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Jessica C Petrov, Masayuki Wada, Kevin G Pinz, Lulu E Yan, Kevin H Chen, Xiao Shuai, Hua Liu, Xi Chen, Lai-Han Leung, Huda Salman, Nabil Hagag, Fang Liu, Xun Jiang, Yupo Ma
Acute myeloid leukemia (AML) bears heterogeneous cells that can consequently offset killing by single-CAR-based therapy, which results in disease relapse. Leukemic stem cells (LSCs) associated with CD123 expression comprise a rare population that also plays an important role in disease progression and relapse. Here, we report on the robust anti-tumor activity of a compound CAR (cCAR) T-cell possessing discrete scFv domains targeting two different AML antigens, CD123, and CD33, simultaneously. We determined that the resulting cCAR T-cells possessed consistent, potent, and directed cytotoxicity against each target antigen population...
February 25, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Olivia Campagne, Audrey Delmas, Sylvain Fouliard, Marylore Chenel, Gurunadh R Chichili, Hua Li, Ralph Alderson, Jean-Michel Scherrmann, Donald E Mager
PURPOSE: Flotetuzumab (MGD006 or S80880) is a bispecific molecule that recognizes CD3 and CD123 membrane proteins, redirecting T-cells to kill CD123-expressing cells for the treatment of acute myeloid leukemia. In this study, we developed a mathematical model to characterize MGD006 exposure-response relationships and to assess the impact of its immunogenicity in cynomolgus monkeys. EXPERIMENTAL DESIGN: 32 animals received multiple escalating doses (100-300-600-1000 ng/kg/day) via intravenous infusion continuously 4-days a week...
February 20, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Andreas T Björklund, Mattias Carlsten, Ebba Sohlberg, Lisa L Liu, Trevor Clancy, Mohsen Karimi, Sarah Cooley, Jeffrey S Miller, Monika Klimkowska, Marie Schaffer, Emma Watz, Kristina I Wikstrom, Pontus Blomberg, Bjorn E Wahlin, Marzia Palma, Lotta Hansson, Per Ljungman, Eva Hellström-Lindberg, Hans-Gustaf Ljunggren, Karl-Johan Malmberg
PURPOSE: To evaluate the safety, efficacy and immunobiological correlates of allogeneic NK cell-based therapy in primary chemotherapy-refractory or relapsed high-risk myelodysplastic syndrome (MDS), secondary AML (MDS/AML), and de novo AML patients. EXPERIMENTAL DESIGN: Sixteen patients received fludarabine/cyclophosphamide conditioning combined with total lymphoid irradiation followed by adoptive immunotherapy with IL-2-activated haploidentical NK cells. RESULTS: NK cell infusions were well tolerated with only transient adverse events observed in the 16 patients...
February 14, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Johannes R Schmidt, Elke Rücker-Braun, Katharina Heidrich, Malte von Bonin, Friedrich Stölzel, Christian Thiede, Jan M Middeke, Gerhard Ehninger, Martin Bornhäuser, Johannes Schetelig, Kristin Schubert, Martin von Bergen, Falk Heidenreich
Targeting of leukemic stem cells with specific immunotherapy would be an ideal approach for the treatment of myeloid malignancies, but suitable epitopes are unknown. The comparative proteome-level characterization of hematopoietic stem and progenitor cells from healthy stem cell donors and patients with acute myeloid leukemia has the potential to reveal differentially expressed proteins which can be used as surface-markers or as proxies for affected molecular pathways. We employed mass spectrometry methods to analyze the proteome of the cytosolic and the membrane fraction of CD34 and CD123 co-expressing FACS-sorted leukemic progenitors from five patients with acute myeloid leukemia...
February 12, 2018: Proteomes
Yufeng Wang, Shu Shang, Qianqian Sun, Junjun Chen, Guanhuan Du, Hong Nie, Xiaozhe Han, Guoyao Tang
OBJECTIVE: Investigation of dendritic cell (DC) subsets and expression patterns of Toll-like receptors (TLRs) was conducted to understand the pathogenesis in oral lichen planus (OLP). STUDY DESIGN: Blood, OLP lesion, and control samples were collected. Four DC subsets (CD11c + CD123 - myeloid DC1 [mDC1], CD141 + mDC2, CD11c - CD123 + plasmacytoid DC [pDC], and CD1a + CD207 + Langerhans cells [LC]) were investigated via flow cytometry (FCM) and immunohistochemical staining...
