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Background: Ciltacabtagene autoleucel (cilta-cel; JNJ-68284528; LCAR-B38M CAR-T cells) is a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen-targeting single-domain antibodies designed to confer avidity. In the phase 1 LEGEND-2 study in China, LCAR-B38M yielded deep, durable responses with a manageable safety profile in patients (pts) with relapsed/refractory multiple myeloma (R/R MM). The phase 1b/2 CARTITUDE-1 study (NCT03548207) is further evaluating cilta-cel in this pt population in the US. We present updated data from the phase 1b portion along with initial phase 2 data. Methods: Eligible pts (aged ≥18 y) were diagnosed with MM per International Myeloma Working Group (IMWG) criteria and had measurable disease, Eastern Cooperative Oncology Group performance status ≤1, received ≥3 prior regimens or were double-refractory to a proteasome inhibitor and immunomodulatory drug, and received an anti-CD38 antibody. After apheresis, bridging therapy was permitted. Cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 daily for 3 d were used for lymphodepletion. A single infusion of cilta-cel at a target dose of 0.75×106 (range 0.5-1.0×106) CAR+ viable T cells/kg was administered 5-7 d after start of lymphodepletion. The primary objective of the phase 1b portion was to characterize cilta-cel safety and establish the recommended phase 2 dose; the primary objective of the phase 2 portion was to evaluate cilta-cel efficacy. Response was assessed per IMWG criteria and minimal residual disease (MRD) by next-generation sequencing. Adverse events (AEs) were graded using CTCAE v5.0. In the phase 1b portion, cytokine release syndrome (CRS) was graded by Lee et al (Blood 2014) and neurotoxicity by CTCAE v5.0; in the phase 2 portion, CRS and neurotoxicity were graded by American Society for Transplantation and Cellular Therapy (ASTCT) criteria. In this combined analysis, Lee et al and CTCAE v5.0 were mapped to ASTCT criteria for CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), respectively. Results: As of the May 20, 2020 clinical cutoff, 97 pts (58.8% male; median age 61.0 y [range 43-78]) with R/R MM received cilta-cel (29 in phase 1b; 68 in phase 2). Median follow-up duration was 8.8 mo (range 1.5-20.4). Pts had received a median of 6 prior lines of therapy (range 3-18); 83.5% were penta-exposed, 87.6% were triple-refractory, 41.2% were penta-refractory, and 97.9% were refractory to last line of therapy. Overall response rate per independent review committee (primary endpoint) was 94.8% (95% CI 88.4-98.3), with a stringent complete response rate of 55.7% (95% CI 45.2-65.8), very good partial response rate of 32.0% (95% CI 22.9-42.2), and partial response rate of 7.2% (95% CI 3.0-14.3). All pts achieved a reduction in M-protein. Median time to first response was 1.0 mo (range 0.9-5.8; 80.4% ≤1.0 mo), and median time to complete response or better was 1.8 mo (range 0.9-12.5; 74.1% ≤3.0 mo); responses deepened over time (Figure). Median duration of response was not reached (NR). Of 52 MRD-evaluable pts, 94.2% were MRD-negative at 10-5. The 6-mo progression-free survival (PFS) and overall survival (OS) rates (95% CI) were 87.4% (78.9-92.7) and 93.8% (86.7-97.2), respectively; median PFS and OS were NR. Ten deaths occurred during the study; 8 were due to AEs (both related and unrelated; CRS/hemophagocytic lymphohistiocytosis, neurotoxicity, respiratory failure, sepsis, septic shock, pneumonia, lung abscess, and acute myelogenous leukemia [n=1 each]), and 2 due to progressive disease. AEs reported in >70% of pts were CRS (94.8%; grade [gr] 3/4 4.1%), neutropenia (90.7%; gr 3/4 90.7%), anemia (81.4%; gr 3/4 68.0%), and thrombocytopenia (79.4%; gr 3/4 59.8%). Median time to CRS onset was 7.0 d (range 1-12) and median duration 4.0 d (range 1-27, excluding n=1 with 97 d). CAR-T cell-related neurotoxicity was reported in 20.6% of pts (gr 3/4 10.3%). Cilta-cel CAR+ T cells showed maximum peripheral expansion at 14 d (range 9-43). Among pts with 6 mo' individual follow-up, 67% had cilta-cel CAR+ T cells below the level of quantification (2 cells/µL) in peripheral blood. Conclusions: Preliminary phase 1b/2 data from CARTITUDE-1 indicate a single low-dose infusion of cilta-cel leads to early, deep, and durable responses in heavily pretreated pts with MM with a safety profile consistent with LEGEND-2. Further investigation of cilta-cel in other MM populations is underway. Disclosures Madduri: Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Foundation Medicine: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau. Berdeja:Teva: Research Funding; Bluebird: Research Funding; Bioclinica: Consultancy; Celgene: Consultancy, Research Funding; EMD Sorono: Research Funding; Kite Pharma: Consultancy; Prothena: Consultancy; Cellularity: Research Funding; Karyopharm: Consultancy; Servier: Consultancy; Legend: Consultancy; Poseida: Research Funding; Lilly: Research Funding; Acetylon: Research Funding; CURIS: Research Funding; Janssen: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Glenmark: Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Constellation: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Amgen: Consultancy, Research Funding; Kesios: Research Funding; Novartis: Research Funding. Usmani:Celgene: Other; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; GSK: Consultancy, Research Funding; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Abbvie: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Research Funding; Array Biopharma: Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding. Jakubowiak:Adaptive, Juno: Consultancy, Honoraria; AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cohen:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Other: Patents/Intellectual property licensed, Research Funding. Stewart:Janssen, BMS, Sanofi-Aventis, GSK: Honoraria; Tempus, Inc., Genomics England LLC: Membership on an entity's Board of Directors or advisory committees. Hari:Amgen: Consultancy; BMS: Consultancy; GSK: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Incyte Corporation: Consultancy. Htut:City of Hope Medical Center: Current Employment. Munshi:OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BMS: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Legend: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; AbbVie: Consultancy; C4: Current equity holder in private company. Deol:Novartis: Consultancy; Kite, a Gilead Company: Consultancy. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Janssen: Research Funding; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; GenMab: Consultancy, Honoraria. Singh:Janssen: Current Employment. Zudaire:Janssen: Current Employment. Yeh:Janssen: Current Employment. Allred:Janssen: Current Employment. Olyslager:Janssen: Current Employment. Banerjee:Janssen: Current Employment. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Schecter:Janssen: Current Employment. Jackson:Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Deraedt:Janssen: Current Employment, Current equity holder in publicly-traded company. Zhuang:Janssen: Current Employment. Infante:Janssen: Current Employment. Geng:Legend Biotech USA Inc.: Current Employment. Wu:Legend Biotech USA Inc.: Current Employment. Carrasco:Legend Biotech USA Inc.: Current Employment. Akram:Legend Biotech USA Inc.: Current Employment. Hossain:Legend Biotech USA Inc.: Current Employment. Rizvi:Legend Biotech USA Inc.: Current Employment. Fan:Legend Biotech USA Inc.: Current Employment. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. Lin:Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Vineti: Consultancy; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees. Martin:AMGEN: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding; GSK: Consultancy; Sanofi: Research Funding.

Background CARTITUDE-2 (NCT04133636) is a phase 2, multicohort, open-label study assessing the efficacy and safety of cilta-cel, a chimeric antigen receptor T (CAR-T) cell therapy with two B-cell maturation antigen (BCMA)-targeting single-domain antibodies, in patients (pts) with multiple myeloma (MM) in various clinical settings. This report describes the mitigation and management strategies implemented to identify and reduce the risk for neurologic adverse events (AEs) in pts with progressive MM after 1–3 prior lines of therapy (Cohort A). Methods Eligible pts (≥18 years) had MM, measurable disease, Eastern Cooperative Oncology Group performance status ≤1, progressive disease after 1–3 prior lines of therapy including a proteasome inhibitor and immunomodulatory drug, and were lenalidomide refractory (no prior BCMA-targeting agent). Cilta-cel was given as a single infusion at the targeted dose of 0.75×106 (range 0.5–1.0×106) CAR+ viable T cells/kg 5–7 days after start of lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 daily for 3 days). Monitoring and mitigation strategies for neurologic AEs included providing more effective bridging therapy to reduce tumor burden prior to lymphodepletion, frequent assessment of CAR-T-related immune effector cell-associated neurotoxicity syndrome (ICANS) using the ICE tool, handwriting assessments to detect micrographia, and brain MRI and electroencephalogram for pts with prior neurologic disease. Management strategies included evaluating infectious and paraneoplastic etiologies upon observation of ICANS ≥grade 1, administration of tocilizumab (if concurrent with cytokine release syndrome [CRS], all grades of ICANS) and/or dexamethasone (grade 2/3) or methylprednisolone (grade 4). ICANS and CRS were graded by American Society for Transplantation and Cellular Therapy criteria; non-ICANS neurotoxicities were graded per Common Terminology Criteria for Adverse Events, v5.0. Results As of 15 Jan 2021 (median follow-up: 5.8 months [2.5–9.8]), 20 pts (65% male, median age 60 years [38–75]) in Cohort A received cilta-cel. Four pts (20%) had neurotoxicities. Three pts had ICANS (grade 1/2) with median time to onset of symptoms of 8 days (7–11) and median duration of 2 days (1–2). Supportive measures to treat ICANS were received by 2/3 pts, including levetiracetam and steroids; 3/3 had concurrent CRS and all recovered. One pt developed isolated facial paralysis (grade 2); onset: Day 29 after cilta-cel infusion, recovered: 51 days after the onset following treatment with dexamethasone for 28 days. No movement or neurocognitive disorders were reported. Conclusion In pts with MM, neurologic AEs were generally manageable following treatment with cilta-cel. With a median of 5.8 months of follow-up, no movement or neurocognitive disorders were reported in pts from Cohort A. These findings suggest that early detection and management of neurologic AEs can lead to better treatment outcomes.

