Publications by authors named "Todd A Fehniger"

88 Publications

Phase 1 trial of N-803, an IL-15 receptor agonist, with rituximab in patients with indolent non-Hodgkin lymphoma.

Clin Cancer Res 2021 Apr 8. Epub 2021 Apr 8.

Dept. of Medicine, Division of Oncology, Washington University in St. Louis School of Medicine

Purpose: N-803 is an IL-15 receptor superagonist complex, designed to optimize in vivo persistence and trans-presentation, thereby activating and expanding natural killer (NK) cells and CD8+ T cells. Monoclonal antibodies (mAb) direct FcR-bearing immune cells, including NK cells, to recognize and eliminate cancer targets. The ability of IL-15R agonists to enhance tumor-targeting mAbs in patients has not been previously reported.

Experimental Design: Relapsed/refractory indolent Non-Hodgkin's lymphoma patients were treated with rituximab and intravenous or subcutaneous N-803 on an open-label, dose-escalation phase 1 study using a 3+3 design (NCT02384954). Primary endpoint was maximum tolerated dose. Immune correlates were performed using multidimensional analysis via mass cytometry and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) which simultaneously measures protein and single-cell RNA expression.

Results: This immunotherapy combination was safe and well-tolerated and resulted in durable clinical responses including in rituximab-refractory patients. Subcutaneous N-803 plus rituximab induced sustained proliferation, expansion, and activation of peripheral blood NK cells and CD8 T cells, with increased NK cell and T cells present 8 weeks following last N-803 treatment. CITE-seq revealed a therapy-altered NK cell molecular program, including enhancement of AP-1 transcription factor. Further, the monocyte transcriptional program was remodeled with enhanced MHC expression and antigen-presentation genes.

Conclusions: N-803 combines with mAbs to enhance tumor-targeting in patients, and warrants further investigation in combination with immunotherapies.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4575DOI Listing
April 2021

Flow cytometry-based murine NK cell cytotoxicity assay.

STAR Protoc 2021 Mar 12;2(1):100262. Epub 2021 Jan 12.

Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Direct killing of diseased cells is a hallmark function of NK cells. This protocol describes a flow-based assay to measure activated murine NK cells' ability to kill target cells . Existing published protocols for assaying NK cell killing utilized the radioactive chromium release assay or were designed for human NK cells. This protocol details specifically an cytotoxicity assay using primary murine NK cells enriched from splenocytes that were activated with poly(I:C). For complete details on the use and execution of this protocol, please refer to Wagner et al. (2020).
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http://dx.doi.org/10.1016/j.xpro.2020.100262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806516PMC
March 2021

Memory-like natural killer cells for cancer immunotherapy.

Semin Hematol 2020 10 17;57(4):185-193. Epub 2020 Nov 17.

Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO. Electronic address:

Natural killer (NK) cells are cytotoxic innate lymphoid cells that protect the host from infection and mediate anti-tumor responses. Classically considered part of the innate immune system, NK cells were previously thought to not possess the specificity or enhanced recall responses associated with adaptive T and B lymphocytes. However, a large body of work has transformed these long-held divisions between innate and adaptive immunity; NK cell memory and memory-like responses are clearly established after hapten exposure, viral infection, and combined cytokine activation. These advances come with opportunities to translate innate NK cell recall responses into the clinic as cancer immunotherapy. Here, we review our current understanding of the heterogeneity of memory and memory-like NK cell responses, with distinct formation, molecular biology, and memory type functions. We elaborate on cytokine-induced memory-like NK cells and highlight their application as adoptive immunotherapy for cancer, and as a platform for engineering optimal NK cell anti-tumor responses.
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http://dx.doi.org/10.1053/j.seminhematol.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810422PMC
October 2020

A Pilot Study of Lenalidomide Maintenance Therapy after Autologous Transplantation in Relapsed or Refractory Classical Hodgkin Lymphoma.

Biol Blood Marrow Transplant 2020 12 20;26(12):2223-2228. Epub 2020 Aug 20.

Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. Electronic address:

For patients with relapsed or refractory classical Hodgkin lymphoma (cHL), salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) remains the standard of care. Even with this aggressive treatment strategy, 5-year progression-free survival is ≤50%, and there remains interest in maintenance strategies to improve long-term disease-free survival. Lenalidomide is an immunomodulatory agent with demonstrated activity in multiple subtypes of lymphoma including cHL, and has also been shown to improve both progression-free and overall survival as maintenance therapy after ASCT in multiple myeloma. This multicenter study evaluated maintenance lenalidomide after ASCT for patients with cHL. Patients were enrolled 60 to 90 days post-transplant and received oral lenalidomide on days 1 to 28 of 28-day cycles for a maximum of 18 cycles. Lenalidomide was started at 15 mg daily and increased to maximum of 25 mg daily if tolerated. The primary objective of this study was to assess the feasibility of this regimen, with a goal <30% rate of discontinuation at or before cycle 12 for drug-related reasons. Twenty-seven patients were enrolled and 26 received at least 1 dose of lenalidomide. With a median follow-up of 51.3 months (range, 12.2 to 76.2 months), 23 of 26 patients were alive. Median event-free survival was 9.4 months and median progression-free survival had not been reached, with 17 of 26 patients (65.4%) remaining in remission at last follow-up. Excluding 4 patients who discontinued therapy for progression and 2 who discontinued due to noncompliance, the discontinuation rate at or before cycle 12 was 52%. Treatment was complicated by a high frequency of hematologic adverse events, with 15 patients (58%) experiencing grade 3 to 4 hematologic toxicity and 5 (19%) experiencing grade 4 hematologic toxicity. We conclude that the regimen of maintenance lenalidomide explored in this study is not feasible for patients with cHL immediately following ASCT. An alternative lenalidomide dose or schedule may be better tolerated following ASCT for patients with relapsed or refractory cHL.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.017DOI Listing
December 2020

Multidimensional Analyses of Donor Memory-Like NK Cells Reveal New Associations with Response after Adoptive Immunotherapy for Leukemia.

Cancer Discov 2020 Dec 21;10(12):1854-1871. Epub 2020 Aug 21.

Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.

