DOCSLIB.ORG

Immunological Analysis of Phase II Glioblastoma Dendritic Cell Vaccine

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Immunological Analysis of Phase II Glioblastoma Dendritic Cell Vaccine Erhart et al. Acta Neuropathologica Communications (2018) 6:135 https://doi.org/10.1186/s40478-018-0621-2 RESEARCH Open Access Immunological analysis of phase II glioblastoma dendritic cell vaccine (Audencel) trial: immune system characteristics influence outcome and Audencel up-regulates Th1-related immunovariables Friedrich Erhart1,2* , Johanna Buchroithner3, René Reitermaier4, Katrin Fischhuber4, Simone Klingenbrunner4, Ido Sloma5, Dror Hibsh5, Renana Kozol5, Sol Efroni5, Gerda Ricken1, Adelheid Wöhrer1, Christine Haberler1, Johannes Hainfellner1, Günther Krumpl4, Thomas Felzmann4, Alexander M. Dohnal6, Christine Marosi7 and Carmen Visus4 Abstract Audencel is a dendritic cell (DC)-based cellular cancer immunotherapy against glioblastoma multiforme (GBM). It is characterized by loading of DCs with autologous whole tumor lysate and in vitro maturation via “danger signals”. The recent phase II “GBM-Vax” trial showed no clinical efficacy for Audencel as assessed with progression-free and overall survival in all patients. Here we present immunological research accompanying the trial with a focus on immune system factors related to outcome and Audencel’s effect on the immune system. Methodologically, peripheral blood samples (from apheresis before Audencel or venipuncture during Audencel) were subjected to functional characterization via enzyme-linked immunospot (ELISPOT) assays connected with cytokine bead assays (CBAs) as well as phenotypical characterization via flow cytometry and mRNA quantification. GBM tissue samples (from surgery) were subjected to T cell receptor sequencing and immunohistochemistry. As results we found: Patients with favorable pre-existing anti-tumor characteristics lived longer under Audencel than Audencel patients without them. Pre-vaccination blood CD8+ T cell count and ELISPOT Granzyme B production capacity in vitro upon tumor antigen exposure were significantly correlated with overall survival. Despite Audencel’s general failure to induce a significant clinical response, it nevertheless seemed to have an effect on the immune system. For instance, Audencel led to a significant up-regulation of the Th1-related immunovariables ELISPOT IFNγ, the transcription factor T-bet in the blood and ELISPOT IL-2 in a dose-dependent manner upon vaccination. Post-vaccination levels of ELISPOT IFNγ and CD8+ cells in the blood were indicative of a significantly better survival. In summary, Audencel failed to reach an improvement of survival in the recent phase II clinical trial. No clinical efficacy was registered. Our concomitant immunological work presented here indicates that outcome under Audencel was influenced by the (Continued on next page) * Correspondence: [email protected] 1Institute of Neurology, Medical University of Vienna, Währinger Gürtel 18-20, 1097 Vienna, Austria 2Department of Neurosurgery, Medical University of Vienna, Währinger Gürtel 18-20, 1097 Vienna, Austria Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Erhart et al. Acta Neuropathologica Communications (2018) 6:135 Page 2 of 14 (Continued from previous page) state of the immune system. On the other hand, Audencel also seemed to have stimulated the immune system. Overall, these immunological considerations suggest that DC immunotherapy against glioblastoma should be studied further – with the goal of translating an apparent immunological response into a clinical response. Future research should concentrate on investigating augmentation of immune reactions through combination therapies or on developing meaningful biomarkers. Keywords: Glioblastoma multiforme, Dendritic cell, Cancer immunotherapy, Immunology, ELISPOT Introduction after DC vaccination – for DC immunotherapy against Glioblastoma multiforme (GBM) is the most frequent and glioblastoma. most aggressive form of brain cancer [30]. Therapeutic This meant finding answers to three questions: (Q1) options are limited. Currently, the standard first line treat- What subgroup of patients based on pre-immunotherapy ment of GBM is maximum surgical resection followed by characteristics of the blood and of the tumor might have a chemotherapy (temozolomide) and radiotherapy. Im- more favorable outcome under Audencel and what are munotherapy is a novel treatment hope currently under hence possible future biomarker candidates? (Q2) Even if investigation [27]. Immunotherapeutic strategies being there was no clinical response of patients to Audencel, did tested in clinical trials include checkpoint inhibitors, pep- it have an effect on the immune system? (Q3) Do immune tide vaccines and Dendritic Cell (DC)-based vaccines [24]. system variable levels post Audencel-application also cor- Given their critical role in guiding anti-cancer immune re- relate with clinical outcome? To answer question (Q1) we actions, deploying DCs against neoplastic cells seems es- assessed immune system variables in apheresis or tumor pecially plausible [20]. A number of DC-based vaccines samples before immunotherapy and correlated them with are currently undergoing clinical development [18]. Feasi- survival. For question (Q2) we studied immune dynamics bility and safety of DC-based immunotherapeutic ap- via measuring blood variables after every cycle of vaccin- proaches have