Context Cilta-cel, a chimeric antigen receptor T (CAR-T) cell therapy with two B-cell maturation antigen (BCMA)-targeting single-domain antibodies demonstrated efficacy in relapsed/refractory multiple myeloma (MM). Objectives To describe mitigation and management strategies to identify and reduce the risk for neurologic adverse events (AEs). Design CARTITUDE-2 (NCT04133636) is an ongoing phase 2, multi-cohort, open-label study. Patients and Other Participants Patients had progressive MM per IMWG criteria, measurable disease, ECOG ≤1, received 1–3 prior lines of therapy (including PI and IMiD), and were lenalidomide refractory (no prior BCMA-targeting agent). Interventions Cilta-cel (target dose: 0.75×106 [0.5–1.0×106] CAR+ viable T cells/kg) was given as a single infusion after lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2). Monitoring and mitigation of neurologic AEs included effective bridging therapy to reduce tumor burden prior to lymphodepletion, assessment of CAR-T-related immune effector cell-associated neurotoxicity syndrome (ICANS) using an ICE tool, handwriting assessments, and neuroimaging and electroencephalogram for prior neurologic disease patients. Management of neurologic AEs included evaluating infectious and paraneoplastic etiologies with ICANS ≥grade 1, administration of tocilizumab (if concurrent CRS, all grades of ICANS), and/or dexamethasone (grade 2/3) or methylprednisolone (grade 4). Main Outcomes Measures ICANS and CRS were graded by ASTCT criteria; non-ICANS neurotoxicities were graded per CTCAE v5.0. Results As of 15 Jan 2021 (median follow-up: 5.8 months), 20 patients in Cohort A (median age: 60 years; 65% males) received cilta-cel. Four patients (20%) had neurotoxicities. Three patients had ICANS (grade 1/2); median time to onset of symptoms: 8 days (7–11) and median duration: 2 days (1–2). Supportive measures, including levetiracetam and steroids, were received by 2/3 patients; all 3 had concurrent CRS and all recovered. One patient developed isolated facial paralysis (grade 2; onset: Day 29 after cilta-cel infusion; recovery: 51 days after the onset; treatment: dexamethasone for 28 days). Conclusions Neurologic AEs were generally manageable in patients with MM following cilta-cel treatment. No movement or neurocognitive disorders were observed in patients from Cohort A. Early detection and management of neurologic AEs can lead to better treatment outcomes Acknowledgements The study was funded by Janssen Research & Development, LLC and Legend Biotech, Inc.

Summary Background CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis. Methods This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 106 CAR-positive viable T cells per kg) was administered 5–7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207. Findings Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 106 CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6–15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2–99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9–1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9–not estimable), neither was progression-free survival (16·8–not estimable). The 12-month progression-free rate was 77% (95% CI 66·0–84·3) and overall survival rate was 89% (80·2–93·5). Haematological adverse events were common; grade 3–4 haematological adverse events were neutropenia (92 [95%] of 97 patients), anaemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5–8) and median duration of 4·0 days (IQR 3–6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events. Interpretation A single cilta-cel infusion at the target dose of 0·75 × 106 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions. Funding Janssen Research & Development and Legend Biotech.

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Background: The phase 1b/2 CARTITUDE-1 study (NCT03548207) is evaluating ciltacabtagene autoleucel (cilta-cel; JNJ-68284528; LCAR-B38M CAR-T cells), a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed/refractory (R/R) multiple myeloma (MM). Cytokine release syndrome (CRS), a known side effect of CAR-T therapy, can be mild to life-threatening and requires careful monitoring and management. Here, we analyzed CRS and cytokine profiles in CARTITUDE-1. Methods: Eligible patients (aged ≥18 years) had a diagnosis of MM per International Myeloma Working Group criteria, measurable disease, Eastern Cooperative Oncology Group performance status ≤1, received ≥3 prior regimens or were double-refractory to a proteasome inhibitor and immunomodulatory drug, and received an anti-CD38 antibody. Bridging therapy was permitted after apheresis. At 5-7 days prior to cilta-cel infusion, lymphodepletion was performed with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 daily for 3 days. Cilta-cel was administered as a single infusion at a target dose of 0.75×106 (range: 0.5-1.0×106) CAR+ viable T cells/kg. CRS was graded using Lee et al (Blood 2014) in the phase 1b portion and American Society for Transplantation and Cellular Therapy (ASTCT) in the phase 2 portion. In this combined analysis, Lee et al criteria were mapped to ASTCT criteria for patients in the phase 1b portion. Serum samples for cytokine profiling were collected prior to lymphodepletion, prior to cilta-cel infusion and 2 hours post-infusion on Day 1, at regular time points until Day 100, and if CRS was suspected or reported. Results: A total of 97 patients with R/R MM were treated with cilta-cel; median follow-up for this analysis was 8.8 months (range: 1.5-20.4). CRS was reported in 92 (94.8%) patients. A total of 48 (49.5%) patients had grade 1 CRS, 38 (39.2%) had grade 2, 4 (4.1%) had grade 3, and 1 had grade 5 (1.0%); maximum toxicity grade according to the ASTCT consensus grading system could not be derived for 1 patient with CRS in the phase 1b portion. Median time to CRS onset from cilta-cel infusion was 7.0 days (range: 1-12). Median duration of CRS was 4.0 days (range: 1-27, excluding n=1 with 97 days). Supportive measures to treat CRS or CRS symptoms were administered to 87 (89.7%) patients, most commonly tocilizumab (69.1%), acetaminophen (68.0%), corticosteroids (20.6%), and anakinra (18.6%). CRS resolved in 91 (98.9%) patients; the patient with grade 5 CRS/hemophagocytic lymphohistiocytosis died on Day 99 subsequent to sequelae of grade 4 CRS. Across all patients, levels of interleukin (IL)-6, IL-10, and interferon-γ peaked at Days 7-14 post-cilta-cel infusion. Conclusions: CRS after cilta-cel treatment was low grade and manageable in most patients with R/R MM. The low rate of grade ≥3 CRS, median time to CRS onset of 7.0 days, and median duration of 4.0 days suggests outpatient dosing of cilta-cel may be feasible; this approach is being explored in the phase 2 CARTITUDE-2 study (NCT04133636). Disclosures Lin: Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Consultancy, Research Funding; Vineti: Consultancy; Takeda: Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding. Martin:Janssen: Research Funding; AMGEN: Research Funding; Sanofi: Research Funding; Seattle Genetics: Research Funding; GSK: Consultancy. Cohen:Novartis: Other: Patents/Intellectual property licensed, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Usmani:Celgene: Other; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; GSK: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Array Biopharma: Research Funding; Merck: Consultancy, Research Funding; Abbvie: Consultancy; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Incyte: Research Funding. Madduri:AbbVie: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Foundation Medicine: Consultancy, Honoraria; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau. Stewart:Janssen, BMS, Sanofi-Aventis, GSK: Honoraria; Tempus, Inc., Genomics England LLC: Membership on an entity's Board of Directors or advisory committees. Singh:Janssen: Current Employment. Zudaire:Janssen: Current Employment. Yeh:Janssen: Current Employment. Allred:Janssen: Current Employment. Olyslager:Janssen: Current Employment. Banerjee:Janssen: Current Employment. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Schecter:Janssen: Current Employment. Jackson:Memorial Sloan Kettering Cancer Center: Consultancy; Janssen: Current Employment. Deraedt:Janssen: Current Employment, Current equity holder in publicly-traded company. Geng:Legend Biotech USA Inc.: Current Employment. Wu:Legend Biotech USA Inc.: Current Employment. Carrasco:Legend Biotech USA Inc.: Current Employment. Akram:Legend Biotech USA Inc.: Current Employment. Hossain:Legend Biotech USA Inc.: Current Employment. Wang:Legend Biotech USA Inc.: Current Employment. Berdeja:CRISPR Therapeutics: Consultancy, Research Funding; EMD Sorono: Research Funding; Teva: Research Funding; Servier: Consultancy; Vivolux: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Consultancy; Kesios: Research Funding; Kite Pharma: Consultancy; Legend: Consultancy; Genentech, Inc.: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cellularity: Research Funding; Constellation: Research Funding; Glenmark: Research Funding; CURIS: Research Funding; Bioclinica: Consultancy; Amgen: Consultancy, Research Funding; Bluebird: Research Funding; Poseida: Research Funding; Acetylon: Research Funding; Prothena: Consultancy; Lilly: Research Funding. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy.