Natural killer (NK) cells are an emerging cancer cellular therapy and potent mediators of antitumor immunity. Cytokine-induced memory-like (ML) NK cellular therapy is safe and induces remissions in patients with acute myeloid leukemia (AML). However, the dynamic changes in phenotype that occur after NK-cell transfer that affect patient outcomes remain unclear. Here, we report comprehensive multidimensional correlates from ML NK cell-treated patients with AML using mass cytometry. These data identify a unique differentiated ML NK-cell phenotype distinct from conventional NK cells. Moreover, the inhibitory receptor NKG2A is a dominant, transcriptionally induced checkpoint important for ML, but not conventional NK-cell responses to cancer. The frequency of CD8α donor NK cells is negatively associated with AML patient outcomes after ML NK therapy. Thus, elucidating the multidimensional dynamics of donor ML NK cells revealed critical factors important for clinical response, and new avenues to enhance NK-cell therapeutics. SIGNIFICANCE: Mass cytometry reveals an memory-like NK-cell phenotype, where NKG2A is a dominant checkpoint, and CD8α is associated with treatment failure after ML NK-cell therapy. These findings identify multiple avenues for optimizing ML NK-cell immunotherapy for cancer and define mechanisms important for ML NK-cell function..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710923PMC
December 2020

CAR-modified memory-like NK cells exhibit potent responses to NK-resistant lymphomas.

Blood 2020 11;136(20):2308-2318

Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO.

Natural killer (NK) cells are a promising cellular immunotherapy for cancer. Cytokine-induced memory-like (ML) NK cells differentiate after activation with interleukin-12 (IL-12), IL-15, and IL-18, exhibit potent antitumor responses, and safely induce complete remissions in patients with leukemia. However, many cancers are not fully recognized via NK cell receptors. Chimeric antigen receptors (CARs) have been used to enhance tumor-specific recognition by effector lymphocytes. We hypothesized that ML differentiation and CAR engineering would result in complementary improvements in NK cell responses against NK-resistant cancers. To test this idea, peripheral blood ML NK cells were modified to express an anti-CD19 CAR (19-CAR-ML), which displayed significantly increased interferon γ production, degranulation, and specific killing against NK-resistant lymphoma lines and primary targets compared with nonspecific control CAR-ML NK cells or conventional CAR NK cells. The 19-CAR and ML responses were synergistic and CAR specific and required immunoreceptor tyrosine-based activation motif signaling. Furthermore, 19-CAR-ML NK cells generated from lymphoma patients exhibited improved responses against their autologous lymphomas. 19-CAR-ML NK cells controlled lymphoma burden in vivo and improved survival in human xenograft models. Thus, CAR engineering of ML NK cells enhanced responses against resistant cancers and warrants further investigation, with the potential to broaden ML NK cell recognition against a variety of NK cell-resistant tumors.
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http://dx.doi.org/10.1182/blood.2020006619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702478PMC
November 2020

CD56 regulates human NK cell cytotoxicity through Pyk2.

Elife 2020 06 8;9. Epub 2020 Jun 8.

Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States.

Human natural killer (NK) cells are defined as CD56CD3. Despite its ubiquitous expression on human NK cells the role of CD56 (NCAM) in human NK cell cytotoxic function has not been defined. In non-immune cells, NCAM can induce signaling, mediate adhesion, and promote exocytosis through interactions with focal adhesion kinase (FAK). Here we demonstrate that deletion of CD56 on the NK92 cell line leads to impaired cytotoxic function. CD56-knockout (KO) cells fail to polarize during immunological synapse (IS) formation and have severely impaired exocytosis of lytic granules. Phosphorylation of the FAK family member Pyk2 at tyrosine 402 is decreased in NK92 CD56-KO cells, demonstrating a functional link between CD56 and signaling in human NK cells. Cytotoxicity, lytic granule exocytosis, and the phosphorylation of Pyk2 are rescued by the reintroduction of CD56. These data highlight a novel functional role for CD56 in stimulating exocytosis and promoting cytotoxicity in human NK cells.
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http://dx.doi.org/10.7554/eLife.57346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358009PMC
June 2020

Stage-Specific Requirement for Eomes in Mature NK Cell Homeostasis and Cytotoxicity.

Cell Rep 2020 06;31(9):107720

Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Natural killer (NK) cells are cytotoxic innate lymphoid cells (ILCs) that mediate antiviral and antitumor responses and require the transcriptional regulator Eomesodermin (Eomes) for early development. However, the role of Eomes and its molecular program in mature NK cell biology is unclear. To address this, we develop a tamoxifen-inducible, type-1-ILC-specific (Ncr1-targeted) cre mouse and combine this with Eomes-floxed mice. Eomes deletion after normal NK cell ontogeny results in a rapid loss of NK cells (but not ILC1s), with a particularly profound effect on penultimately mature stage III NK cells. Mechanisms responsible for stage III reduction include increased apoptosis and impaired maturation from stage II precursors. Induced Eomes deletion also decreases NK cell cytotoxicity and abrogates in vivo rejection of major histocompatibility complex (MHC)-class-I-deficient cells. However, other NK cell functional responses, and stage IV NK cells, are largely preserved. These data indicate that mature NK cells have distinct Eomes-dependent and -independent stages.
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http://dx.doi.org/10.1016/j.celrep.2020.107720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265846PMC
June 2020

Potently Cytotoxic Natural Killer Cells Initially Emerge from Erythro-Myeloid Progenitors during Mammalian Development.

Dev Cell 2020 04 19;53(2):229-239.e7. Epub 2020 Mar 19.

Department of Medicine, Division of Hematology, Washington University in St Louis, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University in St Louis, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University in St Louis, St. Louis, MO 63110, USA. Electronic address:

Natural killer (NK) cells are a critical component of the innate immune system. However, their ontogenic origin has remained unclear. Here, we report that NK cell potential first arises from Hoxa KitCD41CD16/32 hematopoietic-stem-cell (HSC)-independent erythro-myeloid progenitors (EMPs) present in the murine yolk sac. EMP-derived NK cells and primary fetal NK cells, unlike their adult counterparts, exhibit robust degranulation in response to stimulation. Parallel studies using human pluripotent stem cells (hPSCs) revealed that HOXA CD34 progenitors give rise to NK cells that, similar to murine EMP-derived NK cells, harbor a potent cytotoxic degranulation bias. In contrast, hPSC-derived HOXA CD34 progenitors, as well as human cord blood CD34 cells, give rise to NK cells that exhibit an attenuated degranulation response but robustly produce inflammatory cytokines. Collectively, our studies identify an extra-embryonic origin of potently cytotoxic NK cells, suggesting that ontogenic origin is a relevant factor in designing hPSC-derived adoptive immunotherapies.
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http://dx.doi.org/10.1016/j.devcel.2020.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185477PMC
April 2020

Blood natural killer cell deficiency reveals an immunotherapy strategy for atopic dermatitis.

