ALBERT

Description: © The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Lombard, F., Boss, E., Waite, A. M., Vogt, M., Uitz, J., Stemmann, L., Sosik, H. M., Schulz, J., Romagnan, J., Picheral, M., Pearlman, J., Ohman, M. D., Niehoff, B., Moeller, K. M., Miloslavich, P., Lara-Lpez, A., Kudela, R., Lopes, R. M., Kiko, R., Karp-Boss, L., Jaffe, J. S., Iversen, M. H., Frisson, J., Fennel, K., Hauss, H., Guidi, L., Gorsky, G., Giering, S. L. C., Gaube, P., Gallager, S., Dubelaar, G., Cowen, R. K., Carlotti, F., Briseno-Avena, C., Berline, L., Benoit-Bird, K., Bax, N., Batten, S., Ayata, S. D., Artigas, L. F., & Appeltans, W. Globally consistent quantitative observations of planktonic ecosystems. Frontiers in Marine Science, 6, (2019):196, doi:10.3389/fmars.2019.00196.

Description: In this paper we review the technologies available to make globally quantitative observations of particles in general—and plankton in particular—in the world oceans, and for sizes varying from sub-microns to centimeters. Some of these technologies have been available for years while others have only recently emerged. Use of these technologies is critical to improve understanding of the processes that control abundances, distributions and composition of plankton, provide data necessary to constrain and improve ecosystem and biogeochemical models, and forecast changes in marine ecosystems in light of climate change. In this paper we begin by providing the motivation for plankton observations, quantification and diversity qualification on a global scale. We then expand on the state-of-the-art, detailing a variety of relevant and (mostly) mature technologies and measurements, including bulk measurements of plankton, pigment composition, uses of genomic, optical and acoustical methods as well as analysis using particle counters, flow cytometers and quantitative imaging devices. We follow by highlighting the requirements necessary for a plankton observing system, the approach to achieve it and associated challenges. We conclude with ranked action-item recommendations for the next 10 years to move toward our vision of a holistic ocean-wide plankton observing system. Particularly, we suggest to begin with a demonstration project on a GO-SHIP line and/or a long-term observation site and expand from there, ensuring that issues associated with methods, observation tools, data analysis, quality assessment and curation are addressed early in the implementation. Global coordination is key for the success of this vision and will bring new insights on processes associated with nutrient regeneration, ocean production, fisheries and carbon sequestration.

Description: Much of this manuscript flows from discussions of the authors with the members of SCOR working groups 150 (TOMCAT) and 154 (P-OBS) as well as discussions with the greater community in various GOOS workshops. We also thank Mike Sieracki, Cabell Davis, Daniele Iudicone, Eric Karsenti, Sebastien Colin, Colomban de Vargas, Ulf Riebesell, Fabrice Not, David Checkley, George Jackson, Cédric Guigand, Ed Urban, Frank Muller-Karger, Sanae Chiba and Daniel Dunn, who contributed to the initial abstracts to OceanObs'19. FL is supported by the Institut Universitaire de France. EB is supported by the NASA biology and biogeochemistry program. RKi and HH were supported by the German Science Foundation through the Collaborative Research Center 754 ‘Climate-Biogeochemistry Interactions in the Tropical Ocean’. SDA acknowledges the CNRS for her sabbatical year as visiting researcher at ISYEB on the use of genomics and next generation sequencing for plankton studies. HS acknowledges support from the Simons Foundation, the U.S. National Science Foundation, and the U.S. National Oceanic and Atmospheric Administration through the Cooperative Institute for the North Atlantic Region. FL and EB contribution was also inspired by their years of work within the Tara Expeditions initiative.