been proven repeatedly [12, 16, 23]. A ation. Question (Q3) was then approached via combining survival benefit could, however, not yet be established in immunovariable levels post Audencel-treatment with sur- clinical trials [18] – despite recent reports of encouraging vival measures. interim results [16]. The Austrian “GBM-Vax” consortium performed a Materials and methods phase II clinical trial with “Audencel”, an autologous Scientific concept and overview DC-based cancer vaccine. Patient DCs were charged with The present work analyses the clinical trial “GBM-Vax” autologous tumor lysis material. DCs were then matured (NCT01213407/EudraCT2009–015979-27) immunologic- in vitro via immunological “danger signals” (Lipopolysac- ally. The study was approved by the Upper-Austrian ethical charides and Interferon gamma, IFNγ) and injected into review committee (TRX2/P-II-018). All patients gave writ- inguinal lymph nodes. This maturation step as well as the ten informed consent also to concomitant immunological fact that loading with autologous whole tumor lysate gen- research. erates a personalized vaccine should in theory mean a Various complementary immunological methods were technically advanced, promising concept [6, 11]. But the applied to blood and tumor tissue of the participating pa- trial based on the Audencel technique failed to show clin- tients: Functional immune-capabilities were measured in ical efficacy (see Buchroithner et al. [2]) when assessing blood samples via an autologous system: the enzyme-linked progression-free and overall survival in all patients. One immunospot (ELISPOT) assay [4, 14]. It quantifies the po- potential reason identified by Buchroithner et al. for tency of tumor-charged DCs to stimulate T cells in vitro via Audencel’s failure is the temporal proximity to the con- registering IFNγ and Granzyme B (GranzB) produced in comitant chemotherapy weakening the immune system. the co-culture. This replicates the expected functional Here, we present the results of immunological re- interplay between DCs and T cells in the patient’slymph search accompanying the trial. We analyzed both, the nodes. Further cytokines released in vitro were measured peripheral blood (from apheresis or venipuncture) as via cytokine bead assays (CBA) of the ELISPOT co-culture well as the tumor tissue (from surgery) through an supernatant. ELISPOT assays were performed from blood array of complementary methods (see Fig. 1a and Mate- before, during and after Audencel treatment. rials and Methods) that characterize the immune sys- In addition, we quantified blood immune cell popula- tem via “immunovariables”. The main intention of the tions at these time-points via flow cytometry of surface here presented investigation was to understand the role markers. Polarization towards a T helper 1 (Th1), T of the immune system – measured before, during and helper 2 (Th2), T helper 17 (Th17) or regulatory T cell Erhart et al. Acta Neuropathologica Communications (2018) 6:135 Page 3 of 14 Fig. 1 Research questions, samples and techniques (Treg) phenotype was measured via qRT-PCR of charac- [3]. In that case, the maximum number of samples with teristic transcription factors [32, 35, 37, 38]. a reliable readout was used for statistics. Tumor tissue was studied via sequencing of tumor-resident T cell receptors (TCR clonotyping) [7]and Blood: CBA immunohistochemistry (IHC) of tumor-resident immune Supernatant from the ELISPOT GranzB plate was col- cells. lected from the co-culture of PBMCs with or without To take technical peculiarities of different methods into exposure to either DCs unloaded or loaded with tumor account, analysis
Load more

Recommended publications
  • For Inflammatory Bowel Disease
    250 NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedures overview of leukapheresis (white cell apheresis) for inflammatory bowel disease Introduction This overview has been prepared to assist members of the Interventional Procedures Advisory Committee (IPAC) in making recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure. Date prepared This overview was prepared in August 2004. Procedure names • Leukapheresis • White cell apheresis. • Leukocyte removal therapy. • Selective granulocyte and monocyte adsorption apheresis. • Leukocytapheresis. Specialty society • British Society of Gastroenterology. Description Indications Inflammatory bowel disease. Ulcerative colitis and Crohn’s disease are the most common forms of inflammatory bowel disease. Ulcerative colitis causes inflammation and ulceration of the rectum and sometimes the colon. Symptoms include bloody diarrhoea and rectal bleeding. Crohn’s disease usually causes inflammation and ulceration of the small and large intestines, but it can affect any part of the digestive tract. The main symptoms are abdominal pain, diarrhoea and weight loss. Both of these are chronic conditions, characterised by periods of clinical relapse and remission. The incidence of ulcerative colitis is around 10 to 20 per 100,000 per year in the UK and the incidence of Crohn’s disease is approximately 5 to 10 per 100,000 per year.1 Current treatment and alternatives Conservative treatments include dietary measures, and medications to control inflammation. Immunosuppressants may be used if other medical therapies are ineffective at maintaining remission. Patients with ulcerative colitis that does not respond to medical therapy may be treated with surgery to remove the colon.