December 18, 2017: Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Alejandro Avilés-Salas, Myrna Candelaria, Mayra Ponce, Abraham Cañavera-Constantino, Sebastián Burgos
Blastic plasmacytoid dendritic cell neoplasm is a rare hematological malignancy derived from immature plasmacytoid dendritic cells. The tumor cells have an immature blastic appearance, and diagnosis is based on the expression of CD4, CD56 y CD123 in the absence of other lymphoid, natural killer, or myeloid antigens. The majority of affected individuals are older people with a mean age of 66 years. Male to female ratio is approximately 3:1. Common presentation includes cutaneous lesions followed by tumor dissemination...
September 2017: Revista Médica de Chile
Rintaro Ohe, Naing Ye Aung, Yosuke Shiono, Aya Utsunomiya, Takanobu Kabasawa, Nobuyuki Tamazawa, Yuka Tamura, Tomoya Kato, Akane Yamada, Shin Hasegawa, Keiko Aizawa, Kyoko Inokura, Satoshi Ito, Tomomi Toubai, Yuichi Kato, Takahiko Tsunoda, Kosuke Onami, Tamio Suzuki, Kenichi Ishizawa, Mitsunori Yamakawa
Blastic plasmacytoid dendritic cell (pDC) neoplasm (BPDCN) is a relatively rare hematological malignancy with significantly complex clinicopathological features that are still unclear. This study aimed to analyze the clinicopathological data of BPDCN and evaluate immunohistochemical detection of minimal bone marrow (BM) involvement. In this study, we examined skin and BM lesions from 6 patients with BPDCN. Neoplastic cells tested positive for CD303 (polyclonal, 100%; monoclonal, 40%) in the skin lesions and for CD303 (polyclonal, 100%; monoclonal, 67%) in the BM clots...
February 8, 2018: Journal of Clinical and Experimental Hematopathology: JCEH
Pei Liu, Huijuan Jiang, Mengting Che, Rong Fu, Huaquan Wang, Lijuan Li, Wei Zhang, Jinglian Tao, Shan Gao, Zonghong Shao
OBJECTIVE: To investigate the frequencies and biological characteristics of CD25 positive hematopoietic stem cells (HSC) in myelodysplastic syndromes. METHODS: The expression of CD25 on HSC in bone marrow derived from patients with untreated MDS patients, untreated AML patients and normal controls were accessed by flow cytometry (FCM). The correlation analysis was done between CD25+ HSC and clinical parameters in MDS patients. RESULTS: The expression of CD25 on HSC (CD34+ CD38- cells) in MDS patients (28...
December 15, 2017: Leukemia Research
Sonal Jain, Anurag Mehta, Gauri Kapoor, Dinesh Bhurani, Sandeep Jain, Narendra Agrawal, Rayaz Ahmed, Dushyant Kumar
Minimal residual disease is currently the most powerful prognostic indicator in Precursor B lymphoblastic leukemia. Multiparameter flow cytometry is the most commonly used modality. Seventy three B ALL cases and 15 normal marrows were evaluated for expression patterns of leukemia markers (CD38, CD58, CD73) in all 73 cases and CD66c, CD86 and CD123 in 23 cases. CD73 was aberrantly expressed in 90.41% cases and CD86 in 60.87% B ALL cases. Thus addition of these markers in MRD panels can increase the sensitivity of the assay...
January 2018: Indian Journal of Hematology & Blood Transfusion
Xue-Fang Zhang, Shu-Ying Zhang, Hong Zhou, Jia-Wei Feng, Li-Bo Jiang, Yan-Zhang Qu, Heng Guo, Shu-Liang Wang
OBJECTIVE: To explore the relationship between expression of CD96 and CD123 and prognosis of patients with myelodysplastic syndrome(MDS). METHODS: Eight-nine MDS patients(MDS group) and 20 persons without hematologic disease as controls(Control group) were enrolled. The patients were grouped by the risk. All participants received bone marrow biopsy. Mononuclear cells were extracted, CD34+CD38-CD123+ and CD34+CD38-CD96+ cells were counted by using flow cytometry...
