High Cytotoxic Efficiency of Lentivirally and Alpharetrovirally Engineered CD19-Specific Chimeric Antigen Receptor Natural Killer Cells Against Acute Lymphoblastic Leukemia.

Abstract:

:Autologous chimeric antigen receptor-modified (CAR) T cells with specificity for CD19 showed potent antitumor efficacy in clinical trials against relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL). Contrary to T cells, natural killer (NK) cells kill their targets in a non-antigen-specific manner and do not carry the risk of inducing graft vs. host disease (GvHD), allowing application of donor-derived cells in an allogenic setting. Hence, unlike autologous CAR-T cells, therapeutic CD19-CAR-NK cells can be generated as an off-the-shelf product from healthy donors. Nevertheless, genetic engineering of peripheral blood (PB) derived NK cells remains challenging and optimized protocols are needed. In our study, we aimed to optimize the generation of CD19-CAR-NK cells by retroviral transduction to improve the high antileukemic capacity of NK cells. We compared two different retroviral vector platforms, the lentiviral and alpharetroviral, both in combination with two different transduction enhancers (Retronectin and Vectofusin-1). We further explored different NK cell isolation techniques (NK cell enrichment and CD3/CD19 depletion) to identify the most efficacious methods for genetic engineering of NK cells. Our results demonstrated that transduction of NK cells with RD114-TR pseudotyped retroviral vectors, in combination with Vectofusin-1 was the most efficient method to generate CD19-CAR-NK cells. Retronectin was potent in enhancing lentiviral/VSV-G gene delivery to NK cells but not alpharetroviral/RD114-TR. Furthermore, the Vectofusin-based transduction of NK cells with CD19-CARs delivered by alpharetroviral/RD114-TR and lentiviral/RD114-TR vectors outperformed lentiviral/VSV-G vectors. The final generated CD19-CAR-NK cells displayed superior cytotoxic activity against CD19-expressing target cells when compared to non-transduced NK cells achieving up to 90% specific killing activity. In summary, our findings present the use of RD114-TR pseudotyped retroviral particles in combination with Vectofusin-1 as a successful strategy to genetically modify PB-derived NK cells to achieve highly cytotoxic CD19-CAR-NK cells at high yield.

journal_name

Front Immunol

journal_title

Frontiers in immunology

authors

Müller S,Bexte T,Gebel V,Kalensee F,Stolzenberg E,Hartmann J,Koehl U,Schambach A,Wels WS,Modlich U,Ullrich E

doi

10.3389/fimmu.2019.03123

subject

Has Abstract

pub_date

2020-01-24 00:00:00

pages

3123

issn

1664-3224

journal_volume

10

pub_type

杂志文章
  • Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy.

    abstract::The approval of the first two monoclonal antibodies targeting CD38 (daratumumab) and SLAMF7 (elotuzumab) in late 2015 for treating relapsed and refractory multiple myeloma (RRMM) was a critical advance for immunotherapies for multiple myeloma (MM). Importantly, the outcome of patients continues to improve with the inc...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2018.01821

    authors: Cho SF,Anderson KC,Tai YT

    更新日期:2018-08-10 00:00:00

  • Variations in Cellular Responses of Mouse T Cells to Adenosine-5'-Triphosphate Stimulation Do Not Depend on P2X7 Receptor Expression Levels but on Their Activation and Differentiation Stage.

    abstract::A previous report has shown that regulatory T cells (Treg) were markedly more sensitive to adenosine-5'-triphosphate (ATP) than conventional T cells (Tconv). Another one has shown that Tregs and CD45RBlow Tconvs, but not CD45RBhigh Tconvs, displayed similar high sensitivity to ATP. We have previously reported that CD4...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2018.00360

    authors: Safya H,Mellouk A,Legrand J,Le Gall SM,Benbijja M,Kanellopoulos-Langevin C,Kanellopoulos JM,Bobé P

    更新日期:2018-02-27 00:00:00

  • B Cell Functions Can Be Modulated by Antimicrobial Peptides in Rainbow Trout Oncorhynchus mykiss: Novel Insights into the Innate Nature of B Cells in Fish.

