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Neuroblastoma immunotherapy

Hung C Tran, Zesheng Wan, Michael A Sheard, Jianping Sun, Jeremy R Jackson, Jemily Malvar, Yibing Xu, Larry Wang, Richard Sposto, Eugene S Kim, Shahab Asgharzadeh, Robert C Seeger
PURPOSE: Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma. EXPERIMENTAL DESIGN: TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis...
October 10, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Martine Cordeau, Assila Belounis, Martin Lelaidier, Paulo Cordeiro, Hervé Sartelet, Sabine Herblot, Michel Duval
High-risk neuroblastoma (NB) remains a major therapeutic challenge despite the recent advent of disialoganglioside (GD2)-antibody treatment combined with interleukin (IL)-2 and granulocyte monocyte-colony stimulating factor (GM-CSF). Indeed, more than one third of the patients still die from this disease. Here, we developed a novel approach to improve the current anti-GD2 immunotherapy based on NK cell stimulation using toll-like receptor (TLR)-activated plasmacytoid dendritic cells (pDCs). We demonstrated that this strategy led to the efficient killing of NB cells...
2016: PloS One
Elwira Szychot, Jarosław Peregud-Pogorzelski, Paweł Wawryków, Andrzej Brodkiewicz
Neuroblastoma is the most common extra-cranial malignancy of childhood, with the highest incidence in children younger than 4 years. The prognosis depends on many factors, such as age at diagnosis, stage of disease and molecular genetic subtype. More than 50% of children who present with the disease are deemed to have high-risk neuroblastoma. The standard therapy for children with high-risk neuroblastoma consists of intensive chemotherapy, surgery, radiotherapy, myeloablative consolidation with autologous haematopoietic stem cell rescue followed by the treatment of minimal residual disease with 13-cis-retinoic acid...
September 28, 2016: Postȩpy Higieny i Medycyny Doświadczalnej
Joseph G Pressey, Julia Adams, Lualhati Harkins, David Kelly, Zhiying You, Lawrence S Lamb
INTRODUCTION: CD3+ γδ+ T cells comprise 2% to 5% of circulating T cells with Vγ9Vδ2+ cells the dominant circulating subtype. Vγ9Vδ2+ cells recognize non-peptide phosphoantigens and stress-associated NKG2D ligands expressed on malignant cells. Strategies that incorporate the tumoricidal properties of γδ T cells represent a promising immunotherapeutic strategy for treatment of solid malignancies including neuroblastoma (NB). In this prospective, non-randomized Phase I trial, we assessed whether circulating Vγ9Vδ2+ cells could be safely expanded using intravenous ZOL (Zoledronate [Zometa]) and subcutaneous Interleukin-2 (IL-2) in patients with refractory NB...
September 2016: Medicine (Baltimore)
Mohanraj Ramachandran, Di Yu, Matheus Dyczynski, Sathishkumar Baskaran, Lei Zhang, Sirle Saul, Aleksei Lulla, Valeria Lulla, Sven Nelander, Anna Dimberg, Andres Merits, Justyna Leja-Jarblad, Magnus Essand
PURPOSE: Glioblastoma multiforme (GBM) and high-risk neuroblastoma are cancers with poor outcome. Immunotherapy in the form of neurotropic oncolytic viruses is a promising therapeutic strategy for these malignancies. Here we evaluate the oncolytic potential of the neurovirulent and partly interferon (IFN)-β-resistant Semliki Forest virus (SFV)-4 in GBMs and neuroblastomas. To reduce neurovirulence we constructed SFV4miRT, which is attenuated in normal CNS cells through insertion of microRNA target sequences for miR124, miR125, miR134 Experimental Design:Oncolytic activity of SFV4miRT was examined in mouse neuroblastoma and GBM cell lines and in patient-derived human glioblastoma cell cultures (HGCC)...
September 16, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Sonja Textor, Felicitas Bossler, Kai-Oliver Henrich, Moritz Gartlgruber, Julia Pollmann, Nathalie Fiegler, Annette Arnold, Frank Westermann, Nina Waldburger, Kai Breuhahn, Sven Golfier, Mathias Witzens-Harig, Adelheid Cerwenka
Natural Killer (NK) cells are innate effector cells that are able to recognize and eliminate tumor cells through engagement of their surface receptors. NKp30 is a potent activating NK cell receptor that elicits efficient NK cell-mediated target cell killing. Recently, B7-H6 was identified as tumor cell surface expressed ligand for NKp30. Enhanced B7-H6 mRNA levels are frequently detected in tumor compared to healthy tissues. To gain insight in the regulation of expression of B7-H6 in tumors, we investigated transcriptional mechanisms driving B7-H6 expression by promoter analyses...