February 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Deepashri Rao, Manjunatha M Venkataswamy, Ravi Vasanthapuram, P Satishchandra, Anita Desai
One of the commonest HIV-associated opportunistic infections of the central nervous system is neurotuberculosis. Interaction between HIV, Mycobacterium tuberculosis and host immune system in co-infected individuals may result in altered frequencies of immune cells, thereby modulating dissemination and disease progression. We examined the frequencies of natural killer (NK) cell and dendritic cell (DC) subsets in HIV infected individuals with neurotuberculosis (HIVNTB) as compared to individuals with HIV associated systemic TB (HIVSTB), asymptomatic HIV, non-HIV NTB, non-HIV STB and healthy controls...
February 3, 2018: Journal of Medical Virology
Solomiya Grushchak, Cossette Joy, Arielle Gray, Dan Opel, Jodi Speiser, Jeave Reserva, Rebecca Tung, Scott E Smith
RATIONALE: Blastic plasmacytoid dendritic cell neoplasm (BPDCN), derived from precursors of plasmacytoid dendritic cells, is a rare and aggressive malignancy with frequent cutaneous involvement. Although cutaneous lesions are often chemosensitive, BPDCN portends a poor prognosis as most patients relapse after developing drug resistance. PATIENT CONCERNS: We report a case of a 65-year-old man who presented with a rapidly enlarging hyperpigmented plaque on his shoulder with subsequent similarly appearing macules and plaques on his chest, back, and neck...
December 2017: Medicine (Baltimore)
Leigh M Marsh, Katharina Jandl, Gabriele Grünig, Vasile Foris, Mina Bashir, Bahil Ghanim, Walter Klepetko, Horst Olschewski, Andrea Olschewski, Grazyna Kwapiszewska
Increasing evidence points towards an inflammatory component underlying pulmonary hypertension. However, the conclusive characterisation of multiple inflammatory cell populations in the lung is challenging due to the complexity of marker specificity and tissue inaccessibility. We used an unbiased computational flow cytometry approach to delineate the inflammatory landscape of idiopathic pulmonary arterial hypertension (IPAH) and healthy donor lungs.Donor and IPAH samples were discriminated clearly using principal component analysis to reduce the multidimensional data obtained from single-cell flow cytometry analysis...
January 2018: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
Jingwei Lv, Ling Li, Wei Li, Kunqian Ji, Ying Hou, Chuanzhu Yan, Tingjun Dai
To explore the possible mechanism implicated in the recruitment of plasmacytoid dendritic cells (pDCs), we investigated the expression of the chemokine receptors CXCR3, CXCR4, and CCR7 on intramuscular and circulating pDCs from patients with dermatomyositis (DM). Using immunohistochemistry, preferential expression of CXCR3, CXCR4 and CCR7 was identified in the perivascular inflammatory infiltrates within the perimysium in DM muscle. Western-blot analysis showed marked up-regulation of expression of CXCR3, CXCR4 and CCR7 in muscle homogenate from patients with DM compared with that in non-diseased controls...
January 9, 2018: Journal of Neuroimmunology
Frances E Pearson, Karshing Chang, Yoshihito Minoda, Ingrid M Leal Rojas, Oscar L Haigh, Ghazal Daraj, Kirsteen M Tullett, Kristen J Radford
Mice reconstituted with human hematopoietic stem cells are valuable models to study aspects of the human immune system in vivo. We describe a humanized mouse model (hu mice) in which fully functional human CD141+ and CD1c+ myeloid and CD123+ plasmacytoid dendritic cells (DC) develop from human cord blood CD34+ cells in immunodeficient mice. CD141+ DC are the human equivalents of murine CD8+ /CD103+ DC which are essential for the induction of tumor-inhibitory cytotoxic T lymphocyte (CTL) responses, making them attractive targets to exploit for the development of new cancer immunotherapies...