Introduction: Patients (pts) with multiple myeloma (MM) who experience early clinical relapse, defined as disease progression ≤12 mo after autologous stem cell transplantation (ASCT) or start of initial treatment (tx), have median overall survival rates Methods: Eligible pts had MM, received 1 prior line of therapy (PI and IMiD required), had disease progression per IMWG criteria (either ≤12 mo after ASCT or ≤12 mo after start of anti-myeloma therapy for pts who did not undergo ASCT), and were tx-naïve to CAR-T or anti-BCMA therapies. A single cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg) was given 5-7 d after start of lymphodepletion (300 mg/m 2 cyclophosphamide and 30 mg/m 2 fludarabine daily for 3 d). The primary objective was minimal residual disease (MRD) negativity at 10 -5, as assessed by next generation sequencing. Adverse events (AEs) were graded using CTCAE v5.0 (cytokine release syndrome [CRS]) and immune effector cell associated neurotoxicity syndrome (ICANS) by ASTCT criteria. To minimize risk of movement and neurocognitive tx-emergent AEs (TEAEs), pt management strategy was implemented, consisting of enhanced bridging therapy to reduce baseline tumor burden, early aggressive tx of CRS and ICANS, and handwriting assessment tools for early detection of neurotoxicity symptoms. Results: As of the April 15, 2021, data cutoff, 18 pts (median age 57.0 y [range 44-67]; 78% male) received cilta-cel, and 2 pts died before cilta-cel infusion (1 each due to progressive disease and worsening general status). Median follow-up was 4.7 mo (range 0.6-13.5); median time from diagnosis to enrollment was 1.1 y (range 0.5-1.9). Two (11.1%) pts had high cytogenetic risk and 5 (27.8%) had bone marrow plasma cells >30%; 14 (77.8%) pts received prior ASCT, and 15 (83.3%) were refractory to their prior therapy. Overall response rate was 88.9% (95% CI: 65.3-98.6), 27.8% of pts (95% CI: 9.7-53.5) achieved ≥complete response (CR), and 66.7% (95% CI: 41.0-86.7) achieved ≥very good partial response (VGPR). Median time to first response was 0.9 mo (range 0.9-2.6), median time to best response was 1.4 mo (range 0.9-11.8), and median time to ≥CR was 1.8 mo (range 0.9-11.6). Of the 13 pts with ≥3 mo follow up, 5 (38%) achieved ≥CR. Of pts who were MRD-evaluable (n=9), all were MRD 10 -5 negative (100% [95% CI: 66.4-100]). At data cutoff, all but 1 pt remained in clinical response (Figure). Hematologic TEAEs in ≥20% of pts were neutropenia (88.9%), thrombocytopenia (61.1%), anemia (50.0%), leukopenia (27.8%), and lymphopenia (22.2%). CRS occurred in 15 (83.3%) pts (1 gr 4); median time to onset was 8 d (range 5-11), consistent with the heavily pretreated pts in the CARTITUDE-1 study. Median duration of CRS was 4 d (range 1-7). ICANS (gr 1) occurred in 1 pt. One pt experienced movement and neurocognitive TEAEs (gr 3) on Day 38 post cilta-cel infusion. This pt had high disease burden at baseline, progressive disease despite triplet bridging therapy, and gr 4 CRS which have been identified as risk factors for movement and neurocognitive TEAEs. The pt was treated with immune-directed measures and was reported to be stable with some improvements at data cutoff and achieved VGPR. No study deaths occurred post cilta-cel infusion. Conclusions: A single cilta-cel infusion led to early and deep responses in pts who experienced early clinical relapse/tx failure to initial therapy, with a manageable safety profile. MRD negativity was achieved early. Responses continue to deepen, and follow-up is ongoing, including MRD assessment. These findings support the continued exploration of cilta-cel in earlier lines of treatment and incorporation into potentially curative front-line regimens. Figure 1 Figure 1. Disclosures Van de Donk: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cellectis: Research Funding; Takeda: Consultancy; Roche: Consultancy; Novartis /bayer/servier: Consultancy. Delforge: Amgen, Celgene, Janssen, Sanofi: Honoraria, Research Funding. Cohen: Takeda: Consultancy; Janssen: Consultancy; BMS/Celgene: Consultancy; Novartis: Research Funding; AstraZeneca: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Genentech/Roche: Consultancy; Oncopeptides: Consultancy. Cohen: GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Research Funding; Neopharm / Promedico: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hillengass: Curio Science: Speakers Bureau; Beijing Medical Award Foundation: Speakers Bureau; Beijing Life Oasis Public Service Center: Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Skyline: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Axxess Network: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Kerre: BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Elyad: Membership on an entity's Board of Directors or advisory committees. Schecter: Janssen: Current Employment, Current holder of stock options in a privately-held company. De Braganca: Janssen: Current Employment. Varsos: Janssen: Current Employment. Vogel: Janssen Global Services, LLC: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Zudaire: Janssen: Current Employment. Corsale: Janssen: Current Employment. Akram: Legend Biotech USA: Current Employment. Geng: Legend Biotech USA: Current Employment. Nesheiwat: Legend Biotech USA: Current Employment. Pacaud: Legend Biotech: Current Employment. Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Zweegman: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: At the time of abstract submission, cilta-cel is being investigated for the treatment of multiple myeloma but is not yet approved.

Introduction: Ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell (CAR-T) therapy with 2 B-cell maturation antigen (BCMA)-targeting single-domain antibodies, is being evaluated in patients (pts) with relapsed/refractory multiple myeloma (RRMM). In the phase 1b/2 CARTITUDE-1 (NCT03548207) study, a single dose of cilta-cel led to early, deep, and durable responses in heavily pretreated pts with MM, with a manageable safety profile (Berdeja, Lancet, 2021). At median 18 months of follow-up, the overall response rate (ORR) was 98%, with 80% of pts achieving stringent complete response. Median duration of response (DOR) was 21.8 months (95% CI, 21.8-not estimable); 18-month progression-free survival (PFS) and overall survival (OS) rates were 66% and 81%, respectively. Here, we report the efficacy and safety of cilta-cel in various subgroups of pts in CARTITUDE-1. Methods: Eligible pts had MM and received ≥3 prior lines of therapy (LOT) or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), and had received a PI, IMiD, and anti-CD38 antibody. After apheresis, bridging therapy was permitted. Pts received a single cilta-cel infusion (target dose: 0.75×10 6 CAR+ viable T cells/kg; range 0.5-1.0×10 6) 5-7 days after lymphodepletion (300 mg/m 2 cyclophosphamide, 30 mg/m 2 fludarabine daily for 3 days). Primary objectives were to characterize cilta-cel safety, confirm the recommended phase 2 dose (phase 1b), and evaluate efficacy (phase 2). In this combined phase 1b and phase 2 analysis, cytokine release syndrome (CRS) graded by Lee et al (Blood 2014) criteria and neurotoxicity by CTCAE v5.0 were mapped to the ASTCT criteria for CRS and immune effector cell-associated neurotoxicity (ICANS), respectively. Efficacy and safety were evaluated in the following subgroups: ≥65 years of age, Black/African American, 3 prior LOT, ≥4 prior LOT, triple-class refractory, penta-drug refractory, standard- and high-risk cytogenetics, International Staging System stage III, bone marrow plasma cells at baseline (≤30%, >30 to Results: As of February 11, 2021, 97 pts in the overall population received cilta-cel; 58.8% were male, median age was 61 years (range 43-78), and median time from diagnosis to enrollment was 5.9 years (range 1.6-18.2). ORR across all evaluated subgroups was comparable to the overall population, and was consistently high (range 95.1-100%) including in those with high-risk cytogenetics, ISS stage III MM, baseline bone marrow cells ≥60%, and baseline plasmacytomas (Table). Median DOR for most subgroups, including high-risk cytogenetics, was consistent with the overall population or not reached but was shorter in pts with ISS Stage III MM and baseline plasmacytomas (Table). Across all subgroups, 80%-100% of MRD-evaluable pts achieved MRD negativity (10 -5 threshold). 18-month PFS and OS rates were consistent with the overall population in most subgroups, including high-risk cytogenetics, and lower in ISS stage III and baseline plasmacytomas (Table). Incidence of CRS, ICANS, and other CAR T-cell neurotoxicities (events not reported as ICANS [ie, onset after a period of recovery from CRS and ICANS]) in various subgroups was consistent with the overall population, with no new safety signals. Conclusions: At median follow-up of 18 months, a single infusion of cilta-cel yielded deep, durable responses in all evaluated subgroups in CARTITUDE-1. An ORR of 95%-100% was observed in pts across all subgroups, including those with high-risk cytogenetics, ISS stage III MM, baseline bone marrow cells ≥60%, and baseline plasmacytomas. In patients with ISS stage III and with baseline plasmacytomas, median DOR appeared shorter and 18-mo PFS and OS rates lower. Cilta-cel safety profile across the subgroups was consistent with the overall population, with no new safety signals. Ongoing evaluation of cilta-cel in the multicohort CARTITUDE-2 (NCT04133636) study in pts with unmet need in varying stages of treatment for MM will further explore the treatment benefit of cilta-cel, including in those with high-risk disease. Figure 1 Figure 1. Disclosures Jakubowiak: GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Usmani: Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; SkylineDX: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; EdoPharma: Consultancy; Abbvie: Consultancy; Bristol-Myers Squibb: Research Funding. Berdeja: Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; GSK, Ichnos Sciences, Incyte: Research Funding; EMD Sorono, Genentech: Research Funding; Celularity, CRISPR Therapeutics: Research Funding; Lilly, Novartis: Research Funding; Abbvie, Acetylon, Amgen: Research Funding; Poseida, Sanofi, Teva: Research Funding. Cohen: Oncopeptides: Consultancy; Genentech/Roche: Consultancy; Janssen: Consultancy; BMS/Celgene: Consultancy; Takeda: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; AstraZeneca: Consultancy; Novartis: Research Funding. Hari: Karyopharm: Consultancy; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Schecter: Janssen: Current Employment, Current holder of stock options in a privately-held company. Yeh: Janssen: Current Employment. Olyslager: Janssen: Current Employment. Banerjee: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Jackson: Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Allred: Janssen: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Zudaire: Janssen: Current Employment. Deraedt: Janssen: Current Employment. Geng: Legend Biotech USA: Current Employment. Pacaud: Legend Biotech: Current Employment. Lin: Janssen: Consultancy, Research Funding; Vineti: Consultancy; Legend: Consultancy; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Juno: Consultancy; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Takeda: Research Funding; Sorrento: Consultancy; Merck: Research Funding; Gamida Cell: Consultancy. Martin: Janssen: Research Funding; GlaxoSmithKline: Consultancy; Oncopeptides: Consultancy; Amgen: Research Funding; Sanofi: Research Funding. Jagannath: Bristol Myers Squibb: Consultancy; Janssen Pharmaceuticals: Consultancy; Legend Biotech: Consultancy; Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. OffLabel Disclosure: At the time of abstract submission, cilta-cel is being investigated for the treatment of multiple myeloma but is not yet approved.