July 2016: Oncoimmunology
Alice L Yu, Jung-Tung Hung, Ming-Yi Ho, John Yu
All mammalian cells display an array of surface glycans that can modulate cellular interactions, and regulate the development of an organism. In spite of their important implications in health and disease, investigations of glycans pose a great challenge, given their inherent heterogeneity, and the frequently observed cross-reactivities of antibodies against glycosphingolipids (GSLs) with multiple glycans, which may lead to erroneous interpretation and conclusion. We employed matrix-assisted laser desorption ionization- mass spectrometry (MALDI-MS) and tandem MS/MS analyses to systematically delineate changes in GSLs during differentiation of human embryonic stem (ES) and induced pluripotent stem (iPS) cells into various derivatives...
August 9, 2016: Stem Cells and Development
Zulmarie Perez Horta, Jacob L Goldberg, Paul M Sondel
Tumor-specific monoclonal antibodies (mAbs) have demonstrated efficacy in the clinic, becoming an important approach for cancer immunotherapy. Due to its limited expression on normal tissue, the GD2 disialogangloside expressed on neuroblastoma cells is an excellent candidate for mAb therapy. In 2015, dinutuximab (an anti-GD2 mAb) was approved by the US FDA and is currently used in a combination immunotherapeutic regimen for the treatment of children with high-risk neuroblastoma. Here, we review the extensive preclinical and clinical development of anti-GD2 mAbs and the different mechanisms by which they mediate tumor cell killing...
September 2016: Immunotherapy
Michiel Kroesen, Christian Büll, Paul R Gielen, Ingrid C Brok, Inna Armandari, Melissa Wassink, Maaike W G Looman, Louis Boon, Martijn H den Brok, Peter M Hoogerbrugge, Gosse J Adema
Neuroblastoma (NBL) is a childhood malignancy of the sympathetic nervous system. For high-risk NBL patients, the mortality rate is still over 50%, despite intensive multimodal treatment. Anti-GD2 monoclonal antibody (mAB) in combination with systemic cytokine immunotherapy has shown clinical efficacy in high-risk NBL patients. Targeted therapy using histone deacetylase inhibitors (HDACi) is currently being explored in cancer treatment and already shows promising results. Using our recently developed transplantable TH-MYCN NBL model, we here report that the HDAC inhibitor Vorinostat synergizes with anti-GD2 mAb therapy in reducing NBL tumor growth...
June 2016: Oncoimmunology
Joy Bartholomew, Tanea Washington, Sharon Bergeron, Danelle Nielson, Jennifer Saggio, Lindsay Quirk
Therapy combining dinutuximab with granulocyte macrophage colony stimulating factor, interleukin 2, and isotretinoin has significant side effects; however, these complications are generally predictable and can be managed proactively.
July 25, 2016: Journal of Pediatric Oncology Nursing: Official Journal of the Association of Pediatric Oncology Nurses
Annette Künkele, Agne Taraseviciute, Laura S Finn, Adam J Johnson, Carolina Berger, Olivia Finney, Cindy A Chang, Lisa S Rolczynski, Christopher Brown, Stephanie Mgebroff, Michael Berger, Julie R Park, Michael C Jensen
PURPOSE: The identification and vetting of cell surface tumor restricted epitopes for chimeric antigen receptor (CAR) redirected T cell immunotherapy is the subject of intensive investigation. We have focused on CD171 (L1-CAM), an abundant cell surface molecule on neuroblastomas and, specifically, on the glycosylation dependent tumor-specific epitope recognized by the CE7 monoclonal antibody. EXPERIMENTAL DESIGN: CD171 expression was assessed by IHC using CE7 mAb in tumor microarrays of primary, metastatic, and recurrent neuroblastoma, as well as human and rhesus macaque tissue arrays...
July 7, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
L Yang, B S Li, J Chen
No abstract text is available yet for this article.
June 2, 2016: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
Frank Speleman, Julie R Park, Tara O Henderson
Neuroblastoma, an embryonal tumor arising from neural crest-derived progenitor cells, is the most common solid tumor in childhood, with more than 700 cases diagnosed per year in the United States. In the past several decades, significant advances have been made in the treatment of neuroblastoma. Treatment advances reflect improved understanding of the biology of neuroblastoma. Although amplification of MYCN was discovered in the early 1980s, our understanding of neuroblastoma oncogenesis has advanced in the last decade as a result of high-throughput genomic analysis, exome and whole-genome sequencing, genome-wide association studies, and synthetic lethal drug screens...