January 18, 2018: Immunology and Cell Biology
Stefania Parlato, Teresa Chiacchio, Debora Salerno, Linda Petrone, Luciano Castiello, Giulia Romagnoli, Irene Canini, Delia Goletti, Lucia Gabriele
Individuals exposed to Mycobacterium tuberculosis (Mtb) may be infected and remain for the entire life in this condition defined as latent tuberculosis infection (LTBI) or develop active tuberculosis (TB). Among the multiple factors governing the outcome of the infection, dendritic cells (DCs) play a major role in dictating antibacterial immunity. However, current knowledge on the role of the diverse components of human DCs in shaping specific T-cell response during Mtb infection is limited. In this study, we performed a comparative evaluation of peripheral blood circulating DC subsets as well as of monocyte-derived Interferon-α DCs (IFN-DCs) from patients with active TB, subjects with LTBI and healthy donors (HD)...
2018: PloS One
Nicole L Wittwer, Gabriela Brumatti, Ceilidh Marchant, Jarrod J Sandow, Melanie K Pudney, Mara Dottore, Richard J D'Andrea, Angel F Lopez, Paul G Ekert, Hayley S Ramshaw
High expression of the α chain of the interleukin-3 receptor (IL-3Rα; CD123) is a hallmark of acute myeloid leukemia (AML) leukemic stem cells (LSCs). Elevated CD123 expression is part of the diagnostic immunophenotyping of myeloid leukemia, and higher expression is associated with poor prognosis. However, the biological basis of the poorer prognosis is unclear, and may include heightened IL-3 signaling and non-cell autonomous interactions with the bone marrow (BM) microenvironment. We used TF-1 cells expressing different levels of CD123 and found elevated CD123 levels amplified the proliferative response to exogenous IL-3 and maintained viability in reducing IL-3 concentrations...
June 27, 2017: Blood Advances
Tomohiro Yabushita, Hironaga Satake, Hayato Maruoka, Mari Morita, Daisuke Katoh, Yoshimitsu Shimomura, Satoshi Yoshioka, Takeshi Morimoto, Takayuki Ishikawa
Leukemic stem cells (LSCs) play a crucial role in chemotherapy resistance in acute myeloid leukemia (AML). Although the association between the expression of individual LSC markers and poor prognosis has been reported, few studies have evaluated the prognostic effect of multiple LSC markers in patients with AML. Herein, we examined three LSC markers (CD25, CD96, and CD123) and the combined effect of their expression on clinical outcome. We retrospectively analyzed 80 adult patients with de novo AML who received intensive chemotherapy...
December 18, 2017: Leukemia & Lymphoma
Evdokiya Reshetnikova, Sergey Guselnikov, Olga Volkova, Konstantin Baranov, Alexander Taranin, Ludmila Mechetina
BACKGROUND: Fc receptor-like A (FCRLA) is a unique member of a family of Fc receptor like-molecules that lacks a transmembrane region and is an ER-resident protein. In mice and humans, FCRLA has been known as a B cell specific protein. We report here that, in humans, FCRLA is also expressed in a subpopulation of plasmacytoid dendritic cells (pDCs). METHODS: Human peripheral blood mononuclear cells (PBMC), splenocytes, and tonsillar cells were stained for lineage markers followed by fixation/saponin permeabilization and intracellular staining for FCRLA, and then analyzed by flow cytometry with CD123 and CD303 used as pDC markers...
December 13, 2017: Cytometry. Part B, Clinical Cytometry
Rita Assi, Hagop Kantarjian, Farhad Ravandi, Naval Daver
PURPOSE OF REVIEW: This review discusses the rationale, efficacy, and toxicity of a variety of immune approaches being evaluated in the therapy of acute myeloid leukemia (AML) including naked and conjugated monoclonal antibodies, bispecific T-cell engager antibodies, and immune checkpoint blockade via antibodies targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed-death 1 (PD-1). RECENT FINDINGS: The stellar success of immune therapies that harness the power of T cells in solid tumors and an improved understanding of the immune system in patients with hematologic malignancies have resulted in major efforts to develop immune therapies for the treatment of patients with AML...
March 2018: Current Opinion in Hematology
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