    abstract::B cells in fish were recently proven to have potent innate immune activities like macrophages. This inspired us to further explore the innate nature of B cells in fish. Moreover, antimicrobial peptides (AMPs) are representative molecules of innate immunity, and they can modulate the functions of macrophages. These mak...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2017.00388

    authors: Zhang XJ,Wang P,Zhang N,Chen DD,Nie P,Li JL,Zhang YA

    更新日期:2017-04-04 00:00:00

  • Ontogeny of Tissue-Resident Macrophages.

    abstract::The origin of tissue-resident macrophages, crucial for homeostasis and immunity, has remained controversial until recently. Originally described as part of the mononuclear phagocyte system, macrophages were long thought to derive solely from adult blood circulating monocytes. However, accumulating evidence now shows t...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2015.00486

    authors: Hoeffel G,Ginhoux F

    更新日期:2015-09-22 00:00:00

  • Phagocytosis by Thrombocytes is a Conserved Innate Immune Mechanism in Lower Vertebrates.

    abstract::Thrombocytes, nucleated hemostatic blood cells of non-mammalian vertebrates, are regarded as the functional equivalent of anucleated mammalian platelets. Additional immune functions, including phagocytosis, have also been suggested for thrombocytes, but no conclusive molecular or cellular experimental evidence for the...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2014.00445

    authors: Nagasawa T,Nakayasu C,Rieger AM,Barreda DR,Somamoto T,Nakao M

    更新日期:2014-09-16 00:00:00

  • Expression and Localization of Paneth Cells and Their α-Defensins in the Small Intestine of Adult Mouse.

    abstract::Paneth cells contribute to intestinal innate immunity by sensing bacteria and secreting α-defensin. In Institute of Cancer Research (ICR) mice, α-defensin termed cryptdin (Crp) in Paneth cells consists of six major isoforms, Crp1 to 6. Despite accumulating evidences that α-defensin functions in controlling the intesti...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2020.570296

    authors: Nakamura K,Yokoi Y,Fukaya R,Ohira S,Shinozaki R,Nishida T,Kikuchi M,Ayabe T

    更新日期:2020-10-13 00:00:00

  • Targeting Head and Neck Cancer by Vaccination.

    abstract::Head and neck cancer (HNC) is a heterogeneous group of squamous cell cancers that affect the oral cavity, pharynx, and larynx. Worldwide, it is the sixth most common cancer but in parts of Southern and South-East Asia, HNC is one of the most common cancers. A significant proportion of HNC is driven by human papillomav...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2018.00830

    authors: Wang C,Dickie J,Sutavani RV,Pointer C,Thomas GJ,Savelyeva N

    更新日期:2018-04-23 00:00:00

  • Glycolysis Is Required for LPS-Induced Activation and Adhesion of Human CD14+CD16- Monocytes.

    abstract::Monocytes in humans consist of 3 subsets; CD14+CD16- (classical), CD14+CD16+ (intermediate) and CD14dimCD16+ (non-classical), which exhibit distinct and heterogeneous responses to activation. During acute inflammation CD14+CD16- monocytes are significantly elevated and migrate to the sites of injury via the adhesion c...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2019.02054

    authors: Lee MKS,Al-Sharea A,Shihata WA,Bertuzzo Veiga C,Cooney OD,Fleetwood AJ,Flynn MC,Claeson E,Palmer CS,Lancaster GI,Henstridge DC,Hamilton JA,Murphy AJ

    更新日期:2019-09-06 00:00:00

  • Characterization of the Porcine CLEC12A and Analysis of Its Expression on Blood Dendritic Cell Subsets.

    abstract::CLEC12A has been proposed as a suitable target for delivering antigen to dendritic cells (DCs) to enhance vaccine efficacy both in human and mouse. In this study, we have characterized the porcine homolog of CLEC12A (poCLEC12A). Using new monoclonal antibodies (mAb), raised against its ectodomain, poCLEC12A was found ...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2020.00863

    authors: Álvarez B,Nieto-Pelegrín E,Martínez de la Riva P,Toki D,Poderoso T,Revilla C,Uenishi H,Ezquerra A,Domínguez J

    更新日期:2020-05-13 00:00:00

  • An RORγt Oral Inhibitor Modulates IL-17 Responses in Peripheral Blood and Intestinal Mucosa of Crohn's Disease Patients.