In order to solve the problem of low recognition rate of traditional feature extraction operators under low-resolution images, a novel algorithm of expression recognition is proposed, named central oblique average center-symmetric local binary pattern (CS-LBP) with adaptive threshold (ATCS-LBP). Firstly, the features of face images can be extracted by the proposed operator after pretreatment. Secondly, the obtained feature image is divided into blocks. Thirdly, the histogram of each block is computed independently and all histograms can be connected serially to create a final feature vector. Finally, expression classification is achieved by using support vector machine (SVM) classifier. Experimental results on Japanese female facial expression (JAFFE) database show that the proposed algorithm can achieve a recognition rate of 81.9% when the resolution is as low as 16×16, which is much better than that of the traditional feature extraction operators.

e14510 Background: CD4 is highly and uniformly expressed T-cell lymphomas (TCL) including PTCL and CTCL, suggesting its potential as a surface target for CAR-T therapy. However, there is a significant risk of potential antigen masking by CAR introduced into tumor cells, which thereby leads to escape of tumor cells from recognition by CAR-T cells. For example, Ruella M et al ( Nat Med, 2018) reported that contaminating malignant B cells transduced with anti-CD19 CAR (called CAR-B cells) in the manufacturing process led to the CD19 antigen masking by CAR molecules. Hence, CAR-B tumor cells could not be recognized by CAR-T cells, which resulted in relapse of CAR expressing B lymphoma cells. A similar antigen masking effect might occur for the anti-CD4 CAR-T product. Methods: To identify single-chain variable fragment (scFv) without antigen-masking effect, large panels of fully human monoclonal antibodies were converted to format of CAR modality with the scFv-4-1BB-CD3z structure and introduced into CD4+ and CD8+ T cells. After lentiviral transduction, residual CD4+ T cells were quantified and the CARs with complete elimination of CD4+ T cells were selected for further validation. The selected CAR constructs were then introduced into CD4+ TCL cells HH (CAR-HH cells) to mimic the potential risk of introducing CAR into contaminating malignant T cells in the manufacturing process. Thereafter, CAR-HH cells were subject to in vitro killing assay by LB1901. Last, identified CAR constructs were further tested for in vitro and in vivo anti-tumor efficacy and off-target binding and killing. Results: Introduction of LB1901 CAR into CD4+ and CD8+ T cells led to complete elimination of CD4+ T cells, suggesting no masking effect of CAR on CD4 antigen. Furthermore, the introduction of CAR into CD4+ HH cells did not protect HH cells from being recognized and eliminated by LB1901, further confirming that the CAR modality of LB1901 does not mask CD4 antigen. An in vivo anti-tumor efficacy study showed that LB1901 exhibited dose-dependent anti-tumor activity without significant adverse effect. As low as 0.3 million CAR+ cells completely suppressed tumor growth, suggesting the potent anti-tumor activity by LB1901. Immunohistochemical analysis of normal tissues with LB1901 scFV binder showed no off-target binding. Furthermore, no killing toward CD4- cell lines and primary cells derived from vital organs or antigen-independent cytokine release was observed in vitro. Conclusions: Altogether, the in vitro and in vivo studies showed that LB1901 did not “mask” the CD4 antigen but exhibited potent anti-tumor activity without off-target effects. A phase 1 study of LB1901 CAR-T in patients with relapsed or refractory PTCL or CTCL is ongoing in the US to assess the safety and tolerability of LB1901 CAR-T (NCT04712864).

8028 Background: Cilta-cel (JNJ-68284528) is a chimeric antigen receptor T (CAR-T)-cell therapy with 2 BCMA-targeting, single-domain antibodies designed to confer high avidity binding. CARTITUDE-2 (NCT04133636) is a phase 2, multicohort, open-label study assessing the efficacy and safety of cilta-cel in patients (pts) with MM in various clinical settings. Here, we describe the mitigation and management strategies implemented to identify and reduce the risk for neurologic adverse events (AEs) in Cohort A pts (progressive MM after 1−3 prior lines of therapy). Methods: Eligible pts (≥18 years of age) had MM per IMWG criteria, measurable disease, ECOG ≤1, progressive disease after 1−3 prior lines of therapy (including a PI and IMiD) and were lenalidomide refractory (no prior BCMA-targeting agent). Cilta-cel (0.75×106 [range 0.5–1.0×106] CAR+ viable T cells/kg) was given as a single infusion 5–7 days after start of lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 daily for 3 days). Monitoring and mitigation strategies for neurologic AEs include providing more effective bridging therapy to reduce tumor burden prior to lymphodepletion, frequent assessment of CAR-T-related ICANS using the ICE tool, regular handwriting assessments to detect micrographia, and neuroimaging (brain MRI) and EEG for pts with prior neurologic disease. Management strategies include evaluating infectious and paraneoplastic etiologies upon observation of ICANS ≥Grade (gr) 1, administration of tocilizumab (if concurrent CRS, all gr of ICANS) and/or dexamethasone (gr 2/3) or methylprednisolone (gr 4). ICANS and CRS were graded by ASTCT criteria; neurotoxicities not classified as ICANS were graded per CTCAE Version 5.0. Results: As of 15 Jan 2021 (median follow-up: 5.8 months [range: 2.5–9.8 months]), 20 pts in Cohort A received cilta-cel. Median age was 60 years (range: 38–75); 65% were male. Neurotoxicities occurred in 4 pts (20%). Three pts had ICANS (gr 1/2); median time to onset of symptoms was 8 days (range: 7–11) and median duration was 2 days (range: 1–2). Two of the 3 pts received supportive measures to treat ICANS, including levetiracetam and steroids; all 3 had concurrent CRS and all recovered. One pt developed isolated facial paralysis (gr 2) on Day 29 after cilta-cel infusion, and recovered 51 days after the onset of event following treatment with dexamethasone for 28 days. No movement or neurocognitive disorders were reported. Conclusions: Neurologic AEs were generally manageable in pts with MM following treatment with cilta-cel. With a median of 5.8 months of follow-up, there were no movement or neurocognitive disorders in pts from Cohort A. These results suggest that early detection and management of neurologic AEs can lead to better treatment outcomes. Clinical trial information: NCT04133636.

In this paper, a fast fingerprint enhancement algorithm that can improve the singularity enhancement of fingerprint is proposed. It can overcome the problem that the Gabor filter can destroy the ridge structure near the fingerprint singularity point, and the directional Fourier filter can not repair the fingerprint line effect is not obviously. The new method (FS-Gabor) can quickly repair fingerprint lines while retaining the fingerprint structure in the vicinity of the singular points. The experimental results show that the EER of the fingerprint image filtered by the FS-Gabor method is lower than the method of directional Fourier filter and Gabor.

Summary Background Platinum chemotherapy has a role in the treatment of metastatic triple-negative breast cancer but its full potential has probably not yet been reached. We assessed whether a cisplatin plus gemcitabine regimen was non-inferior to or superior to paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer. Methods For this open-label, randomised, phase 3, hybrid-designed trial undertaken at 12 institutions or hospitals in China, we included Chinese patients aged 18–70 years with previously untreated, histologically confirmed metastatic triple-negative breast cancer, and an ECOG performance status of 0–1. These patients were randomly assigned (1:1) to receive either cisplatin plus gemcitabine (cisplatin 75 mg/m 2 on day 1 and gemcitabine 1250 mg/m 2 on days 1 and 8) or paclitaxel plus gemcitabine (paclitaxel 175 mg/m 2 on day 1 and gemcitabine 1250 mg/m 2 on days 1 and 8) given intravenously every 3 weeks for a maximum of eight cycles. Randomisation was done centrally via an interactive web response system using block randomisation with a size of eight, with no stratification factors. Patients and investigator were aware of group assignments. The primary endpoint was progression-free survival and analyses were based on all patients who received at least one dose of assigned treatment. The margin used to establish non-inferiority was 1·2. If non-inferiority of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine was achieved, we would then test for superiority. The trial is registered with ClinicalTrials.gov, number NCT01287624. Findings From Jan 14, 2011, to Nov 14, 2013, 240 patients were assessed for eligibility and randomly assigned to treatment (120 in the cisplatin plus gemcitabine group and 120 in the paclitaxel plus gemcitabine group). 236 patients received at least one dose of assigned chemotherapy and were included in the modified intention-to-treat analysis (118 per group). After a median follow-up of 16·3 months (IQR 14·4–26·8) in the cisplatin plus gemcitabine group and 15·9 months (10·7–25·4) in the paclitaxel plus gemcitabine group, the hazard ratio for progression-free survival was 0·692 (95% CI 0·523–0·915; p non-inferiority superiority =0·009, thus cisplatin plus gemcitabine was both non-inferior to and superior to paclitaxel plus gemcitabine. Median progression-free survival was 7·73 months (95% CI 6·16–9·30) in the cisplatin plus gemcitabine group and 6·47 months (5·76–7·18) in the paclitaxel plus gemcitabine group. Grade 3 or 4 adverse events that differed significantly between the two groups included nausea (eight [7%] vs one [ vs one [ vs ten [8%]), anaemia (39 [33%] vs six [5%]), and thrombocytopenia (38 [32%] vs three [3%]), for the cisplatin plus gemcitabine compared with the paclitaxel plus gemcitabine groups, respectively. In addition, patients in the cisplatin plus gemcitabine group had significantly fewer events of grade 1–4 alopecia (12 [10%] vs 42 [36%]) and peripheral neuropathy (27 [23%] vs 60 [51%]), but more grade 1–4 anorexia (33 [28%] vs 10 [8%]), constipation (29 [25%] vs 11 [9%]), hypomagnesaemia (27 [23%] vs five [4%]), and hypokalaemia (10 [8%] vs two [2%]). Serious drug-related adverse events were seen in three patients in the paclitaxel plus gemcitabine group (interstitial pneumonia, anaphylaxis, and severe neutropenia) and four in the cisplatin plus gemcitabine group (pathological bone fracture, thrombocytopenia with subcutaneous haemorrhage, severe anaemia, and cardiogenic syncope). There were no treatment-related deaths. Interpretation Cisplatin plus gemcitabine could be an alternative or even the preferred first-line chemotherapy strategy for patients with metastatic triple-negative breast cancer. Funding Shanghai Natural Science Foundation.