Description: Introduction: BCMA is a tumor necrosis factor (TNF) receptor superfamily transmembrane glycoprotein essential for the maturation and survival of plasma cells. CC-93269 is an asymmetric 2-arm humanized IgG TCE that binds bivalently to BCMA and monovalently to CD3ε in a 2+1 format (Seckinger A, et al. Cancer Cell. 2017;31:396-410). The CC-93269-mediated interaction between T cells and BCMA-expressing myeloma cells induces T cell receptor/CD3 crosslinking leading to T cell activation, and release of proinflammatory cytokines and cytolytic enzymes, resulting in myeloma cell death. In preclinical studies with CC-93269 and related molecules, 2+1 BCMA TCEs induced tumor regression in animal models and promoted myeloma cell death in primary pt myeloma cells. Here we report interim results from a phase 1 dose-finding study (CC-93269-MM-001; NCT03486067) evaluating CC-93269 in pts with RRMM. Methods: Eligible pts had RRMM and had received ≥ 3 prior regimens without prior BCMA-directed therapy. In dose escalation, CC-93269 was administered intravenously over 2 hours on Days 1, 8, 15, and 22 for Cycles 1-3; Days 1 and 15 for Cycles 4-6; and on Day 1 for Cycle 7 and beyond, all in 28-day cycles. Dose escalation involved 2 stages: in stage 1, CC-93269 was given in fixed doses; in stage 2, pts received a fixed first dose on Cycle 1 Day 1, followed by intrapatient dose escalation on Cycle 1 Day 8. Primary objectives were to assess the safety and tolerability of CC-93269 and define the maximum tolerated dose (MTD), non-tolerated dose (NTD), and/or recommended phase 2 dose (RP2D). Minimal residual disease (MRD) was assessed after clinical response in pt bone marrow aspirate samples by Next Generation Flow using the EuroFlow panel. MRD negativity was reported only if a minimum sensitivity of 〈 1 tumor cell in 105 nucleated cells was achieved. Results: As of May 24, 2019, 19 pts had received CC-93269. Median age was 64 years (range 51-78), with a median of 6.2 years (range 1.4-13.9) since initial diagnosis. The median number of prior regimens was 6 (range 3-12) and included treatment with autologous stem cell transplantation (73.7%), allogenic stem cell transplantation (10.5%), lenalidomide (100%), pomalidomide (84.2%), bortezomib (100%), carfilzomib (84.2%), and daratumumab (DARA; 94.7%). All pts had MM refractory to their last line of therapy, with 16 (88.9%) refractory to DARA, 17 (89.5%) to their last proteasome inhibitor, and 16 (84.2%) to their last immunomodulatory agent. CC-93269 doses ranged from 0.15 to 10 mg; median duration of treatment was 14.6 weeks (range 1.6-32.0) with pts receiving a median of 4 cycles (range 1-8). Grade 3-4 treatment-emergent adverse events were reported in 15 (78.9%) pts and included 10 (52.6%) pts with neutropenia, 8 (42.1%) with anemia, 5 (26.3%) with infections, and 4 (21.1%) with thrombocytopenia. No pt required dose modifications. Cytokine release syndrome (CRS) was reported in 17 (89.5%) pts, the majority of whom reported a maximum grade 1 (n = 11 [57.9%]) or grade 2 (n = 5 [26.3%]), and occurred most frequently with the first or second dose (n = 22 of 27 events [81.5%]). CRS prophylaxis was implemented with dexamethasone for first dose and dose increases in pts receiving ≥ 6 mg. Of 27 CRS events, 8 (29.6%) were managed with dexamethasone and 10 (37.0%) with tocilizumab. One pt receiving 6 mg CC-93269 as first dose and 10 mg on Cycle 1 Day 8 died on study in the setting of CRS, with a potential infection as a contributing factor. Dose-related pharmacodynamic activity, including peripheral blood immune cell redistribution and transient release of pro- and anti-inflammatory cytokines, was observed in pts. Of the 12 pts treated with ≥ 6 mg CC-93269 in Cycle 1, 10 pts achieved a partial response (PR) or better (overall response rate; 83.3%), including 7 (58.3%) with a very good partial response (VGPR) or better and 4 (33.3%) with a stringent complete response (sCR) (Table); 9 (75.0%) pts achieved MRD negativity. The median time to response was 4.2 weeks (range 4.0-13.1), and 10 of 10 responses