    abstract::Background and Aims: Despite the negative results of blocking IL-17 in Crohn's disease (CD) patients, selective modulation of Th17-dependent responses warrants further study. Inhibition of retinoic acid-related orphan receptor gamma (RORγt), the master regulator of the Th17 signature, is currently being explored in in...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2018.02307

    authors: Bassolas-Molina H,Raymond E,Labadia M,Wahle J,Ferrer-Picón E,Panzenbeck M,Zheng J,Harcken C,Hughes R,Turner M,Smith D,Calderón-Gómez E,Esteller M,Carrasco A,Esteve M,Dotti I,Corraliza AM,Masamunt MC,Arajol C,Guardio

    更新日期:2018-10-22 00:00:00

  • Paclitaxel Enhances the Innate Immunity by Promoting NLRP3 Inflammasome Activation in Macrophages.

    abstract::Microtubules play critical roles in regulating the activation of NLRP3 inflammasome and microtubule-destabilizing agents such as colchicine have been shown to suppress the activation of this inflammasome. However, it remains largely unknown whether paclitaxel, a microtubule-stabilizing agent being used in cancer thera...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2019.00072

    authors: Zeng QZ,Yang F,Li CG,Xu LH,He XH,Mai FY,Zeng CY,Zhang CC,Zha QB,Ouyang DY

    更新日期:2019-01-29 00:00:00

  • A Neutrophil-Driven Inflammatory Signature Characterizes the Blood Transcriptome Fingerprint of Psoriasis.

    abstract::Transcriptome profiling approaches have been widely used to investigate the mechanisms underlying psoriasis pathogenesis. Most researchers have measured changes in transcript abundance in skin biopsies; relatively few have examined transcriptome changes in the blood. Although less relevant to the study of psoriasis pa...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2020.587946

    authors: Rawat A,Rinchai D,Toufiq M,Marr AK,Kino T,Garand M,Tatari-Calderone Z,Kabeer BSA,Krishnamoorthy N,Bedognetti D,Karim MY,Sastry KS,Chaussabel D

    更新日期:2020-11-24 00:00:00

  • Characterization of γδ T Cells from Zebrafish Provides Insights into Their Important Role in Adaptive Humoral Immunity.

    abstract::γδ T cells represent an evolutionarily primitive T cell subset characterized by distinct T cell receptors (TCRs) and innate and adaptive immune functions. However, the presence of this T cell subset in ancient vertebrates remains unclear. In this study, γδ T cells from a zebrafish (Danio rerio) model were subjected to...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2016.00675

    authors: Wan F,Hu CB,Ma JX,Gao K,Xiang LX,Shao JZ

    更新日期:2017-01-09 00:00:00

  • Ankylosing Spondylitis: A Trade Off of HLA-B27, ERAP, and Pathogen Interconnections? Focus on Sardinia.

    abstract::The frequency of HLA-B27 in patients with Ankylosing Spondylitis (AS) is over 85%. There are more than 170 recognized HLA-B27 alleles but the majority of them is not sufficiently represented for genetic association studies. So far only two alleles, the HLA-B*2706 in Asia and the HLA-B*2709 in Sardinia, have not been f...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2019.00035

    authors: Paladini F,Fiorillo MT,Tedeschi V,Cauli A,Mathieu A,Sorrentino R

    更新日期:2019-01-25 00:00:00

  • Functionally Convergent B Cell Receptor Sequences in Transgenic Rats Expressing a Human B Cell Repertoire in Response to Tetanus Toxoid and Measles Antigens.

    abstract::The identification and tracking of antigen-specific immunoglobulin (Ig) sequences within total Ig repertoires is central to high-throughput sequencing (HTS) studies of infections or vaccinations. In this context, public Ig sequences shared by different individuals exposed to the same antigen could be valuable markers ...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2017.01834

    authors: Bürckert JP,Dubois ARSX,Faison WJ,Farinelle S,Charpentier E,Sinner R,Wienecke-Baldacchino A,Muller CP

    更新日期:2017-12-22 00:00:00

  • Complement Inhibitors in Clinical Trials for Glomerular Diseases.