Sci Transl Med 2020 02;12(532)

Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.

Atopic dermatitis (AD) is a widespread, chronic skin disease associated with aberrant allergic inflammation. Current treatments involve either broad or targeted immunosuppression strategies. However, enhancing the immune system to control disease remains untested. We demonstrate that patients with AD harbor a blood natural killer (NK) cell deficiency that both has diagnostic value and improves with therapy. Multidimensional protein and RNA profiling revealed subset-level changes associated with enhanced NK cell death. Murine NK cell deficiency was associated with enhanced type 2 inflammation in the skin, suggesting that NK cells play a critical immunoregulatory role in this context. On the basis of these findings, we used an NK cell-boosting interleukin-15 (IL-15) superagonist and observed marked improvement in AD-like disease in mice. These findings reveal a previously unrecognized application of IL-15 superagonism, currently in development for cancer immunotherapy, as an immunotherapeutic strategy for AD.
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http://dx.doi.org/10.1126/scitranslmed.aay1005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433875PMC
February 2020

KIR B donors improve the outcome for AML patients given reduced intensity conditioning and unrelated donor transplantation.

Blood Adv 2020 02;4(4):740-754

Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN.

Natural killer (NK) cell recognition and killing of target cells are enhanced when inhibitory killer immunoglobulin-like receptors (KIR) are unable to engage their cognate HLA class I ligands. The genes of the KIR locus are organized into either KIR B haplotypes, containing 1 or more activating KIR genes or KIR A haplotypes, which lack those genes. Analysis of unrelated donor (URD) hematopoietic cell transplants (HCT), given to acute myeloid leukemia (AML) patients between 1988 and 2009, showed that KIR B haplotype donors were associated with better outcomes, primarily from relapse protection. Most of these transplants involved marrow grafts, fully myeloablative (MAC) preparative regimens, and significant HLA mismatch. Because the practice of HCT continues to evolve, with increasing use of reduced intensity conditioning (RIC), peripheral blood stem cell grafts, and better HLA match, we evaluated the impact of URD KIR genotype on HCT outcome for AML in the modern era (2010-2016). This analysis combined data from a prospective trial testing URD selection based on KIR genotypes (n = 243) with that from a larger contemporaneous cohort of transplants (n = 2419). We found that KIR B haplotype donors conferred a significantly reduced risk of leukemia relapse and improved disease-free survival after RIC, but not MAC HCT. All genes defining KIR B haplotypes were associated with relapse protection, which was significant only in transplant recipients expressing the C1 epitope of HLA-C. In the context of current HCT practice using RIC, selection of KIR B donors could reduce relapse and improve overall outcome for AML patients receiving an allogeneic HCT.
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http://dx.doi.org/10.1182/bloodadvances.2019001053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042994PMC
February 2020

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition).