were ongoing with follow-up ranging from 2.1 to 4.7 months. The NTD, MTD, and RP2D have not yet been reached. Conclusions: CC-93269, a 2+1 BCMA TCE, shows a manageable safety profile and promising efficacy, including MRD-negative sCRs, in pts with heavily pretreated RRMM. The study continues to enroll in the dose escalation phase. Updated safety and efficacy data will be presented at the meeting. Disclosures Costa: Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Karyopharm: Consultancy; Abbvie: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau. Wong:Genentech: Research Funding; Janssen: Research Funding; Celgene Corporation: Research Funding; Fortis: Research Funding; Juno: Research Funding. Bermúdez:MSD: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Fresenius: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de la Rubia:AMGEN: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Mateos:Pharmamar: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; EDO: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ocio:BMS: Honoraria; Sanofi: Research Funding; Mundipharma: Research Funding; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding; Pharmamar: Consultancy; Novartis: Consultancy, Honoraria; AbbVie: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Rodríguez-Otero:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Takeda: Consultancy; BMS: Honoraria; Kite Pharma: Consultancy. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Li:Celgene Corporation: Employment, Equity Ownership. Sarmiento:Celgene Corporation: Employment. Lardelli:Celgene Corporation: Employment, Equity Ownership. Gaudy:Celgene Corporation: Employment, Equity Ownership. Boss:Celgene Corporation: Employment, Equity Ownership. Kelly:Celgene Corporation: Employment. Burgess:University of California: Other: Volunteer clinical faculty, without salary, Patents & Royalties: Patent - T315A and F317I mutations of BCR-ABL kinase domain; Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: Patent - CD47 antibodies and methods of use thereof. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant.

Description: Background: Loss of immune surveillance, mediated through immune checkpoint (ICP) interactions, is thought to be a key step in the development of cancers including AML and HR-MDS. AZA is a standard therapy for pts with AML who are unfit for IC and for pts with HR-MDS. AZA can promote immune recognition of tumor cells and potentially increase expression of ICP molecules, which can mediate resistance to AZA. As myeloid cell lines and samples from pts treated with hypomethylating agents demonstrated up-regulation of PD-L1 expression, blockade of the PD-L1 ICP with durva in combination with AZA may enhance antitumor activity and improve clinical outcomes. Here, we report the final results from a large phase 2 study evaluating the efficacy and safety of AZA+durva vs. AZA alone in pts with HR-MDS or AML (NCT02775903). Methods: This randomized, open-label, international, multicenter study enrolled untreated pts in 2 cohorts: 1) MDS (aged ≥18 years; IPSS-R intermediate, high, and very high) and 2) older AML pts (aged ≥65 years) who were ineligible for IC. All pts had ECOG performance status 0-2 and were separately randomized (1:1) to receive SC AZA 75 mg/m2 Days 1-7 and durva 1500 mg IV on Day 1 Q4W (Arm A) or AZA alone (Arm B) and stratified according to cytogenetic risk (MDS, very good/good/intermediate vs. poor/very poor; AML, intermediate vs. poor). Treatment was planned to continue until progression or unacceptable toxicity. Disease status was evaluated every third treatment cycle. Primary MDS endpoints included overall response rate (ORR, defined as complete remission [CR], marrow [m]CR, partial response [PR], or hematologic improvement [HI]) based on IWG 2006 response criteria, while for AML ORR was defined as CR or CR with incomplete blood recovery (CRi) based on modified IWG 2003 response criteria. Secondary endpoints included PFS, OS, and safety. Peripheral blood samples were collected to assess changes in DNA methylation using the