efficacy. The study is ongoing for long-term safety and follow-up. A phase 1b/2 clinical study is ongoing in the United States (CARTITUDE-1, NCT03548207, JNJ-4528), and a phase 2 confirmatory study is ongoing in China (CARTIFAN-1, NCT03758417, LCAR-B38M). Pts in both of these studies will undergo Cy/Flu lymphodepletion and 1 single infusion of drug product. Disclosures Xu: National Natural Science Foundation of China: Other: Grants; Shanghai Rising-Star Program: Other: Grants; Shanghai Excellent Youth Medical Talents Training Program: Other: Grants.