Authors:
Andrea Cossarizza Hyun-Dong Chang Andreas Radbruch Andreas Acs Dieter Adam Sabine Adam-Klages William W Agace Nima Aghaeepour Mübeccel Akdis Matthieu Allez Larissa Nogueira Almeida Giorgia Alvisi Graham Anderson Immanuel Andrä Francesco Annunziato Achille Anselmo Petra Bacher Cosima T Baldari Sudipto Bari Vincenzo Barnaba Joana Barros-Martins Luca Battistini Wolfgang Bauer Sabine Baumgart Nicole Baumgarth Dirk Baumjohann Bianka Baying Mary Bebawy Burkhard Becher Wolfgang Beisker Vladimir Benes Rudi Beyaert Alfonso Blanco Dominic A Boardman Christian Bogdan Jessica G Borger Giovanna Borsellino Philip E Boulais Jolene A Bradford Dirk Brenner Ryan R Brinkman Anna E S Brooks Dirk H Busch Martin Büscher Timothy P Bushnell Federica Calzetti Garth Cameron Ilenia Cammarata Xuetao Cao Susanna L Cardell Stefano Casola Marco A Cassatella Andrea Cavani Antonio Celada Lucienne Chatenoud Pratip K Chattopadhyay Sue Chow Eleni Christakou Luka Čičin-Šain Mario Clerici Federico S Colombo Laura Cook Anne Cooke Andrea M Cooper Alexandra J Corbett Antonio Cosma Lorenzo Cosmi Pierre G Coulie Ana Cumano Ljiljana Cvetkovic Van Duc Dang Chantip Dang-Heine Martin S Davey Derek Davies Sara De Biasi Genny Del Zotto Gelo Victoriano Dela Cruz Michael Delacher Silvia Della Bella Paolo Dellabona Günnur Deniz Mark Dessing James P Di Santo Andreas Diefenbach Francesco Dieli Andreas Dolf Thomas Dörner Regine J Dress Diana Dudziak Michael Dustin Charles-Antoine Dutertre Friederike Ebner Sidonia B G Eckle Matthias Edinger Pascale Eede Götz R A Ehrhardt Marcus Eich Pablo Engel Britta Engelhardt Anna Erdei Charlotte Esser Bart Everts Maximilien Evrard Christine S Falk Todd A Fehniger Mar Felipo-Benavent Helen Ferry Markus Feuerer Andrew Filby Kata Filkor Simon Fillatreau Marie Follo Irmgard Förster John Foster Gemma A Foulds Britta Frehse Paul S Frenette Stefan Frischbutter Wolfgang Fritzsche David W Galbraith Anastasia Gangaev Natalio Garbi Brice Gaudilliere Ricardo T Gazzinelli Jens Geginat Wilhelm Gerner Nicholas A Gherardin Kamran Ghoreschi Lara Gibellini Florent Ginhoux Keisuke Goda Dale I Godfrey Christoph Goettlinger Jose M González-Navajas Carl S Goodyear Andrea Gori Jane L Grogan Daryl Grummitt Andreas Grützkau Claudia Haftmann Jonas Hahn Hamida Hammad Günter Hämmerling Leo Hansmann Goran Hansson Christopher M Harpur Susanne Hartmann Andrea Hauser Anja E Hauser David L Haviland David Hedley Daniela C Hernández Guadalupe Herrera Martin Herrmann Christoph Hess Thomas Höfer Petra Hoffmann Kristin Hogquist Tristan Holland Thomas Höllt Rikard Holmdahl Pleun Hombrink Jessica P Houston Bimba F Hoyer Bo Huang Fang-Ping Huang Johanna E Huber Jochen Huehn Michael Hundemer Christopher A Hunter William Y K Hwang Anna Iannone Florian Ingelfinger Sabine M Ivison Hans-Martin Jäck Peter K Jani Beatriz Jávega Stipan Jonjic Toralf Kaiser Tomas Kalina Thomas Kamradt Stefan H E Kaufmann Baerbel Keller Steven L C Ketelaars Ahad Khalilnezhad Srijit Khan Jan Kisielow Paul Klenerman Jasmin Knopf Hui-Fern Koay Katja Kobow Jay K Kolls Wan Ting Kong Manfred Kopf Thomas Korn Katharina Kriegsmann Hendy Kristyanto Thomas Kroneis Andreas Krueger Jenny Kühne Christian Kukat Désirée Kunkel Heike Kunze-Schumacher Tomohiro Kurosaki Christian Kurts Pia Kvistborg Immanuel Kwok Jonathan Landry Olivier Lantz Paola Lanuti Francesca LaRosa Agnès Lehuen Salomé LeibundGut-Landmann Michael D Leipold Leslie Y T Leung Megan K Levings Andreia C Lino Francesco Liotta Virginia Litwin Yanling Liu Hans-Gustaf Ljunggren Michael Lohoff Giovanna Lombardi Lilly Lopez Miguel López-Botet Amy E Lovett-Racke Erik Lubberts Herve Luche Burkhard Ludewig Enrico Lugli Sebastian Lunemann Holden T Maecker Laura Maggi Orla Maguire Florian Mair Kerstin H Mair Alberto Mantovani Rudolf A Manz Aaron J Marshall Alicia Martínez-Romero Glòria Martrus Ivana Marventano Wlodzimierz Maslinski Giuseppe Matarese Anna Vittoria Mattioli Christian Maueröder Alessio Mazzoni James McCluskey Mairi McGrath Helen M McGuire Iain B McInnes Henrik E Mei Fritz Melchers Susanne Melzer Dirk Mielenz Stephen D Miller Kingston H G Mills Hans Minderman Jenny Mjösberg Jonni Moore Barry Moran Lorenzo Moretta Tim R Mosmann Susann Müller Gabriele Multhoff Luis Enrique Muñoz Christian Münz Toshinori Nakayama Milena Nasi Katrin Neumann Lai Guan Ng Antonia Niedobitek Sussan Nourshargh Gabriel Núñez José-Enrique O'Connor Aaron Ochel Anna Oja Diana Ordonez Alberto Orfao Eva Orlowski-Oliver Wenjun Ouyang Annette Oxenius Raghavendra Palankar Isabel Panse Kovit Pattanapanyasat Malte Paulsen Dinko Pavlinic Livius Penter Pärt Peterson Christian Peth Jordi Petriz Federica Piancone Winfried F Pickl Silvia Piconese Marcello Pinti A Graham Pockley Malgorzata Justyna Podolska Zhiyong Poon Katharina Pracht Immo Prinz Carlo E M Pucillo Sally A Quataert Linda Quatrini Kylie M Quinn Helena Radbruch Tim R D J Radstake Susann Rahmig Hans-Peter Rahn Bartek Rajwa Gevitha Ravichandran Yotam Raz Jonathan A Rebhahn Diether Recktenwald Dorothea Reimer Caetano Reis e Sousa Ester B M Remmerswaal Lisa Richter Laura G Rico Andy Riddell Aja M Rieger J Paul Robinson Chiara Romagnani Anna Rubartelli Jürgen Ruland Armin Saalmüller Yvan Saeys Takashi Saito Shimon Sakaguchi Francisco Sala-de-Oyanguren Yvonne Samstag Sharon Sanderson Inga Sandrock Angela Santoni Ramon Bellmàs Sanz Marina Saresella Catherine Sautes-Fridman Birgit Sawitzki Linda Schadt Alexander Scheffold Hans U Scherer Matthias Schiemann Frank A Schildberg Esther Schimisky Andreas Schlitzer Josephine Schlosser Stephan Schmid Steffen Schmitt Kilian Schober Daniel Schraivogel Wolfgang Schuh Thomas Schüler Reiner Schulte Axel Ronald Schulz Sebastian R Schulz Cristiano Scottá Daniel Scott-Algara David P Sester T Vincent Shankey Bruno Silva-Santos Anna Katharina Simon Katarzyna M Sitnik Silvano Sozzani Daniel E Speiser Josef Spidlen Anders Stahlberg Alan M Stall Natalie Stanley Regina Stark Christina Stehle Tobit Steinmetz Hannes Stockinger Yousuke Takahama Kiyoshi Takeda Leonard Tan Attila Tárnok Gisa Tiegs Gergely Toldi Julia Tornack Elisabetta Traggiai Mohamed Trebak Timothy I M Tree Joe Trotter John Trowsdale Maria Tsoumakidou Henning Ulrich Sophia Urbanczyk Willem van de Veen Maries van den Broek Edwin van der Pol Sofie Van Gassen Gert Van Isterdael René A W van Lier Marc Veldhoen Salvador Vento-Asturias Paulo Vieira David Voehringer Hans-Dieter Volk Anouk von Borstel Konrad von Volkmann Ari Waisman Rachael V Walker Paul K Wallace Sa A Wang Xin M Wang Michael D Ward Kirsten A Ward-Hartstonge Klaus Warnatz Gary Warnes Sarah Warth Claudia Waskow James V Watson Carsten Watzl Leonie Wegener Thomas Weisenburger Annika Wiedemann Jürgen Wienands Anneke Wilharm Robert John Wilkinson Gerald Willimsky James B Wing Rieke Winkelmann Thomas H Winkler Oliver F Wirz Alicia Wong Peter Wurst Jennie H M Yang Juhao Yang Maria Yazdanbakhsh Liping Yu Alice Yue Hanlin Zhang Yi Zhao Susanne Maria Ziegler Christina Zielinski Jakob Zimmermann Arturo Zychlinsky

Eur J Immunol 2019 Oct;49(10):1457-1973

Max Planck Institute for Infection Biology, Berlin, Germany.