    abstract::Defective complement action is a cause of several human glomerular diseases including atypical hemolytic uremic syndrome (aHUS), anti-neutrophil cytoplasmic antibody mediated vasculitis (ANCA), C3 glomerulopathy, IgA nephropathy, immune complex membranoproliferative glomerulonephritis, ischemic reperfusion injury, lup...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2019.02166

    authors: Zipfel PF,Wiech T,Rudnick R,Afonso S,Person F,Skerka C

    更新日期:2019-09-27 00:00:00

  • Deletion of the Mineralocorticoid Receptor in Myeloid Cells Attenuates Central Nervous System Autoimmunity.

    abstract::Myeloid cells play an important role in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Monocytes, macrophages, and microglia can adopt two distinct phenotypes, with M1-polarized cells being more related to inflammation and autoimmunity while M2-polariz...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2017.01319

    authors: Montes-Cobos E,Schweingruber N,Li X,Fischer HJ,Reichardt HM,Lühder F

    更新日期:2017-10-13 00:00:00

  • Targeting Lipid Rafts-A Potential Therapy for COVID-19.

    abstract::COVID-19 is a global pandemic currently in an acute phase of rapid expansion. While public health measures remain the most effective protection strategy at this stage, when the peak passes, it will leave in its wake important health problems. Historically, very few viruses have ever been eradicated. Instead, the virus...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2020.574508

    authors: Sviridov D,Miller YI,Ballout RA,Remaley AT,Bukrinsky M

    更新日期:2020-09-29 00:00:00

  • Role of Epstein-Barr Virus in Pathogenesis and Racial Distribution of IgA Nephropathy.

    abstract::IgA nephropathy (IgAN) is the dominant type of primary glomerulonephritis worldwide. However, IgAN rarely affects African Blacks and is uncommon in African Americans. Polymeric IgA1 with galactose-deficient hinge-region glycans is recognized as auto-antigen by glycan-specific antibodies, leading to formation of circul...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2020.00267

    authors: Zachova K,Kosztyu P,Zadrazil J,Matousovic K,Vondrak K,Hubacek P,Julian BA,Moldoveanu Z,Novak Z,Kostovcikova K,Raska M,Mestecky J

    更新日期:2020-02-28 00:00:00

  • Neuroimmunology of Behavioral Comorbidities Associated With Cancer and Cancer Treatments.

    abstract::Behavioral comorbidities (depression, anxiety, fatigue, cognitive disturbances, and neuropathic pain) are prevalent in cancer patients and survivors. These mental and neurological health issues reduce quality-of-life, which is a significant societal concern given the increasing rates of long-term survival after variou...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2018.01195

    authors: Santos JC,Pyter LM

    更新日期:2018-06-07 00:00:00

  • Common Variable Immunodeficiency Non-Infectious Disease Endotypes Redefined Using Unbiased Network Clustering in Large Electronic Datasets.

    abstract::Common variable immunodeficiency (CVID) is increasingly recognized for its association with autoimmune and inflammatory complications. Despite recent advances in immunophenotypic and genetic discovery, clinical care of CVID remains limited by our inability to accurately model risk for non-infectious disease developmen...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2017.01740

    authors: Farmer JR,Ong MS,Barmettler S,Yonker LM,Fuleihan R,Sullivan KE,Cunningham-Rundles C,USIDNET Consortium.,Walter JE

    更新日期:2018-01-09 00:00:00

  • Pregnancy, Viral Infection, and COVID-19.

    abstract::Pregnancy comprises a unique immunological condition, to allow fetal development and to protect the host from pathogenic infections. Viral infections during pregnancy can disrupt immunological tolerance and may generate deleterious effects on the fetus. Despite these possible links between pregnancy and infection-indu...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2020.01672

    authors: Alberca RW,Pereira NZ,Oliveira LMDS,Gozzi-Silva SC,Sato MN

    更新日期:2020-07-07 00:00:00

  • CIITA-Driven MHC Class II Expressing Tumor Cells as Antigen Presenting Cell Performers: Toward the Construction of an Optimal Anti-tumor Vaccine.

    abstract::Construction of an optimal vaccine against tumors relies on the availability of appropriate tumor-specific antigens capable to stimulate CD4+ T helper cells (TH) and CD8+ cytolytic T cells (CTL). CTL are considered the major effectors of the anti-tumor adaptive immune response as they recognize antigens presented on M...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2019.01806

    authors: Accolla RS,Ramia E,Tedeschi A,Forlani G

    更新日期:2019-07-30 00:00:00

  • Ménage-à-Trois: The Ratio of Bicarbonate to CO2 and the pH Regulate the Capacity of Neutrophils to Form NETs.