    [Show full text]
  • Audencel Immunotherapy Based on Dendritic Cells Has No Effect on Overall and Progression-Free Survival in Newly Diagnosed Glioblastoma: a Phase II Randomized Trial
    Supplementary Materials: Audencel Immunotherapy Based on Dendritic Cells Has No Effect on Overall and Progression-Free Survival in Newly Diagnosed Glioblastoma: a Phase II Randomized Trial Johanna Buchroithner, Friedrich Erhart, Josef Pichler, Georg Widhalm, Commented [FE1]: Authorship order was changed by Matthias Preusser, Günther Stockhammer, Martha Nowosielski, Sarah Iglseder, Christian F. request from the senior corresponding author – details see Freyschlag, Stefan Oberndorfer, Karin Bordihn, Gord von Campe, Markus Hoffermann, email Reinhard Ruckser, Karl Rössler, Sabine Spiegl-Kreinecker, Michael B. Fischer, Thomas Czech, Carmen Visus, Günther Krumpl, Thomas Felzmann and Christine Marosi Figure S1. Influence of extent-of-resection (EOS) on overall survival (OS). Patients of the Audencel cohort and the SOC cohort were stratified into three groups based on the EOR that could be achieved (100% vs 90-99% vs. 70-90%). A minimal EOR of 70% was an inclusion criterion for the study, so no study patient was below that threshold. Kaplan-Meier analysis shows that EOR did not have an influence on the OS outcome in the Audencel cohort compared to the SOC cohort (p = 0.762). Commented [M2]: “ml” in figure s2a should be changed to “mL” Commented [FE3R2]: I would rather prefer to have “ml” here Figure S2. Relation of DC vaccine quality control and overall survival (OS). One main quality control parameter measured during the production of the personalized, autologous vaccine was the IL-12 production capacity of every single vaccine. When analyzing a possible correlation with OS, no such connection could be made (a, p = 0.891). Similarly, the T cell proliferation capacity of the DC vaccine did not have a connection to survival — for three different DC: T cell ratios tested: 1:5 (b),1:10 (c), 1:20 (d).