These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
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http://dx.doi.org/10.1002/eji.201970107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350392PMC
October 2019

Open-Sourced CIViC Annotation Pipeline to Identify and Annotate Clinically Relevant Variants Using Single-Molecule Molecular Inversion Probes.

JCO Clin Cancer Inform 2019 10;3:1-12

Washington University School of Medicine, St Louis, MO.

Purpose: Clinical targeted sequencing panels are important for identifying actionable variants for patients with cancer; however, existing approaches do not provide transparent and rationally designed clinical panels to accommodate the rapidly growing knowledge within oncology.

Materials And Methods: We used the Clinical Interpretations of Variants in Cancer (CIViC) database to develop an Open-Sourced CIViC Annotation Pipeline (OpenCAP). OpenCAP provides methods to identify variants within the CIViC database, build probes for variant capture, use probes on prospective samples, and link somatic variants to CIViC clinical relevance statements. OpenCAP was tested using a single-molecule molecular inversion probe (smMIP) capture design on 27 cancer samples from 5 tumor types. In total, 2,027 smMIPs were designed to target 111 eligible CIViC variants (61.5 kb of genomic space).

Results: When compared with orthogonal sequencing, CIViC smMIP sequencing demonstrated a 95% sensitivity for variant detection (n = 61 of 64 variants). Variant allele frequencies for variants identified on both sequencing platforms were highly concordant (Pearson's = 0.885; n = 61 variants). Moreover, for individuals with paired tumor and normal samples (n = 12), 182 clinically relevant variants missed by orthogonal sequencing were discovered by CIViC smMIP sequencing.

Conclusion: The OpenCAP design paradigm demonstrates the utility of an open-source and open-access database built on attendant community contributions with peer-reviewed interpretations. Use of a public repository for variant identification, probe development, and variant interpretation provides a transparent approach to build dynamic next-generation sequencing-based oncology panels.
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http://dx.doi.org/10.1200/CCI.19.00077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873961PMC
October 2019

MicroRNA-142 Is Critical for the Homeostasis and Function of Type 1 Innate Lymphoid Cells.

Immunity 2019 09 8;51(3):479-490.e6. Epub 2019 Aug 8.

Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, MO, USA. Electronic address:

Natural killer (NK) cells are cytotoxic type 1 innate lymphoid cells (ILCs) that defend against viruses and mediate anti-tumor responses, yet mechanisms controlling their development and function remain incompletely understood. We hypothesized that the abundantly expressed microRNA-142 (miR-142) is a critical regulator of type 1 ILC biology. Interleukin-15 (IL-15) signaling induced miR-142 expression, whereas global and ILC-specific miR-142-deficient mice exhibited a cell-intrinsic loss of NK cells. Death of NK cells resulted from diminished IL-15 receptor signaling within miR-142-deficient mice, likely via reduced suppressor of cytokine signaling-1 (Socs1) regulation by miR-142-5p. ILCs persisting in Mir142 mice demonstrated increased expression of the miR-142-3p target αV integrin, which supported their survival. Global miR-142-deficient mice exhibited an expansion of ILC1-like cells concurrent with increased transforming growth factor-β (TGF-β) signaling. Further, miR-142-deficient mice had reduced NK-cell-dependent function and increased susceptibility to murine cytomegalovirus (MCMV) infection. Thus, miR-142 critically integrates environmental cues for proper type 1 ILC homeostasis and defense against viral infection.
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http://dx.doi.org/10.1016/j.immuni.2019.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750984PMC
September 2019

Mystery Solved: IL-15.

Authors:
Todd A Fehniger

J Immunol 2019 06;202(11):3125-3126

Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110

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http://dx.doi.org/10.4049/jimmunol.1900419DOI Listing
June 2019

A deep learning approach to automate refinement of somatic variant calling from cancer sequencing data.

Nat Genet 2018 12 5;50(12):1735-1743. Epub 2018 Nov 5.

McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.

Cancer genomic analysis requires accurate identification of somatic variants in sequencing data. Manual review to refine somatic variant calls is required as a final step after automated processing. However, manual variant refinement is time-consuming, costly, poorly standardized, and non-reproducible. Here, we systematized and standardized somatic variant refinement using a machine learning approach. The final model incorporates 41,000 variants from 440 sequencing cases. This model accurately recapitulated manual refinement labels for three independent testing sets (13,579 variants) and accurately predicted somatic variants confirmed by orthogonal validation sequencing data (212,158 variants). The model improves on manual somatic refinement by reducing bias on calls otherwise subject to high inter-reviewer variability.
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http://dx.doi.org/10.1038/s41588-018-0257-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428590PMC
December 2018

Lenalidomide consolidation benefits patients with CLL receiving chemoimmunotherapy: results for CALGB 10404 (Alliance).

Blood Adv 2018 07;2(14):1705-1718

Department of Medicine, University of Chicago Comprehensive Cancer Center, Chicago, IL.

Prior to novel targeted agents for chronic lymphocytic leukemia (CLL), the best chemoimmunotherapy regimen in patients with non-del(11q) disease was unclear. The role of lenalidomide was also not defined. This phase 2 study randomized 342 untreated patients with non-del(11q) CLL requiring therapy to fludarabine plus rituximab (FR; n = 123), FR plus lenalidomide consolidation (FR+L; n = 109), or FR plus cyclophosphamide (FCR; n = 110) and compared 2-year progression-free survival (PFS) rates of each to the historical control rate with FC (60%). Patients with del(11q) in at least 20% of pretreatment cells continued with FCR (n = 27) or were reassigned to FCR+L (n = 31) and excluded from the primary analysis. Among non-del(11q) patients, 2-year PFS rates were 64% (90% confidence interval [CI], 57-71; FR), 72% (90% CI, 65-79; FR+L), and 74% (90% CI, 66-80; FCR); FR+L and FCR had rates significantly greater than historical control. Median PFS was significantly shorter with FR compared with FR+L ( = .04) and FCR ( < .001): 43 (95% CI, 33-50), 61 (95% CI, 45-71), and 97 (95% CI, 61 to not reached) months, respectively. Median follow-up was 73 months and median overall survival (OS) was only reached with FCR (101 months; 95% CI, 96 to not reached). With FR+L, the risk of death decreased over time and was lower than with FR at later time points ( = .01), but not significantly different from FCR ( = .21). Future studies incorporating short courses of lenalidomide into other novel treatment regimens are justified.
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http://dx.doi.org/10.1182/bloodadvances.2017015396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058242PMC
July 2018

Comment on: Evidence of innate lymphoid cell redundancy in humans.