    abstract::In this study, we identified and characterized the potential of a high ratio of bicarbonate to CO2 and a moderately alkaline pH to render neutrophils prone to undergo neutrophil extracellular trap (NET) formation. Both experimental settings increased the rate of spontaneous NET release and potentiated the NET-inducing...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2016.00583

    authors: Maueröder C,Mahajan A,Paulus S,Gößwein S,Hahn J,Kienhöfer D,Biermann MH,Tripal P,Friedrich RP,Munoz LE,Neurath MF,Becker C,Schett GA,Herrmann M,Leppkes M

    更新日期:2016-12-09 00:00:00

  • Structurally Mapping Antibody Repertoires.

    abstract::Every human possesses millions of distinct antibodies. It is now possible to analyze this diversity via next-generation sequencing of immunoglobulin genes (Ig-seq). This technique produces large volume sequence snapshots of B-cell receptors that are indicative of the antibody repertoire. In this paper, we enrich these...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2018.01698

    authors: Krawczyk K,Kelm S,Kovaltsuk A,Galson JD,Kelly D,Trück J,Regep C,Leem J,Wong WK,Nowak J,Snowden J,Wright M,Starkie L,Scott-Tucker A,Shi J,Deane CM

    更新日期:2018-07-23 00:00:00

  • Ly9 (CD229) Cell-Surface Receptor is Crucial for the Development of Spontaneous Autoantibody Production to Nuclear Antigens.

    abstract::The Signaling Lymphocyte Activation Molecule Family (SLAMF) genes, which encode cell-surface receptors that modulate innate and adaptive immune responses, lay within a genomic region of human and mouse chromosome 1 that confers a predisposition for the development of systemic lupus erythematosus (SLE). Herein, we demo...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2013.00225

    authors: de Salort J,Cuenca M,Terhorst C,Engel P,Romero X

    更新日期:2013-07-31 00:00:00

  • Factors Affecting the Immunity to Respiratory Syncytial Virus: From Epigenetics to Microbiome.

    abstract::Respiratory syncytial virus (RSV) is a common pathogen that infects virtually all children by 2 years of age and is the leading cause of hospitalization of infants worldwide. While most children experience mild symptoms, some children progress to severe lower respiratory tract infection. Those children with severe dis...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2018.00226

    authors: Fonseca W,Lukacs NW,Ptaschinski C

    更新日期:2018-02-19 00:00:00

  • Monkeying Around: Using Non-human Primate Models to Study NK Cell Biology in HIV Infections.

    abstract::Natural killer (NK) cells are the major innate effectors primed to eliminate virus-infected and tumor or neoplastic cells. Recent studies also suggest nuances in phenotypic and functional characteristics among NK cell subsets may further permit execution of regulatory and adaptive roles. Animal models, particularly no...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2019.01124

    authors: Manickam C,Shah SV,Nohara J,Ferrari G,Reeves RK

    更新日期:2019-05-22 00:00:00

  • Role of Dendritic Cells in Natural Immune Control of HIV-1 Infection.

    abstract::Dendritic cells (DCs) are professional antigen-presenting cells that link innate and adaptive immunity and are critical for the induction of protective immune responses against pathogens. Proportions of these cells are markedly decreased in the blood of untreated HIV-1-infected individuals, suggesting they might be in...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2019.01306

    authors: Martin-Gayo E,Yu XG

    更新日期:2019-06-06 00:00:00

  • Expression and Roles of Antimicrobial Peptides in Innate Defense of Airway Mucosa: Potential Implication in Cystic Fibrosis.

    abstract::The treatment of respiratory infections is associated with the dissemination of antibiotic resistance in the community and clinical settings. Development of new antibiotics is notoriously costly and slow; therefore, alternative strategies are needed. Antimicrobial peptides (AMPs), the central effector molecules of the...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2020.01198

    authors: Geitani R,Moubareck CA,Xu Z,Karam Sarkis D,Touqui L

    更新日期:2020-06-30 00:00:00