    [Show full text]
  • Statistical Analysis Plan
    STATISTICAL ANALYSIS PLAN NCT Number: NCT03259334 Study Title: A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and Safety Study of SHP647 as Induction Therapy in Subjects with Moderate to Severe Ulcerative Colitis (FIGARO UC 301) Study Number: SHP647-301 SAP Version and Date: Version 3.0: 04 Nov 2020 STATISTICAL ANALYSIS PLAN SHP647 PHASE 3 A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel group Efficacy and Safety Study of SHP647 as Induction Therapy in Subjects with Moderate to Severe Ulcerative Colitis (FIGARO UC 301) PROTOCOL IDENTIFIER: SHP647-301 Study Sponsor(s): Shire Human Genetic Therapies, Inc. ("Shire"), 300 Shire Way, Lexington, MA 02421 USA Author: , PPD Protocol: V1 (06 Jul 2017); Amendment 1, 05 Sep 2018; Amendment 2, 11 Nov 2019 SAP Version #: 3.0 SAP Date: For non-commercial04 Nov 2020 use only Status: Final Shire CONFIDENTIAL Page 2 SHP647-301 Statistical Analysis Plan v 3.0 SHP647 04 Nov 2020 REVISION HISTORY Version Issue Date Summary of Changes 1.0 30 Aug 2019 Final 2.0 13 Aug 2020 Incorporated Protocol Amendment 2 Updates. - Added Hypersensitivity AEs. - Changed study treatment name. - Changed sample size calculation. - Changed the term ‘dimension’ to ‘domain’ for IBDQ Domain Scores. - Updated Prior medication definition to remove restriction for stop date. Due to the early discontinuation of the study before full enrollment, previously planned supplementary and subgroup analyses were removed. - Removed Per-protocol Set and Completers Set. - Removed supplementary analyses for efficacy endpoints (per-protocol, completer, missing data assumptions, etc). - Removed subgroup for efficacy endpoints beyond the actual randomization factors.
    [Show full text]
  • Appendix 1 – Protocol for Preventing Or Reversing Chronic Disease The
    Appendix 1 – Protocol for Preventing or Reversing Chronic Disease The first author has developed a protocol over the past decade for preventing or reversing chronic disease based on the following systemic medical principle: “at the present time, removal of cause is a necessary, but not necessarily sufficient, condition for restorative treatment to be effective”[1]. The protocol methodology refines the age-old principles of both reducing harm in addition to providing treatment, and allows better identification of factors that contribute to the disease process (so that they may be eliminated if possible). These contributing factors are expansive and may include a combination of Lifestyle choices (diet, exercise, smoking), iatrogenic and biotoxin exposures, environmental/occupational exposures, and psychosocial stressors. This strategy exploits the existing literature to identify patterns of biologic response using biomarkers from various modalities of diagnostic testing to capture a much broader list of potential contributing factors. Existing inflammatory bowel diseases (IBD) Biomarker Identification to Remove Contributing Factors and Implement Treatment The initial protocol steps are diagnostic. The main output of these diagnostics will be identification of the biomarker levels and symptoms that reflect abnormalities, and the directions of change required to eliminate these abnormalities. In the present study, hundreds of general and specific biomarkers and symptoms were identified from the core IBD literature. The highest frequency (based on numbers of record appearances) biomarkers and symptoms were extracted, and are listed in Table 1 (highest frequency items first, reading down each column before proceeding to the next column). They are not necessarily consensus biomarkers. They are biomarkers whose values were altered by a treatment or contributing factor, and reported in the core IBD literature.
    [Show full text]
  • The Production Cycle of Blood and Transfusion: What the Clinician Should Know
    MEDICAL EDUCATION The production cycle of blood and transfusion: what the clinician should know O ciclo de produção do sangue e a transfusão: o que o médico deve saber Gustavo de Freitas Flausino1, Flávio Ferreira Nunes2, Júnia Guimarães Mourão Cioffi3, Anna Bárbara de Freitas Carneiro-Proietti4 DOI: 10.5935/2238-3182.20150047 ABSTRACT Since the history of mankind, blood has been associated with the concept of life. How- 1 Medical School student at the Federal University of Ouro Preto – UFOP. Ouro Preto, MG – Brazil. ever, improper use of blood and blood products increases the risk of transfusion-related 2 MD, Occupational Physician. Hemominas Foundation, complications and adverse events to recipients. It also contributes to the shortage of Hospital Foundation of Minas Gerais State – FHEMIG. Belo Horizonte, MG – Brazil. blood products and possibility of unavailability to patients in real need. Objective: 3 MD, Hematologist. President of the Hemominas Founda- this study aims to describe the history of blood transfusion and correct way of using tion. Belo Horizonte, MG – Brazil. 4 MD, Hematologist. Post-doctorate in Hematology. Re- hemotherapy, aiming to clarify to medical students and residents, as well as interested searcher and international consultant at the Hemominas doctors, the importance of this knowledge when prescribing a hemo-component. Meth- Foundation. Belo Horizonte, MG – Brazil. odology: the topics described correspond to the summary of knowledge taught during the training courses offered by the Hemominas Foundation for medical students and residents. Conclusion: the doctor’s performance is undeniably linked to the scientific conception of his fundamentals gradually and continuously obtained since the begin- ning of medical training.