Nat Immunol 2018 08;19(8):788-789

Department of Pediatrics, Division of Rheumatology, Washington University, St. Louis, MO, USA.

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http://dx.doi.org/10.1038/s41590-018-0164-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736524PMC
August 2018

Loss-of-Function Mutations Derepress ASH1L to Increase Gene Expression and Promote Leukemogenesis.

Cancer Res 2018 07 3;78(13):3510-3521. Epub 2018 May 3.

Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.

Point mutations in the seed sequence of miR-142-3p are present in a subset of acute myelogenous leukemia (AML) and in several subtypes of B-cell lymphoma. Here, we show that mutations associated with AML result both in loss of miR-142-3p function and in decreased miR-142-5p expression. loss altered the hematopoietic differentiation of multipotent hematopoietic progenitors, enhancing their myeloid potential while suppressing their lymphoid potential. During hematopoietic maturation, loss of increased ASH1L protein expression and consequently resulted in the aberrant maintenance of gene expression in myeloid-committed hematopoietic progenitors. loss also enhanced the disease-initiating activity of -mutant hematopoietic cells in mice. Together these data suggest a novel model in which miR-142, through repression of ASH1L activity, plays a key role in suppressing expression during normal myeloid differentiation. AML-associated loss-of-function mutations of disrupt this negative signaling pathway, resulting in sustained expression in myeloid progenitors/myeloblasts and ultimately contributing to leukemic transformation. These findings provide mechanistic insights into the role of miRNAs in leukemogenesis and hematopoietic stem cell function. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-3592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030481PMC
July 2018

A Phase 1 Trial of CNDO-109-Activated Natural Killer Cells in Patients with High-Risk Acute Myeloid Leukemia.

Biol Blood Marrow Transplant 2018 08 27;24(8):1581-1589. Epub 2018 Mar 27.

Fortress Biotech, Inc., New York, New York.

Natural killer (NK) cells are an emerging immunotherapy approach to acute myeloid leukemia (AML); however, the optimal approach to activate NK cells before adoptive transfer remains unclear. Human NK cells that are primed with the CTV-1 leukemia cell line lysate CNDO-109 exhibit enhanced cytotoxicity against NK cell-resistant cell lines. To translate this finding to the clinic, CNDO-109-activated NK cells (CNDO-109-NK cells) isolated from related HLA-haploidentical donors were evaluated in a phase 1 dose-escalation trial at doses of 3 × 10 (n = 3), 1 × 10 (n = 3), and 3 × 10 (n = 6) cells/kg in patients with AML in first complete remission (CR1) at high risk for recurrence. Before CNDO-109-NK cell administration, patients were treated with lymphodepleting fludarabine/cyclophosphamide. CNDO-109-NK cells were well tolerated, and no dose-limiting toxicities were observed at the highest tested dose. The median relapse-free survival (RFS) by dose level was 105 (3 × 10), 156 (1 × 10), and 337 (3 × 10) days. Two patients remained relapse-free in post-trial follow-up, with RFS durations exceeding 42.5 months. Donor NK cell microchimerism was detected on day 7 in 10 of 12 patients, with 3 patients having evidence of donor cells on day 14 or later. This trial establishes that CNDO-109-NK cells generated from related HLA haploidentical donors, cryopreserved, and then safely administered to AML patients with transient persistence without exogenous cytokine support. Three durable complete remissions of 32.6 to 47.6+ months were observed, suggesting additional clinical investigation of CNDO-109-NK cells for patients with myeloid malignancies, alone or in combination with additional immunotherapy strategies, is warranted.
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http://dx.doi.org/10.1016/j.bbmt.2018.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232080PMC
August 2018

First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation.

Blood 2018 06 20;131(23):2515-2527. Epub 2018 Feb 20.

Blood and Marrow Transplant Program and.

New therapies for patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) are needed. Interleukin 15 (IL-15) is a cytokine that stimulates CD8 T-cell and natural killer (NK) cell antitumor responses, and we hypothesized this cytokine may augment antileukemia/antilymphoma immunity in vivo. To test this, we performed a first-in-human multicenter phase 1 trial of the IL-15 superagonist complex ALT-803 in patients who relapsed >60 days after allo-HCT. ALT-803 was administered to 33 patients via the IV or subcutaneous (SQ) routes once weekly for 4 doses (dose levels of 1, 3, 6, and 10 μg/kg). ALT-803 was well tolerated, and no dose-limiting toxicities or treatment-emergent graft-versus-host disease requiring systemic therapy was observed in this clinical setting. Adverse events following IV administration included constitutional symptoms temporally related to increased serum IL-6 and interferon-γ. To mitigate these effects, the SQ route was tested. SQ delivery resulted in self-limited injection site rashes infiltrated with lymphocytes without acute constitutional symptoms. Pharmacokinetic analysis revealed prolonged (>96 hour) serum concentrations following SQ, but not IV, injection. ALT-803 stimulated the activation, proliferation, and expansion of NK cells and CD8 T cells without increasing regulatory T cells. Responses were observed in 19% of evaluable patients, including 1 complete remission lasting 7 months. Thus, ALT-803 is a safe, well-tolerated agent that significantly increased NK and CD8 T cell numbers and function. This immunostimulatory IL-15 superagonist warrants further investigation to augment antitumor immunity alone and combined with other immunotherapies. This trial was registered at www.clinicaltrials.gov as #NCT01885897.
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http://dx.doi.org/10.1182/blood-2017-12-823757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992862PMC
June 2018

Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination? Vaccination Strategies Based on NK Cell and ILC Memory.

Cold Spring Harb Perspect Biol 2018 10 1;10(10). Epub 2018 Oct 1.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110.