Introduction The aim of the study was to analyze clinicopathologic characteristics and survival and to identify prognostic factors for Chinese patients with HER2-positive metastatic breast cancer. Material and methods A total of 243 patients with HER2-positive metastatic breast cancer, treated during the period 2002 to 2009, were followed up from initial disease diagnosis to death or date of last follow-up (December 2011). Cumulative survival curves were created using Kaplan-Meier analysis with the log-rank test. Prognostic factors were analyzed by univariate and multivariate Cox proportional hazards regression analysis. Results During follow-up, 205 patients died, with a median OS of 27 months (95% CI: 23.5, 30.5 months), and the 1-, 3-, and 5-year survival rates were 84.4%, 38.6%, and 18.1%, respectively. The median OS of HR+ patients was significantly higher than that of HR– patients (p < 0.001). Surgery (hazard ratio = 0.60, p = 0.002), endocrine therapy (hazard ratio = 0.53, p < 0.01), and anti-HER2 therapy (hazard ratio = 0.63, p = 0.003) were favorable independent prognostic factors for patients with HER2-positive metastatic breast cancer. Conclusions These results indicated that surgical intervention, endocrine therapy, and anti-HER2 therapy were good for these HER2 positive patients with metastatic breast cancer, but ECOG performance status < 1 and metastasis to brain were unfavorable independent prognostic factors. HR status was not an independent prognostic factor.

The objective of this study was to investigate the relationship between selenium content in hair and the incidence of Kashin-Beck disease (KBD) and Keshan disease (KD) in China. A prospective cohort study was conducted among children aged 5-12 years with different levels of low-selenium (group 1, Se ≤ 110 ng/g; group 2, 110 Se ≤ 150 ng/g; and group 3, 150 Se ≤ 200 ng/g) or selenium-supplemented (group 4, Se 200 ng/g) exposure. A person-years approach was used to calculate the incidence and rate of positive clinical signs. Relative risk (RR), attributable risk, and etiologic fraction were used to determine the strength of association between selenium and disease incidence. Seven new KBD cases were diagnosed during 3-year follow-up. Positive clinical signs of KBD were found in 17.78 (95% confidence interval [CI] 14.27-21.29) cases per 100 person-years in group 1, 13.28 (9.82-16.74) in group 2, 12.95 (9.34-16.56) in group 3, and 8.18 (5.50-10.85) in group 4. Compared with group 4, the RR (95% CI) of groups 1, 2, and 3 were 2.17 (1.48-3.19), 1.62 (1.07-2.47), and 1.58 (1.03-2.43), respectively. Positive clinical signs of KD were 25.90 (18.62-33.18) cases per 100 person-years in group 1, 5.66 (1.26-10.06) in group 2, 4.60 (0.20-9.00) in group 3, and 14.62 (8.54-20.69) in group 4. Compared with group 4, the RR (95% CI) were 1.77 (1.07-2.93), 0.39 (0.16-0.93), and 0.31 (0.11-0.89), respectively. In children, the onset of KBD was negatively correlated with selenium content within a certain range. However, there may be a U-shaped association between selenium content and KD in children.

Pro-poor growth in Third World countries aimed at recasting the development goals of the new century. Eradicating poverty and promoting the comprehensive development of the poor are the essential requirement of pro-poor growth. China cooperation mechanism with the GMS countries aims at strengthening economic ties, eliminating poverty and promoting development, while the national poverty, income inequality and the distribution status and other factors seriously affect the steady development of the region. Referring to the practices and experiences for the countries have more remarkable achievement in pro-poor growth for more extensive cooperation and steady development and friendly relations in the sub-region.

JNJ-4528 is a chimeric antigen receptor T cell (CAR-T) therapy containing two B-cell maturation antigen (BCMA)-targeting single-domain antibodies designed to confer avidity. We present translational data from the phase 1b cohort of an ongoing phase 1b/2 study conducted in the US to explore the safety and efficacy of JNJ-4528 in patients with R/R MM (NCT03548207). Apheresis samples were collected from 25 patients, and T cells were selected and transduced with a lentivirus encoding the BCMA CAR construct. Immune cell composition of both the apheresis samples and transduced cells following expansion ("drug product" [DP]) was evaluated by multiparametric flow cytometry. The median proportion of CAR+ T cells in the DP was 16% (range 6-28%) of total cells, with a median proportion of 12% (range 4-22%) CD4+ CAR+ and 7% (range 3-20%) CD8+ CAR+ T cells. The CD4:CD8 ratio of CAR+ T cells in the DP was variable between patients, with a median of 1.5 (range 0.62-4.40). Significant variability between patients was observed in the composition of the DP regarding T cell subsets (i.e., naïve, Tscm, Tcm, Tem, Teff, Temra) although this profile was comparable in the CAR- and CAR+ T cell subpopulations within each patient. Patients were administered a single infusion of the JNJ-4528 DP at a target dose of 0.75x106 CAR+ T cells/kg (target range 0.5-1.0x106). Of the 21 patients with a postbaseline disease evaluation, the overall response rate was 91% at a median follow-up of 3 months (range 1-10). Among the 15 patients with post-infusion day 28 evaluable bone marrow (BM) samples by next generation flow cytometry and/or next generation sequencing, 10 were minimal residual disease negative at the 10-5 level of sensitivity, 2 at 10-4 level of sensitivity, and 3 had unidentified clones. All patients expressed BCMA in BM tumor cells at baseline, as assessed by flow cytometry, although levels varied among patients. Clinical responses appear independent of BM BCMA expression. Following infusion, CAR+ T cells expanded reaching a peak between 20-87% of the total T cells in blood between days 10-14 post-infusion. The CD4:CD8 ratio and the proportion of T cell memory subsets in the final DP did not correlate with peak CAR+ T cell expansion. Peak CAR+ T cell expansion did not correlate with response. Ten patients had a follow-up of enumeration of CAR+ T cells in blood of at least 8 weeks. In 5 patients, CAR+ T cells decreased to below the limit of quantification (BLOQ) of the flow cytometry assay (5 cells/µl) within 8 weeks (range 2-7) post-infusion. Although preliminary, no difference was observed in the response rate between these patients compared with patients with measurable CAR+ T cells after 8 weeks. A similar trend was observed when expansion and persistence were assessed by measuring transgene levels. While both CD4+ and CD8+ CAR+ T cells expanded in vivo, the CD4:CD8 CAR+ ratio decreased at peak expansion compared with the final DP (from a median of 1.35 to 0.35), indicating a preferential expansion of CD8+ CAR+ T cells in blood. At peak expansion, CD8+ CAR+ T cells showed predominantly a central memory (Tcm) phenotype (CCR7+ CD45RO+; median of 90% [range 29.3-98.5%]). In contrast, CD4+ CAR+ T cells were enriched in effector memory (Tem) cells (CCR7- CD45RO+; median of 87% [range 69.5-98.1%]) at peak expansion. A similar trend in the CD4:CD8 ratio, as well as the T cell memory subset composition, was observed in BM of all 11 patients with evaluable samples at day 28. CD8+ CAR- T cells showed an approximate 50:50 ratio of stem memory (Tscm):Tcm subsets while CD4+ CAR- T cells showed an approximate 50:50 ratio of Tcm:Tem subsets, indicating a differential T cell maturation course for CD4+ and CD8+ CAR+ and CAR- T cells. Expansion of CAR+ T cells correlated with increases in serum cytokines levels (i.e., IL-6, IFNγ, IL-10) which peaked around day 10, coinciding with maximal expansion of CAR+ T cells. Generally, increases in some proinflammatory cytokines (i.e., IL-6) correlated with onset of cytokine release syndrome symptoms (median time to onset of 7 days [range 2-12]). Findings from the ongoing CARTITUDE-1 trial suggest that JNJ-4528 is a differentiated CAR-T cell therapy that is highly active at a relatively low dose, potentially related to a preferential and consistent in vivo expansion of CD8+ CAR+ T cells displaying a central memory phenotype. Disclosures Zudaire: Janssen R&D: Employment, Equity Ownership. Madduri:Foundation Medicine: Consultancy; Takeda: Consultancy; AbbVie: Consultancy; Celgene: Consultancy. Usmani:Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Patents & Royalties, Research Funding; Celgene: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Janssen: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Skyline DX: Consultancy; Amgen: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Array Biopharma: Patents & Royalties, Research Funding; Sanofi: Patents & Royalties, Research Funding, Speakers Bureau; Takeda: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau. Jakubowiak:Adaptive Biotechnologies: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Consultancy, Honoraria. Berdeja:AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding; Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy. Geng:Legend Biotech: Employment, Equity Ownership. Rizvi:Legend Biotech: Employment, Equity Ownership. Nesheiwat:Legend Biotech: Employment, Equity Ownership. Schecter:Janssen R&D, LLC: Employment, Equity Ownership. Goldberg:Janssen R&D: Employment, Equity Ownership. Banerjee:Janssen R&D: Employment, Equity Ownership. Allred:Janssen R&D: Employment, Equity Ownership. Singh:Janssen R&D: Employment, Equity Ownership. Verona:Janssen R&D: Employment, Equity Ownership. McCaffery:Janssen R&D: Employment, Equity Ownership. Jagannath:Celgene Corporation: Consultancy; AbbVie: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Merck & Co.: Consultancy.