    [Show full text]
  • Title Efficacy and Safety of Granulocyte and Monocyte Adsorption
    Efficacy and safety of granulocyte and monocyte adsorption Title apheresis for ulcerative colitis: A meta-analysis. Yoshino, Takuya; Nakase, Hiroshi; Minami, Naoki; Yamada, Author(s) Satoshi; Matsuura, Minoru; Yazumi, Shujiro; Chiba, Tsutomu Digestive and liver disease : official journal of the Italian Citation Society of Gastroenterology and the Italian Association for the Study of the Liver (2014), 46(3): 219-226 Issue Date 2014-03 URL http://hdl.handle.net/2433/182932 © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd.; This is not the published version. Please cite only Right the published version.; この論文は出版社版でありません。 引用の際には出版社版をご確認ご利用ください。 Type Journal Article Textversion author Kyoto University Yoshino et al. Efficacy and Safety of Granulocytes and Monocytes Adsorption Apheresis for Ulcerative Colitis -A Meta-Analysis Study- Takuya Yoshino, MD, PhD1, 2, Hiroshi Nakase, MD, PhD1, Naoki Minami, MD1, Satoshi Yamada, MD1, Minoru Matsuura, MD, PhD1, Shujiro Yazumi, MD, PhD2, Tsutomu Chiba, MD, PhD1 1. Department of Gastroenterology & Hepatology, Graduate School of Medicine, Kyoto University 2. Division of Gastroenterology & Hepatology, Digestive Disease Center, Kitano Hospital Correspondence to Hiroshi Nakase, MD, PhD Department of Gastroenterology & Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan Phone: +81-75-751-4319 Fax: +81-75-751-4303 1 Yoshino et al. Acknowledgement: This work was supported by Japan Society for the Promotion of Science “KAKENHI” Grant Number 25130706, 24229005, 24659363, 24590941, 25860532 and 24590941 by Health and Labour Sciences Research Grants for Research on Rare and Intractable Disease from the Ministry of Health, Labour and Welfare, Japan. 2 Yoshino et al.
    [Show full text]
  • Current Status on the Clinical Usefulness of Apheresis in Patients with Inflammatory Bowel Disease
    100 ANNALS OF GASTROENTEROLOGYJ.K. TRIANTAFILLIDIS, 2003, 16(2):100-104 et al Current view Current status on the clinical usefulness of apheresis in patients with inflammatory bowel disease J.K. Triantafillidis, P. Cherakakis 2-10 SUMMARY USA and Europe. This kind of treatment, termed apheresis, has been In this review the current aspects concerning the applica- investigated in several diseases such as rheumatoid ar- tion of leukocytapheresis in patients with inflammatory thritis, ophthalmic Graves disease, Behcets disease, bowel disease are briefly discussed. Leukocytapheresis has pemphigus vulgaris, systemic lupus erythematosus, renal already been applied in patients suffering mainly from dis- disorders, multiple sclerosis, acute leukemia, and inflam- eases affecting the immunological balance. The procedure matory bowel disease.11,12 It seems, however, that today a has recently been tried in patients with ulcerative colitis new era has arrived concerning the application of leuko- and Crohns disease as well, with promising results. Leu- cytapheresis in inflammatory bowel disease, because of kocytapheresis is gaining in interest as a therapeutic pro- the tremendous progress achieved in the field of patho- cedure of the near future, because it removes - in a short physiology of IBD and the understanding of the role of time- a number of immunologically active cells, which are immunocytes and their products in the initiation and well known to actively participate in the inflammatory cas- perpetuation of inflammation in the intestinal wall. cade, leading to tissue damage. However, further studies are needed in order to better clarify the role of leukocyta- Technique pheresis in the maintenance treatment of patients with in- Two methods of removal of leukocytes from the cir- flammatory bowel disease, either alone, or in combination culation have been reported.