Studies over the last decade have decisively shown that innate immune natural killer (NK) cells exhibit enhanced long-lasting functional responses following a single activation event. With the increased recognition of memory and memory-like properties of NK cells, questions have arisen with regard to their ability to effectively mediate vaccination responses in humans. Moreover, recently discovered innate lymphoid cells (ILCs) could also potentially exhibit memory-like functions. Here, we review different forms of NK cell memory, and speculate about the ability of these cells and ILCs to meaningfully contribute to vaccination responses.
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http://dx.doi.org/10.1101/cshperspect.a029512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169813PMC
October 2018

Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control.

JCI Insight 2017 12 7;2(23). Epub 2017 Dec 7.

Department of Pediatrics, Division of Rheumatology, Washington University School of Medicine, St. Louis, Missouri, USA.

NK cell activation has been shown to be metabolically regulated in vitro; however, the role of metabolism during in vivo NK cell responses to infection is unknown. We examined the role of glycolysis in NK cell function during murine cytomegalovirus (MCMV) infection and the ability of IL-15 to prime NK cells during CMV infection. The glucose metabolism inhibitor 2-deoxy-ᴅ-glucose (2DG) impaired both mouse and human NK cell cytotoxicity following priming in vitro. Similarly, MCMV-infected mice treated with 2DG had impaired clearance of NK-specific targets in vivo, which was associated with higher viral burden and susceptibility to infection on the C57BL/6 background. IL-15 priming is known to alter NK cell metabolism and metabolic requirements for activation. Treatment with the IL-15 superagonist ALT-803 rescued mice from otherwise lethal infection in an NK-dependent manner. Consistent with this, treatment of a patient with ALT-803 for recurrent CMV reactivation after hematopoietic cell transplant was associated with clearance of viremia. These studies demonstrate that NK cell-mediated control of viral infection requires glucose metabolism and that IL-15 treatment in vivo can reduce this requirement and may be effective as an antiviral therapy.
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http://dx.doi.org/10.1172/jci.insight.95128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752285PMC
December 2017

Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial.

Blood 2018 01 26;131(2):182-190. Epub 2017 Oct 26.

Division of Oncology and Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO.

Most patients with follicular lymphoma (FL) experience multiple relapses necessitating subsequent lines of therapy. Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor approved for the treatment of several B-cell malignancies, showed promising activity in FL in a phase 1 study. We report the results of a phase 2 trial evaluating ibrutinib in recurrent FL. Forty patients with recurrent FL were treated with ibrutinib 560 mg/d until progression or intolerance. The primary end point was overall response rate (ORR). Exploratory analyses included correlations of outcome with recurrent mutations identified in a cancer gene panel that used next-generation sequencing in pretreatment biopsies from 31 patients and results of early interim positron emission tomography/computed tomography scans in 20 patients. ORR was 37.5% with a complete response rate of 12.5%, median progression-free survival (PFS) of 14 months, and 2-year PFS of 20.4%. Response rates were significantly higher among patients whose disease was sensitive to rituximab (52.6%) compared with those who were rituximab refractory (16.7%) ( = .04). CARD11 mutations were present in 16% of patients (5 of 31) and predicted resistance to ibrutinib with only wild-type patients responding ( = .002). Maximum standardized uptake value at cycle 1 day 8 correlated with response and PFS. Ibrutinib was well-tolerated with a toxicity profile similar to labeled indications. Ibrutinib is a well-tolerated treatment with modest activity in relapsed FL. Evaluation of BTK inhibitors in earlier lines of therapy may be warranted on the basis of improved response rates in rituximab-sensitive disease. Somatic mutations such as may have an impact on response to ibrutinib, may inform clinical decisions, and should be evaluated in larger data sets. This trial was registered at www.clinicaltrials.gov as #NCT01849263.
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http://dx.doi.org/10.1182/blood-2017-09-804641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757691PMC
January 2018

Patterns of infectious complications in acute myeloid leukemia and myelodysplastic syndromes patients treated with 10-day decitabine regimen.

Cancer Med 2017 Dec 23;6(12):2814-2821. Epub 2017 Oct 23.

Department of Internal Medicine, Division of Oncology, Washington University, Saint Louis, Missouri.

Decitabine has been explored as a reduced-intensity therapy for older or unfit patients with acute myeloid leukemia (AML). To better understand the risk of infections during decitabine treatment, we retrospectively examined the culture results from each infection-related serious adverse event that occurred among 85 AML and myelodysplastic syndromes (MDS) patients treated in a prospective clinical study using 10-day cycles of decitabine at Washington University School of Medicine. Culture results were available for 163 infection-related complications that occurred in 70 patients: 90 (55.2%) events were culture-negative, 32 (19.6%) were gram-positive bacteria, 20 (12.3%) were gram-negative bacteria, 12 (7.4%) were mixed, 6 (3.7%) were viral, 2 (1.2%) were fungal, and 1 (0.6%) was mycobacterial. Infection-related mortality occurred in 3/24 (13%) of gram-negative events, and 0/51 gram-positive events. On average, nearly one third of patients experienced an infection-related complication with each cycle, and the incidence did not decrease during later cycles. In summary, in patients receiving 10-day decitabine, infectious complications are common and may occur during any cycle of therapy. Although febrile events are commonly culture-negative, gram-positive infections are the most frequent source of culture-positive infections, but gram-negative infections represent a significant risk of mortality in AML and MDS patients treated with decitabine.
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http://dx.doi.org/10.1002/cam4.1231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727246PMC
December 2017

Guidelines for the use of flow cytometry and cell sorting in immunological studies.