EPIC methylation array (Illumina). Bone marrow (BM) aspirates were obtained for quantitation of PD-L1 surface expression by flow cytometry and values are reported as molecules of equivalent soluble fluorochrome. Results: A total of 213 pts, 84 with MDS (each arm, n=42) and 129 with AML (Arm A, n=64; Arm B, n=65) were randomized. As of October 31, 2018, 32 pts (MDS, n=14; AML, n=18) continued to receive trial treatment while 181 (MDS, n=70; AML, n=111) had discontinued. Baseline demographics and disease characteristics were generally balanced across treatment groups in both cohorts. Median number of treatment cycles for AML Arm A vs. B, 6.5 vs. 6.7; for MDS Arm A vs. B, 7.9 vs. 7.0. No statistically significant differences in ORR between treatment arms were observed in either cohort (Tables 1 and 2). In MDS Arm A vs. B, median OS was 11.6 vs. 16.7 months (mo) and PFS was 8.7 vs. 8.6 mo. In the AML cohort, median OS was 13.0 vs. 14.4 mo and PFS was 8.1 vs. 7.2 mo. Caution should be used when interpreting results because 〉50% of patients were censored. The most frequent TEAEs (≥15%) were hematologic and GI toxicity. In the MDS and AML cohorts, 7 and 17, respectively, immune-mediated AEs were observed; all were treated and resolved. AZA induced similar trends in global hypomethylation, along with focal hypomethylation of PD-L1 and PD-L2 gene loci, at the end of treatment cycle 1 in all treatment groups and cohorts. Mean PD-L1 surface expression in BM immune cells at baseline was highest in monocytes (MDS=1,425; AML=1,536), followed by granulocytes (MDS=550; AML=758) and myeloid blasts (MDS=532; AML=735). Increased surface expression of PD-L1, but not PD-L2, was observed at the end of treatment cycle 3 on BM granulocytes and monocytes from MDS pts and on BM monocytes from AML pts, but no increase was detected on myeloid blasts. Conclusions: To our knowledge, this is the first large randomized trial of AZA with or without ICP blockade in older unfit AML and HR-MDS pts reported to date. No clinically meaningful difference in efficacy was observed between treatments for either cohort. No new safety signals or potential overlapping risks were identified with the combination. While the hypomethylating activity of AZA on PD-L1 gene was confirmed, no treatment-mediated induction of PD-L1 surface expression was observed on myeloid blasts. Disclosures Zeidan: Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria. Voso:Novartis: Speakers Bureau; Celgene: Research Funding, Speakers Bureau. Taussig:Celgene: Research Funding. Boss:Celgene Corporation: Employment, Equity Ownership. Copeland:Celgene Corporation: Employment, Equity Ownership. Gray:Celgene Corporation: Employment, Equity Ownership. Previtali:Celgene Corporation: Employment, Equity Ownership. O'Connor:Celgene Corporation: Employment, Equity Ownership. Rose:Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. OffLabel Disclosure: Durvalumab is a PD-L1 blocking antibody indicated for the treatment of patients with 1) locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy, or 2) unresectable, stage 3 NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.

Description: Adenosine dialdehyde and nitrous oxide, specific S-adeno- sylhomocysteine hydrolase and methionine synthetase inhibitors, respectively, induced differentiation of the human promyelocytic cell line HL-60. Their effect did not appear to be mediated through changes in transmethylation or decreased S-adenosylmethionine synthesis because (1) there was little correlation between the concentrations of adenosine dialdehyde that induced differentiation and those that changed the ratio of the intracellular concentrations of S- adenosylmethionine to S-adenosylhomocysteine, and (2) inhibition of methionine adenosyltransferase by cycloleucine did not induce differentiation. The differentiation induced by adenosine dialdehyde was prevented by homocysteine and that by nitrous oxide was inversely related to the medium methionine concentration. This suggested that differentiation was secondary to decreased methionine synthesis.