    [Show full text]
  • Interventional Studies on Immunological Balance in Ibd and Allergic Asthma
    From Department of Medicine Solna Clinical Immunology and Allergy Unit Karolinska Institutet, Stockholm, Sweden INTERVENTIONAL STUDIES ON IMMUNOLOGICAL BALANCE IN IBD AND ALLERGIC ASTHMA Vladislaw Muratov Stockholm 2011 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by Reproprint AB © Vladislaw Muratov, 2011 ISBN 978-91-7457-191-2 Printed by 2010 Gårdsvägen 4, 169 70 Solna “… les étoiles sont éclairées afin que chacun puisse un jour retrouver la sienne.” (”…the stars are lit so everyone may one day find their own”.) A. de Saint-Exupéry ABSTRACT We have studied a role of immunological balance in connection to allergen challenge in asthma patients and in connection to apheresis treatment in inflammatory bowel disease (IBD) patients. It has been suggested that T-helper type 2 cells become recruited into the bronchial mucosa and regulate allergic asthma reaction. Patients who mounted a late-phase reaction in connection to allergen challenge were designated dual responders opposite to single responders. Our finding that IL4+CD4+ cells decreased in the patient group and IFN-γ + CD4+ cells decreased in the single responders after allergen challenge suggests the active traffic of both Th1 and Th2 cells into bronchial mucosa. A diminished capacity to down-regulate the Th2 response by recruitment of sufficient number of IFN-γ positive CD4+ lymphocytes was suggested as explanation to the late phase symptoms in the dual responders. A previously proposed mechanism of granulocyte- and monocyte adsorbing apheresis (GMA) is that in removing activated granulocytes and monocytes the production of pro-inflammatory cytokines, predominantly TNF-α will be reduced.
    [Show full text]
  • 39000:2039),46KA61M 1/3472 (2013.01); Too A61M (2939), I/3486 Phagocytosise., and Killingcee of Staphylococcus EN"E" Aureus'
    USO09567568B2 (12) United States Patent (10) Patent No.: US 9,567,568 B2 MeVOrach (45) Date of Patent: Feb. 14, 2017 (54) METHOD OF PREPARING APOPTOTIC 4,801,531 A 1/1989 Frossard MONOCYTES 4,838,852 A 6, 1989 Edelson et al. 4,879,219 A 11/1989 Wands et al. 5,011,771 A 4, 1991 Bellet et al. (71) Applicant: Enlivex Therapeutics Ltd., Jerusalem 5, 192,659 A 3, 1993 Simons (IL) 5,272,057. A 12/1993 Smulson et al. 5,281.521 A 1/1994 Trojanowski et al. (72) Inventor: Dror Mevorach, Jerusalem (IL) 5,591.457 A 1, 1997 Bolton 5,951,509 A 9, 1999 Morris (73) Assignee: ENTYES THERAPEUTICS LTD., 6,219,5845,985,914 B1A 11/19994/2001 ZeldLee is et al. Jerusalem (IL) 6,354.297 B1 3/2002 Eiseman 6,607,722 B2 8, 2003 Edelson et al. (*) Notice: Subject to any disclaimer, the term of this 7,109,031 B2 9, 2006 Edelson et al. patent is extended or adjusted under 35 7,989,203 B2 * 8/2011 Albert ................ A61K 39,0008 U.S.C. 154(b) by 0 days. 435,347 2005, OO31618 A1 2/2005 Mevorach (21) Appl. No.: 14/499,279 2005/0202098 A1 9, 2005 Mevorach (22) Filed: Sep. 29, 2014 FOREIGN PATENT DOCUMENTS O O WO WO 97,387O7 10, 1997 (65) Prior Publication Data WO WO 99.35493 7, 1999 WO WO O2/060376 8, 2002 US 2015/OO56678 A1 Feb. 26, 2015 WO WO 2006/117786 11 2006 Related U.S.
    [Show full text]
  • 120391 1 Supp 0 N3hrvt.Pdf
    Supplemental Material and Data Mesothelin-specific Chimeric Antigen Receptor mRNA-Engineered T cells Induce Anti-Tumor Activity in Solid Malignancies Gregory L. Beatty1,3, Andrew R. Haas1, 2, Marcela V. Maus1,3, Drew A. Torigian1,5, Michael C. Soulen1,5, Gabriela Plesa1, Anne Chew1, Yangbing Zhao1,4, Bruce L. Levine1,4,6, Steven M. Albelda1,2, Michael Kalos1,4, Carl H. June1,4,6 Affiliations: 1Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA 2Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 3Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 4Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 5Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 6Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA Supplemental Results Safety of RNA CARTmeso cell infusions MPM patient 17510-105 experienced no adverse events on schedule 1. However, patient 17510-105 developed anaphylaxis shortly after receiving the 1st infusion on Schedule 2, which prompted a short intensive care unit admission and was considered as “definitely related” to CARTmeso cell treatment. The patient was resuscitated with full clinical recovery. Extensive laboratory investigation demonstrated evidence of systemic mast cell degranulation probably related to an IgE-mediated anti-murine response to the murine CARTmeso construct sequences (1). PDA patient 21211-101 was enrolled onto Schedule 3 with a course complicated by bacterial sepsis after receiving five doses of CARTmeso cells that was determined to be unrelated to study treatment.