Authors:
Andrea Cossarizza Hyun-Dong Chang Andreas Radbruch Mübeccel Akdis Immanuel Andrä Francesco Annunziato Petra Bacher Vincenzo Barnaba Luca Battistini Wolfgang M Bauer Sabine Baumgart Burkhard Becher Wolfgang Beisker Claudia Berek Alfonso Blanco Giovanna Borsellino Philip E Boulais Ryan R Brinkman Martin Büscher Dirk H Busch Timothy P Bushnell Xuetao Cao Andrea Cavani Pratip K Chattopadhyay Qingyu Cheng Sue Chow Mario Clerici Anne Cooke Antonio Cosma Lorenzo Cosmi Ana Cumano Van Duc Dang Derek Davies Sara De Biasi Genny Del Zotto Silvia Della Bella Paolo Dellabona Günnur Deniz Mark Dessing Andreas Diefenbach James Di Santo Francesco Dieli Andreas Dolf Vera S Donnenberg Thomas Dörner Götz R A Ehrhardt Elmar Endl Pablo Engel Britta Engelhardt Charlotte Esser Bart Everts Anita Dreher Christine S Falk Todd A Fehniger Andrew Filby Simon Fillatreau Marie Follo Irmgard Förster John Foster Gemma A Foulds Paul S Frenette David Galbraith Natalio Garbi Maria Dolores García-Godoy Jens Geginat Kamran Ghoreschi Lara Gibellini Christoph Goettlinger Carl S Goodyear Andrea Gori Jane Grogan Mor Gross Andreas Grützkau Daryl Grummitt Jonas Hahn Quirin Hammer Anja E Hauser David L Haviland David Hedley Guadalupe Herrera Martin Herrmann Falk Hiepe Tristan Holland Pleun Hombrink Jessica P Houston Bimba F Hoyer Bo Huang Christopher A Hunter Anna Iannone Hans-Martin Jäck Beatriz Jávega Stipan Jonjic Kerstin Juelke Steffen Jung Toralf Kaiser Tomas Kalina Baerbel Keller Srijit Khan Deborah Kienhöfer Thomas Kroneis Désirée Kunkel Christian Kurts Pia Kvistborg Joanne Lannigan Olivier Lantz Anis Larbi Salome LeibundGut-Landmann Michael D Leipold Megan K Levings Virginia Litwin Yanling Liu Michael Lohoff Giovanna Lombardi Lilly Lopez Amy Lovett-Racke Erik Lubberts Burkhard Ludewig Enrico Lugli Holden T Maecker Glòria Martrus Giuseppe Matarese Christian Maueröder Mairi McGrath Iain McInnes Henrik E Mei Fritz Melchers Susanne Melzer Dirk Mielenz Kingston Mills David Mirrer Jenny Mjösberg Jonni Moore Barry Moran Alessandro Moretta Lorenzo Moretta Tim R Mosmann Susann Müller Werner Müller Christian Münz Gabriele Multhoff Luis Enrique Munoz Kenneth M Murphy Toshinori Nakayama Milena Nasi Christine Neudörfl John Nolan Sussan Nourshargh José-Enrique O'Connor Wenjun Ouyang Annette Oxenius Raghav Palankar Isabel Panse Pärt Peterson Christian Peth Jordi Petriz Daisy Philips Winfried Pickl Silvia Piconese Marcello Pinti A Graham Pockley Malgorzata Justyna Podolska Carlo Pucillo Sally A Quataert Timothy R D J Radstake Bartek Rajwa Jonathan A Rebhahn Diether Recktenwald Ester B M Remmerswaal Katy Rezvani Laura G Rico J Paul Robinson Chiara Romagnani Anna Rubartelli Beate Ruckert Jürgen Ruland Shimon Sakaguchi Francisco Sala-de-Oyanguren Yvonne Samstag Sharon Sanderson Birgit Sawitzki Alexander Scheffold Matthias Schiemann Frank Schildberg Esther Schimisky Stephan A Schmid Steffen Schmitt Kilian Schober Thomas Schüler Axel Ronald Schulz Ton Schumacher Cristiano Scotta T Vincent Shankey Anat Shemer Anna-Katharina Simon Josef Spidlen Alan M Stall Regina Stark Christina Stehle Merle Stein Tobit Steinmetz Hannes Stockinger Yousuke Takahama Attila Tarnok ZhiGang Tian Gergely Toldi Julia Tornack Elisabetta Traggiai Joe Trotter Henning Ulrich Marlous van der Braber René A W van Lier Marc Veldhoen Salvador Vento-Asturias Paulo Vieira David Voehringer Hans-Dieter Volk Konrad von Volkmann Ari Waisman Rachael Walker Michael D Ward Klaus Warnatz Sarah Warth James V Watson Carsten Watzl Leonie Wegener Annika Wiedemann Jürgen Wienands Gerald Willimsky James Wing Peter Wurst Liping Yu Alice Yue Qianjun Zhang Yi Zhao Susanne Ziegler Jakob Zimmermann

Eur J Immunol 2017 10;47(10):1584-1797

Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Murtenstrasse, Bern.

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http://dx.doi.org/10.1002/eji.201646632DOI Listing
October 2017

CD56bright NK cells exhibit potent antitumor responses following IL-15 priming.

J Clin Invest 2017 Nov 3;127(11):4042-4058. Epub 2017 Oct 3.

Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.

NK cells, lymphocytes of the innate immune system, are important for defense against infectious pathogens and cancer. Classically, the CD56dim NK cell subset is thought to mediate antitumor responses, whereas the CD56bright subset is involved in immunomodulation. Here, we challenge this paradigm by demonstrating that brief priming with IL-15 markedly enhanced the antitumor response of CD56bright NK cells. Priming improved multiple CD56bright cell functions: degranulation, cytotoxicity, and cytokine production. Primed CD56bright cells from leukemia patients demonstrated enhanced responses to autologous blasts in vitro, and primed CD56bright cells controlled leukemia cells in vivo in a murine xenograft model. Primed CD56bright cells from multiple myeloma (MM) patients displayed superior responses to autologous myeloma targets, and furthermore, CD56bright NK cells from MM patients primed with the IL-15 receptor agonist ALT-803 in vivo displayed enhanced ex vivo functional responses to MM targets. Effector mechanisms contributing to IL-15-based priming included improved cytotoxic protein expression, target cell conjugation, and LFA-1-, CD2-, and NKG2D-dependent activation of NK cells. Finally, IL-15 robustly stimulated the PI3K/Akt/mTOR and MEK/ERK pathways in CD56bright compared with CD56dim NK cells, and blockade of these pathways attenuated antitumor responses. These findings identify CD56bright NK cells as potent antitumor effectors that warrant further investigation as a cancer immunotherapy.
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http://dx.doi.org/10.1172/JCI90387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663359PMC
November 2017

CD70 turns on NK cells to attack lymphoma.

Authors:
Todd A Fehniger

Blood 2017 07;130(3):238-239

WASHINGTON UNIVERSITY SCHOOL OF MEDICINE.

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http://dx.doi.org/10.1182/blood-2017-06-786244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520476PMC
July 2017