This paper introduces a design of ultra-low phase noise frequency source based on high phase detection frequency. Frequency source is a very important part of modern electronic system. Radar, communication, space technology and so on are inseparable from frequency source. Its performance index directly affects the whole electronic system, and phase noise is one of the most important indicators. In this paper, the scheme of phase-locked technology with high phase detection is mainly used,the phase noise is better than -116dBc/Hz@1kHz, -120dBc/Hz@10kHz, -121dBc/Hz@100kHz when the output frequency is 4.5GHz. The technology of high phase discrimination and low phase noise frequency synthesis in this paper can also be extended to higher and more special frequency bands. It provides a solution of ultra-low phase noise for frequency sources of modern radar, electronic jamming and countermeasure systems.

This paper analyzes the modular design method of the photovoltaic power generation system and presents a 5KW solar power inverter with variety of operating modes. Depending on the signal interface model, the hardware circuit is divided into several modules, including DC-DC main power circuit, DC-DC control circuit, DC-AC main power circuit, DC-AC control circuit and auxiliary power supply module. The circuit detail design is given and this system has been already used in the solar power stations. The circuit has a reusable and beneficial photovoltaic inverter standardized design. The experiment results prove that this system has features of reliability, easy maintenance, strong scalability and meets the requirements of the solar-energy generation system.

Background and Objectives Belatacept is a first-in-class, selective co-stimulation blocker recently approved for the prophylaxis of organ rejection in adult kidney transplant recipients. The objective of this study was to report the pharmacokinetics, pharmacodynamics, and immunogenicity of belatacept. Methods The pharmacokinetics, pharmacodynamics (CD86 receptor occupancy), and immunogenicity of belatacept were studied in de novo adult kidney transplant recipients in phase II and III clinical studies. Results Following multiple doses of 5 or 10 mg/kg, the geometric mean (percentage coefficient of variation) maximum serum concentration and area under the serum concentration–time curve over one dosing interval of belatacept were 136 (20 %) and 238 (27 %) μg/mL, and 13,587 (27 %) and 21,241 (35 %) μg·h/mL, respectively. The median belatacept elimination half-life was 8–9 days. Belatacept exhibited concentration-dependent binding to CD86 receptors. The pre-dose CD86 receptor occupancy by belatacept decreased from 94 to 65 % between day 5 and 1 year post-transplant, with corresponding pre-dose trough serum concentrations of belatacept decreasing from ~35 to 4 μg/mL during this period. The cumulative incidence of developing anti-belatacept antibodies was 5.3 % up to 3 years post-transplant and had no impact on belatacept exposure. Conclusions Belatacept in adult kidney transplant demonstrated linear pharmacokinetics with low variability, concentration-dependent pharmacodynamics, and a low incidence of anti-drug antibodies.

In this paper, through the test to determine the polystyrene granule as aggregate, the cement foaming slurry as cementitious material, with various additives for the performance adjustment material, optimum matching of polystyrene particles made of lightweight aggregate cellular concrete heat preservation material ratio, was the influence of raw materials on the performance and the thermal insulation of building production technology product form and key.

Tiopronin-conjugated gold nanoparticles (TPN@GNPs), with glutathione (GSH)-responsive drug release property, were developed for acute liver injury therapy. The TPN@GNPs were prepared using a one-pot synthesis method and characterized by UV-vis and transmission electronic microscopy methods. The TPN@GNPs displayed typical surface plasmon resonance of nanogold with a narrow size distribution (ca. 2 nm). The in vitro drug release profiles of the conjugates indicated that TPN@GNPs were able to release TPN in a sustained fashion for 4 h at a simulated intracellular level of GSH. pH values or ionic strengths of the release media had no obvious influence on TPN release from the surface of nanoparticles. The pharmacokinetic studies in rats showed that the TPN@GNPs had longer MRT (7.71 h) than TPN (3.96 h), indicating sustained release pattern of TPN@GNPs in vivo. The sustained release of TPN at the relative high GSH concentration could ameliorate the instability of TPN and enable the drug release in the target cells. Although the IC50 value of TPN@GNPs with TPN/AuCl4(-) of 3:1 (mol/mol) showed slight increase in comparison with that of the free TPN in HepG2 cells (1.26±1.07 vs. 1.73±1.16 mg/mL), the TPN@GNPs displayed better effects over TPN in the treatment of acute liver injury in vivo. In a liver injury mice model induced by CCl4, the histological analysis showed both the TPN@GNPs and free TPN group could repair the liver injury. In addition, the biochemical parameters showed TPN@GNPs could reduced the aminotransferase to a lower level compared with TPN, which might be due to the sustained drug release and passive liver targeting properties of TPN@GNPs. It demonstrated that gold nanoparticle-based drug delivery system allowed smart functions and superior properties by taking advantages of the unique small size effects and surface chemical properties.

This paper analyzes the principle of boundary mode flyback topology, presents a five-output auxiliary power supply of 3KW solar power inverter without the optocoupler feedback regulator circuit. The circuit has the characteristics of a simple structure, low cost, high efficiency and high reliability . The multi-output auxiliary power supply of the PV inverter schematic and a high frequency flyback transformer detail design are given. This power supply has been already used in an inverter. The experiment results prove that the auxiliary power supply has a stable work state, a low output ripple, a transformer without fever phenomenon, and meet the requirements of Solar power inverters.

Multi-targets tracking data association can generate three areas: correctly correlated area, unstable correlated area, and mistaken correlated area. Any radar cannot choose its tracking environment and target distance, but can enhance scan frequency and improve data association algorithm, etc. to decrease unstable correlated area and mistaken correlated area.

Multi-target tracking data association is a difficulty and also a key problem to be solved firstly in multi-target tracking. When tracking single target under situation of returns in density, the continuous occurrence of the measurement from near targets in the tracking gates causes continuous disturbance.

Purely from the perspective of target tracking, we have completed the pretreatment of group-target measurement, group-target track initiation, single group-target data correlating and track maintenance, and multi-group-target data correlating and track maintenance.

Designing the three dimensional (3D) GIS software used in monitoring mineral pipeline transporting system. The software can truly show and restore the geography of project and the features of terrain .The operator can not only examine and grasp the true situation of the distribution of pipeline, but also keep watch on the secure running of the pipeline by real-time remote video in the remote control room. The practical application indicates that the pipeline can run safely, stably and efficiently with the monitoring system.

The iron ore concentrate transport is one of an important factor in restricting the mining economic development; pipeline is a good solution with the hydraulic. The Dongchuan pipes are the use of the gravitational potential energy to achieve transporting concentrates by the way of self-flowing drop. The project is highly energy saving demonstration. However, it has a high demand of the control system of the end of the pipe dehydration station running due to the complex topography. Centralized control system given in this paper, having the characteristic of high reliability, operating performance, real-time strong, versatile and high economic benefits. The system realize the intelligent monitoring of the whole plant, all equipment control, the detection signal into the control room, remote control of the bottom pump system on the mountain, all equipment automatically switches to control. The system has a certain generalization.

A low power 640×480 OLED-on-silicon chip design that used in microdisplay was presented. A novel pixel circuit was proposed to meet the special requirement of OLED-on-silicon. The novel pixel consists of three transistors and one capacitor (3T1C). It has simple structure and can effectively reduce the current glitch generated during the AC driving from 55 μA to 7.5 μA, so that it can improve the precision of grayscale of display as well as extend the lifetime of OLED material. Except for the pixel array, low power row driver, column driver and other functional modules were also integrated on the chip. Several techniques were adopted to reduce the power consumption and frequency requirement of the chip. Finally, a 16×3×12 resolution chip was fabricated with standard 0.35 μm CMOS process of CSM and the chip can operate correctly.

Current studies of T-cell acute lymphoblastic leukemia (T-ALL) show promise for improving the treatment for this previously difficult to cure neoplasm. This has been facilitated by the increased understanding of the molecular basis of leukemogenesis in T-cells as well as advanced analytical technologies in modern molecular biology. Combined with intensive conventional therapies, novel drugs as well as improved diagnostic protocols have been developed for the rational therapy of T-ALL, resulting in a cure rate up to 80%. An understanding of the detailed molecular mechanism of action for T-ALL specific alterations in gene expression has led to the design and development of targeted molecular therapies of this aggressive cancer. Several novel, target-specific drugs are now available, including mitotic inhibitors with more specificity and potency for growth inhibition, γ-secretase inhibitors (GSIs) for leukemic NOTCHI signaling blockage in T-ALL as well as growth inhibition, tyrosine kinase inhibitors for correction of uncontrolled proliferation caused by certain genetic lesions, and inhibitors of BCL2 proteins leading to sensitization of leukemic cells to apoptosis induction. Some of these drugs are under development in the different phase of clinic trials, but others are currently included in successful therapeutic protocols, and, as hoped, they cause the remission of patients that suffered from certain types of T-ALLs, and who previously were poor responders using conventional treatment protocols. However, these new approaches still often need to be combined with highly toxic conventional treatment to obtain satisfactory overall outcome. The encouraging achievements in targeted molecular therapy challenge researchers to achieve no-event complete remission in T-ALL patient by developing novel therapies with even more specific targeting and efficacy to minimize complications. Finally, with the development of targeted molecular therapy, rational approaches for individually tailored treatment of T-ALL patients in the near future now may be an achievable goal.

Overexpression of human epidermal growth factor receptor-2 (HER2) in metastatic breast cancer (MBC) is associated with poor prognosis. This single-arm open-label trial (EGF109491; NCT00508274) was designed to confirm the efficacy and safety of lapatinib in combination with capecitabine in 52 heavily pretreated Chinese patients with HER2-positive MBC. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included progression-free survival (PFS), time to response (TTR), duration of response (DoR), central nervous system (CNS) as first site of relapse, and safety. The results showed that there were 23 patients with partial responses and 7 patients with stable disease, resulting in a CBR of 57.7%. The median PFS was 6.34 months (95% confidence interval, 4.93-9.82 months). The median TTR and DoR were 4.07 months (range, 0.03-14.78 months) and 6.93 months (range, 1.45-9.72 months), respectively. Thirteen (25.0%) patients had new lesions as disease progression. Among them, 2 (3.8%) patients had CNS disease reported as the first relapse. The most common toxicities were palmar-plantar erythrodysesthesia (59.6%), diarrhea (48.1%), rash (48.1%), hyperbilirubinemia (34.6%), and fatigue (30.8%). Exploratory analyses of oncogenic mutations of PIK3CA suggested that of 38 patients providing a tumor sample, baseline PIK3CA mutation status was not associated with CBR (P = 0.639) or PFS (P = 0.989). These data confirm that the lapatinib plus capecitabine combination is an effective and well-tolerated treatment option for Chinese women with heavily pretreated MBC, irrespective of PIK3CA status.