    [Show full text]
  • Granulocyte and Monocyte Adsorptive Apheresis Ameliorates Sepsis in Rats Shuai Ma1†, Qingqing Xu1†, Bo Deng1, Yin Zheng2, Hongyan Tian1, Li Wang1* and Feng Ding1*
    Ma et al. Intensive Care Medicine Experimental (2017) 5:18 Intensive Care Medicine DOI 10.1186/s40635-017-0129-2 Experimental RESEARCH Open Access Granulocyte and monocyte adsorptive apheresis ameliorates sepsis in rats Shuai Ma1†, Qingqing Xu1†, Bo Deng1, Yin Zheng2, Hongyan Tian1, Li Wang1* and Feng Ding1* * Correspondence: [email protected]; Abstract [email protected] †Equal contributors Background: Overwhelming activation of granulocytes and monocytes is central to 1Division of Nephrology & Unit of inflammatory responses during sepsis. Granulocyte and monocyte adsorptive apheresis Critical Nephrology, Shanghai Ninth (GMA) is an extracorporeal leukocyte apheresis device filled with cellulose acetate People’s Hospital, School of Medicine, Shanghai Jiaotong beads and selectively adsorbs granulocytes and monocytes from the peripheral blood. University, 639 Zhizaoju Road, Methods: In this study, septic rats received the GMA treatment for 2 h at 18 h after Shanghai 200011, China Full list of author information is cecal ligation and puncture. available at the end of the article Results: GMA selectively adsorbed activated neutrophils and monocytes from the peripheral blood, reduced serum inflammatory cytokine expression, and seemed to improve organ injuries and animal survival. GMA potentially reduced lung injury by alleviating the infiltration of inflammatory cells and the secretion of cytokines. Conclusions: This study showed that selective granulocyte and monocyte adsorption with cellulose acetate beads might ameliorate cecal ligation and puncture (CLP)-induced sepsis and improve survival and organ function. Keywords: Sepsis, Inflammation, Granulocyte, Monocyte, Adsorption, Cellulose acetate Background Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection [1]. Despite progress in antibiotics and critical care therapy, sepsis remains the most common cause of death in the intensive care unit [2].
    [Show full text]
  • CAR T Cells REPORT by CLINSCIENCE Clinscience Sp
    CAR T cells REPORT BY CLINSCIENCE Clinscience Sp. z o.o. ul. Erazma Ciołka 10 01-402 Warszawa KRS 0000720389 REGON 369551560 NIP 5272839995 [email protected] clinscience.com 2 CAR T CELLS / REPORT BY CLINSCIENCE INTRODUCTION One type of cells which are Chimeric antigen receptor T cells, known also present in the blood are as CAR T cells are the T cells produced by our leukocytes. Leukocytes are cells body’s white blood cells, which have been of the immune system and are genetically engineered to produce an artificial involved in protecting the body T-cell receptor for use in immunotherapy. against both infectious disease Those chimeric antigen receptors (CAR) are and foreign invaders. Among the receptors for proteins that have been the white blood cells, are engineered to give T cells the new ability to distinguished specific types of target the specific proteins i.e. the proteins of cells i.e. neutrophils, eosinophils, the cancer cells or dysfunctional proteins, which basophils, and lymphocytes, are produced by the dysfunctional organ of which are divided into three the body. The receptors are chimeric, because main subpopulations: B cells, T they combine both antigen-binding and T cell cells and NK cells. activating functions into a single receptor. The production process of CAR T cells is complicated. The first step is to gather and isolate the T cells from human blood. It can be done from the patient’s own blood (autologous treatment) or from healthy donor’s blood (allogenic treatment). The manufacturing process is the same, but the blood is either taken from the patient or from a donor.
    [Show full text]