Trastuzumab has been the standard treatment in first-line treatment of HER-2-positive advanced breast cancer (H2ABC). This study explored whether the delayed and repeated use of trastuzumab could influence overall survival (OS). A total of 128 patients with H2ABC who had received at least one line of trastuzumab-based regimens were included. The primary endpoint was OS defined as from the date of first diagnosis of H2ABC to death. The median OS of initiating trastuzumab in first-line group (n = 56), in the second-line group (n = 32), and the third- or more-line group (n = 40) was 40.6 m, 39.5 m, and 38 m, respectively (P = 0.867). For patients who had received over one line of trastuzumab (n = 46), the median OS was 44 m, and for those receiving only one line (n = 67), it was 27.6 m (P = 0.059). The delayed use of trastuzumab has no negative effect on the OS of patients with H2ABC. There is a trend of improved OS over the repeated use of trastuzumab.

Background Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection and hospitalization in infants. Prophylaxis for RSV infection is only recommended for the highest risk infants, leaving the majority of infants unprotected. MK-1654 is a fully human monoclonal antibody targeting the RSV fusion (F) protein with Fc domain mutations to extend half-life that is being developed to provide passive immunity against RSV in infants. The safety profile, development of anti-drug antibodies (ADAs), serum neutralizing antibody (SNA) titers, and pharmacokinetics (PK) in healthy adult volunteers receiving single-ascending doses of MK-1654 was evaluated. Methods In this double-blinded ongoing Phase 1 study, healthy adults of non-childbearing potential (19 to 59 years) were randomized in a 3:1 ratio to receive a single dose of MK-1654 or placebo (0.9% sodium chloride injection, USP) as a bolus intramuscular injection (IM) or in an intravenous infusion (IV) for at least 2.5 hours. Dose levels included 100 and 300 mg IM, and 300, 1,000, and 3,000 mg IV. Standard methods were used to assess safety and tolerability. Serum was tested for ADAs and RSV A SNA titers at time points up to day 120 and up to day 90, respectively. MK-1654 adult PK and estimated PK for infants will be reported separately. Results A total of 152 subjects (male = 117, female = 35) have been enrolled (mean age = 41 years). No deaths, serious adverse events, discontinuations due to AEs, clinically significant laboratory AEs, or dose-dependent pattern of drug-related AEs were reported. Sixty-six subjects reported 181 clinical AEs (97.8% mild and 2.2% moderate in intensity). The most common AEs (≥5%) were headache, nasal congestion, vessel puncture site hemorrhage, oropharyngeal pain, rhinorrhea and nausea. No treatment emergent ADAs have been identified through time points tested. Administration of MK-1654 resulted in a dose-dependent increase in RSV A SNA titers through Day 90 (figure). Updated safety, SNA titers and ADAs will be provided. Conclusion MK-1654 was generally well tolerated at doses up to 300 mg IM and up to 3,000 mg IV and resulted in a dose-dependent increase in SNA titers, reflecting biologically active MK-1654 in the serum. No treatment emergent ADAs have been observed. Disclosures A. Aliprantis, Merck: Employee and Shareholder, Salary and stock options. D. Wolford, Merck: Employee and Shareholder, Salary and stock options. L. Caro, Merck: Employee and Shareholder, Salary and stock options. B. Maas, Merck: Employee and Shareholder, Salary and stock options. H. Ma, Merck: Employee and Shareholder, Salary and stock options. K. Vora, Merck: Employee, Salary. D. Geng, Merck: Employee and Shareholder, Salary and stock options. R. Railkar, Merck: Employee and Shareholder, Salary and stock options. A. Lee, Merck: Employee and Shareholder, Salary and stock options. L. Sterling, Merck: Investigator, Research grant. E. Lai, Merck: Employee and Shareholder, Salary and stock options.

The brain is one of the most common metastatic sites of breast cancer. Brain metastases develop in 10%-15% of patients with breast cancer and are associated with poor prognosis. The purpose of this retrospective study was to analyze the clinical characteristics and survival of patients with brain metastases due to breast cancer of different subtypes and to identify the prognostic factors that affect clinical outcome.A total of 89 patients with breast cancer brain metastases diagnosed between October 1997 and July 2008 at Sun Yat-sen University Cancer Center were included in this study. Among the 89 patients, the number of luminal A, luminal B, human epidermal growth factor receptor 2 (HER-2), and triple-negative (TN) subtypes were 30, 20, 16, and 14, respectively; 9 patients had an unknown subtype. The clinical characteristics, pathologic features, and prognostic factors were analyzed both at the initial diagnosis and at the diagnosis of brain metastases. Endocrine therapy for patients with luminal subtypes was further studied.The median age of patients was 46 years (range 28-74 years). The median survival time was 8.0 months (range, 0-80 months), the 1-year survival rate was 32% and the 5-year survival rate was 4%. The time to brain metastasis differed according to clinical stage at the initial diagnosis, and the time for patients with the luminal A subtype was the longest (P0.001). Multivariate analysis demonstrated that performance status score1, multiple brain metastases and without whole brain radiotherapy (WBRT) in combination with chemotherapy were associated with poor prognosis. Compared with the luminal A subtype, features of the HER-2 and TN subtypes included early metastases, rapid progression after first-line treatment (8.0 months vs. 11.0 months), and poor overall survival (25.0 months vs. 63.0 months). The luminal A subtype showed a tendency for good prognosis and slow growth. Tamoxifen could improve the survival of luminal A/B subtypes (median survival 24.0 months vs. 7.0 months, respectively, P = 0.002).The prognosis of brain metastases from breast cancer was poor, especially in patients with HER-2 and TN subtypes. Generally, WBRT in combination with chemotherapy was the standard treatment modality. Patients with the luminal subtypes could benefit from tamoxifen.

The AC driving scheme for OLEDs, which uses the pixel circuit with two transistors and one capacitor (2T1C), can extend the lifetime of the active matrix organic light-emitting diode (AMOLED) on silicon, but there are switching effects during the switch of AC signals, which result in the voltage variation on the storage capacitor and cause the current glitch in OLED. That would decrease the gray scale of the OLED. This paper proposes a novel pixel circuit consisting of three transistors and one capacitor to realize AC driving for the OLED-on-silicon while restraining the switching effects. Simulation results indicate that the proposed circuit is less sensitive to switching effects. Also, another pixel circuit is proposed to further reduce the driving current to meet the current constraints for the OLED-on-silicon.

Currently, NFC security authentication solutions widely use third-party authentication platforms, but their high cost and power consumption are not conducive to popularize NFC technology. To solve this problem, this paper presents a security authentication algorithm entirely based on a Hash function. It is an independent and complete algorithm without the aid of third-party certification platform. The main research process is transplanting an authentication algorithm in RFID, and then applying it to the NFC field after a wide range of optimization and improvement. This paper first changes the initiating mechanism to reduce the system error rate and save the power consumption of initiating device. Then, it removes some key data to save the storage resources. This scheme doesn't reduce the level of security. At last, the improved algorithm is simulated by Java Socket to obtain a kind of wider adaptability among devices. Experimental results from the simulation show that, the method can maintain the safety performance, improve efficiency and save storage space. It can be competent for the application in the relevant field, such as micro-payment, access controlling, etc.

Immunogenicity has always been an important consideration in the evaluation of pharmaceutical protein biologics. In this article, method validation parameters relevant to enzyme immunoassays are described for assays applied to the analysis of anti-drug antibodies, with special considerations for immunogenicity to therapeutic monoclonal antibodies. Common strategies for experimental investigation of various validation parameters are proposed. In addition, a novel, yet simple, approach is proposed to categorize the validation effort into two mutually interdependent phases, based on the characterization of validation parameters as "system descriptive" or "system controlled". System descriptive parameters are those that must be characterized but need not have pre-specified acceptance criteria for assay validation. In contrast, system-controlled parameters should be understood early in assay development, and optimized and confirmed using a priori acceptance criteria in validation to assure sufficient control over them during routine bioanalysis. This approach not only streamlines the validation process but also eliminates unnecessary redundancies. This validation method can be achieved with proper scientific rigor and remain within the realm of GLP compliance. The authors hope that other research groups would engage in discussions on validation of anti-drug antibody assays in order to establish a consistent approach across the industry and academia.

Objective: High dose chemotherapy supported by autologous hematopoietic stem cells transplantation (AHSCT) has developed dramaticly in recent years and become the most effective approach to improve radical treatment for the chemo-sensitive lymphoma. The purposes of this study was to evaluate the efficacy and tolerance of preparative regimen BEAC and hematopoietic reconstitution after high dose chemotherapy in Chinese patients with advanced and recurrent lymphoma. Methods: After confirmed complete or partial remission from conventional chemotherapy, 24 patients with advanced or recurrent lymphoma including 1 recurrent HD and 23 NHL, 16 male and 8 female with median age of 29 (13–50) years, were enrolled into this study and treated by BEAC regimen (CTX 3600–4000 mg/m2, VP-16 1200 mg/m2. BCNU 300 mg/m2 and Ara-C 1500–2000 mg/m2). 3 patients were supported by ABMT and 21 by APBSCT. Mobilization regimen for APBSCT was CTX 3500 mg/m2 + G-CSF 3.5–5 µg/kg + Dexamethasone 10 mg. Autologous hematopoietic stem cells was re-infused 24–48 h after completion of high dose chemotherapy. Results: MNC 1.3 (1.0–1.7)×108/kg and MNC 1.8 (1.0–4.4)×108, CFU-GM 5.1 (1.9–9.6)×105/kg plus CD34 + cells 2.9 (1.9–8.7)×106/kg were re-infused in the ABMT group and APBSCT group respectively. All patients obtained prompt and sustained hematopoietic reconstitution. ANC≥0.5×109/L and Pt≥2.0×109/L were at day 9 (6–17) and day 10 (0–31) respectively. 16 patients were alive with median 21 (2–69) months follow-up till end of May, 2001. 1, 2 and 3 years survival rate were 60.5%, 50.1% and 50.1%, respectively. Non-hematologic toxicity was mild and tolerable. Conclusions: High dose chemotherapy supported by AHSCT in the treatment of previously-untreated poor-prognostic and recurrent lymphoma was a safe and effective modality. Further investigation was warranted.

The low power design of a field sequential color (FSC) liquid crystal on silicon (LCoS) chip for near-to-eye application is presented in this paper. Dual power supplies are used in the design, that is, the supply for part of driving circuits is 3.3 V, and the one for the active matrix is 5.0 V. Serial-to-parallel conversion circuits are adopted to lower the pixel clock frequency of the chip. Also, an idle state is inserted into the pixel clock signal to decrease the switching activity factor to further reduce the power consumption. The LCoS chip is fabricated with 0.35 µm CMOS process and its power consumption is only about 300 mW.

Objective: A pilot study to test the feasibility and efficacy of hig h dose IFO and standard dose ADR and DTIC with G-CSF support in treatment of advanced soft tissue sarcoma (STS). Methods: 35 patients of no prior chemotherapy with metastatic or locally advanced unresectable STS were treated by this regimen, including 18 rhabdomyosarcomas, 7 malignant fibrous histiocytomas, 2 neurofibrosarcomas, 2 fibrosarcomas, 2 leiomyosarcomas, 2 synoviosarcomas, and 2 malignant hemangiopericytomas. IFO dose was 2 g/m2 on day 1-5 (with mesna uroprotection), ADR 50mg/m 2 on day 1 and DTIC 250 mg/m 2 on day 1-5. G-CSF (2 Ixg/kg/d) was administered on day 6 to 15 or until recovery of leukocytes account. The cycles were repeated every 3 weeks. Result: There were five complete responses (CR including pathologic CR) and eleven partial responses for overall 46% objective response rate. Most responses were observed within two cycles. The median survival was 15 months. Following CR, two patients remain disease free at 45 and 28 months, respectively. 6/120 (5%) cycles were complicated by grade IV neutropenia, 46/120 (38%) cycles had grade III neutropenia. No patients had treatmentrelated deaths. Nonhematologic toxicity consisted predominantly of anorexia and vomiting. No other severe toxicities were seen, especially no severe cardiotoxicity. Conclusion: This regimen is well tolerated and has substantial benefits for patients with advanced soft tissue sarcomas.

Given the use of tamoxifen as standard treatment for hormone receptor&ndash, positive breast cancer, the use of toremifene as an adjuvant endocrine therapy has not been widely examined. The present retrospective study compared the efficacy and safety of toremifene and tamoxifen in the treatment of operable hormone receptor&ndash, positive breast cancer in premenopausal women. Premenopausal patients with hormone receptor&ndash, positive operable breast cancer were eligible. Enrolled patients (n = 1847) received either 60 mg toremifene (n = 396) or 20 mg tamoxifen (n = 1451) daily for a minimum of 5 years after surgery. Disease-free survival (dfs) was the primary endpoint. Overall survival (os) and time to distant recurrence were secondary endpoints. Treatment with toremifene and tamoxifen resulted in no between-group differences in dfs (p = 0.659) or os (p = 0.364). Mean dfs was 10.3 years for both groups. Mean os was 11.2 years for the toremifene group and 11.1 years for tamoxifen group. The 5-year dfs rate was 87.0% in the toremifene group and 85.0% in the tamoxifen group. The 5-year survival rate was 94.3% in the toremifene group and 93.5% in the tamoxifen group. Adverse events rates were similar in the two groups, with the exception of irregular menses, which occurred at a higher rate in the tamoxifen group than in the toremifene group (10.0% vs. 6.3%, p = 0.025). In this retrospective study, the efficacy and safety profiles of toremifene and tamoxifen for the treatment of operable hormone receptor&ndash, positive breast cancer in premenopausal women were similar.

The high-pressure piston diaphragm is the croe of slurry pipeline implementing agencies ,need to focus on monitoring and maintenance. Because of its working conditions is extremely complex, the common means of detection can’t get the fault information. Based on the acoustic emission technique, sound signals, indirect monitoring of diaphragm pumps. This paper presents an on-line monitoring idea, which is a fault diagnosis of the high-pressure piston diaphragm pump based on acoustic emission. It is technically feasible, and has the considerable propagableness.

The clinical significance of bilateral breast cancer is unclear and its influence on prognosis is controversial. We compared the characteristics and prognosis of bilateral breast cancer and unilateral breast cancer.Our study included 4,183 patients with breast cancer who were treated at Sun Yat-sen University Cancer Center between January 1, 2000, and December 31, 2007. Bilateral breast cancer was categorized as synchronous (within 3 months) or metachronous (diagnosed after 3 months of first cancer). SPSS was used for data analysis.106 (2.5%) and 31 (0.7%) patients were diagnosed with metachronous and synchronous bilateral cancer. Women with bilateral cancer had more frequent postmenopause, HER-2 negativity, and advanced disease than in patients with unilateral cancer. Young age at diagnosis, invasive lobular carcinoma, ER/PR negativity, HER-2 positivity, radiation, large tumor size (T5 cm), and stage III disease of the first cancer were risk factors for contralateral cancer. The 5-year disease-free survival and overall survival rates were 76 and 83% for unilateral cancer, while 32 and 72% for bilateral cancer (P = 0.000 for both).Bilateral cancer was associated with shorter disease-free survival and overall survival than unilateral cancer. The prognosis of metachronous bilateral cancer, especially those diagnosed within 2 years after the first cancer was significantly worse than synchronous bilateral cancer.

Glucose transporter (Glut), a cellular transmembrane receptor, plays a key role in cell glucose metabolism and is linked to a poor prognosis in various human cancers. In this study, we prepared γ-Fe(2)O(3) NPs coated with DMSA, in which modified with 2-DG, then γ-Fe(2)O(3)@DMSA-DG NPs was constructed. The specific interactions between Glut1-overexpressing tumor cells (MDA-MB-231) and γ-Fe(2)O(3)@DMSA-DG NPs were observed using Prussian blue staining and transmission electron microscope (TEM), and found that γ-Fe(2)O(3)@DMSA-DG NPs were absorbed targetedly by the cells. Furthermore, the capacity of transporting SPIOs into tumor cells using these γ-Fe(2)O(3)@DMSA-DG NPs was evaluated with a 1.5 T clinical magnetic resonance imaging (MRI) scanner. It was found that the acquired MRI T2 signal intensity of MDA-MB-231 cells that were treated with the γ-Fe(2)O(3)@DMSA-DG NPs decreased significantly, and it was inhibited by competition with antibody of Glut1. Our results suggest that γ-Fe(2)O(3)@DMSA-DG NPs are a useful targeting to Glut1-overexpressing tumor cells in vitro and that γ-Fe(2)O(3)@DMSA-DG NPs may serve as a MRI-targeted tumor agent for better tumor imaging.

This paper introduces the data acquisition and monitoring system used in complex terrain long distance pipeline transportation of iron ore. The system realizes that Pump Station No. 1-5 accessed OA network, SCADA networks and Internet networks, established “triple play” safely and reliably. The Pump Station No. 1-5 accessed VoIP, achieved IP video production monitoring, audio and conferencing of production scheduling accessed data acquisition and monitoring system. The systems improved productivity and reliability; achieve the scientific planning and scheduling enterprise resource.

Traditional evaluation method of camouflage texture effect is subjective evaluation. It's very tedious and inconvenient to direct the texture designing. In this paper, a systemic and rational method for direction and evaluation of camouflage texture designing is proposed. A new camouflage texture evaluation method based on WSSIM (Weight structural similarity) is given to access the effects of camouflage texture at first. Then nature image features between the camouflage texture and the background image are calculated to help direct the designing camouflage texture. Primary experimental results show that the proposed method is helpful for evaluation and design of the camouflage texture.

In this paper, a novel method to extract legal amount from color Chinese bank check images for recognition task is presented. Firstly, global binarization method is applied to each channel of color legal amount images to get multiple binarization of source images, and get coarse binarization result through combining multiple binarization results. Then, a new method based on writing-rule of legal amount is proposed to locate text area and remove noise. Finally, local binarization method is applied to text area to refine result. Experimental results are given in the paper to demonstrate effectiveness of the proposed method.

The design of liquid crystal cell is an important factor to determine the display quality of LCoS display device. The goal of this paper is to gain VGA field sequential color (FSC) LCoS device used for near-to-eye system. The characteristics of optics and electrooptics for the twist nematic liquid crystal material and the material requirements of the FSC LCoS were studied. The LCOS liquid crystal cell optimized by dynamic parameter space method had an uniform reflectivity (about 90%) for the light with wave length from 450nm to 650nm. Both considering the electrooptic response curve of liquid crystal and the relationship between the contrast ratio and pixel size, we determined to use high speed twist nematic liquid crystal working in normally white mode. The liquid crystal cell gap and the pixel size were determined as 2.5um and 12um, respectively. The VGA FSC LCoS device was fabricated with SMIC 0.35um CMOS process and filled with LC-A liquid crystal of Merck in Varitronix. The measurement showed that the response time of liquid crystal from light to dark was 1.8ms and from dark to light was 4.4ms. The contrast ratio is bigger than 50:1. The LCoS displays well.