2016: American Society of Clinical Oncology Educational Book
Gengwen Tian, Amy N Courtney, Bipulendu Jena, Andras Heczey, Daofeng Liu, Ekaterina Marinova, Linjie Guo, Xin Xu, Hiroki Torikai, Qianxing Mo, Gianpietro Dotti, Laurence J Cooper, Leonid S Metelitsa
Vα24-invariant natural killer T cells (NKTs) localize to tumors and have inherent antitumor properties, making them attractive chimeric antigen receptor (CAR) carriers for redirected cancer immunotherapy. However, clinical application of CAR-NKTs has been impeded, as mechanisms responsible for NKT expansion and the in vivo persistence of these cells are unknown. Here, we demonstrated that antigen-induced expansion of primary NKTs in vitro associates with the accumulation of a CD62L+ subset and exhaustion of CD62L- cells...
June 1, 2016: Journal of Clinical Investigation
Franz Blaes, Backialakshmi Dharmalingam
Opsoclonus-myoclonus syndrome (OMS) is a rare and primarily immune-mediated disease in children and adults. The main symptoms include opsoclonus, myoclonus and ataxia. In children, the symptoms also include irritability, and, over a long-term course, learning and behavioural disturbances. OMS can be idiopathic, parainfectious or occur as a paraneoplastic (tumour-associated) syndrome. Paraneoplastic OMS in children is almost exclusively associated with neuroblastoma, whereas in adults, small cell lung cancer and breast cancer are the main underlying tumours...
June 2016: Expert Review of Neurotherapeutics
Peifu Jiao, Mario Otto, Qiaohong Geng, Chencan Li, Faming Li, Elizabeth R Butch, Scott E Snyder, Hongyu Zhou, Bing Yan
Although nanomaterials have been widely investigated for drug delivery, imaging and immunotherapy, their potential roles in triggering innate cellular immune responses while simultaneously serving as imaging enhancer remain unexplored. In this work, gold nanoparticles (GNPs) conjugated to the tumor-targeting anti-GD2 antibody hu14.18K322A, namely HGNPs, were designed and synthesized to specifically enhance computerized tomography (CT) imaging contrast and to stimulate the attack of neuroblastoma and melanoma cells by natural killer (NK) cells...
January 20, 2016: Journal of Materials Chemistry. B, Materials for Biology and Medicine
Dov B Shamir, Nina Rosenqvist, Suhail Rasool, Jan T Pedersen, Einar M Sigurdsson
INTRODUCTION: Tau immunotherapy has emerged as a promising approach to clear tau aggregates from the brain. Our previous findings suggest that tau antibodies may act outside and within neurons to promote such clearance. METHODS: We have developed an approach using flow cytometry, a human neuroblastoma cell model overexpressing tau with the P301L mutation, and paired helical filament (PHF)-enriched pathologic tau to effectively screen uptake and retention of tau antibodies in conjunction with PHF...
March 22, 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Christin Eger, Nikolai Siebert, Diana Seidel, Maxi Zumpe, Madlen Jüttner, Sven Brandt, Hans-Peter Müller, Holger N Lode
Vaccination with proteins mimicking GD2 that is highly expressed on neuroblastoma (NB) cells is a promising strategy in treatment of NB, a pediatric malignancy with poor prognosis. We previously showed efficacy of ganglidiomab in vivo, a murine anti-idiotype (anti-Id) IgG1. In order to tailor immune responses to variable regions, we generated a new human/mouse chimeric anti-Id antibody (Ab) ganglidiximab by replacing murine constant fragments with corresponding human IgG1 regions. DNA sequences encoding for variable regions of heavy (VH) and light chains (VL) were synthesized by RT-PCR from total RNA of ganglidiomab-producing hybridoma cells and further ligated into mammalian expression plasmids with coding sequences for constant regions of human IgG1 heavy and light chains, respectively...
2016: PloS One
Yumeng Mao, Nina Eissler, Katarina Le Blanc, John Inge Johnsen, Per Kogner, Rolf Kiessling
PURPOSE: Neuroblastoma is the most common extracranial solid cancer type in childhood, and high-risk patients have poor prognosis despite aggressive multimodal treatment. Neuroblastoma-driven inflammation contributes to the induction of suppressive myeloid cells that hamper efficient antitumor immune responses. Therefore, we sought to enhance antitumor immunity by removing immunosuppression mediated by myeloid cells. EXPERIMENTAL DESIGN: The prognostic values of myeloid cells are demonstrated by analyzing genomic datasets of neuroblastoma patients...
August 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Alessandra Dondero, Fabio Pastorino, Mariella Della Chiesa, Maria Valeria Corrias, Fabio Morandi, Vito Pistoia, Daniel Olive, Francesca Bellora, Franco Locatelli, Aurora Castellano, Lorenzo Moretta, Alessandro Moretta, Cristina Bottino, Roberta Castriconi
The prognosis of high-risk neuroblastoma (NB) remains poor, although immunotherapies with anti-GD2 antibodies have been reported to provide some benefit. Immunotherapies can be associated with an IFNγ storm that induces in tumor cells the "adaptive immune resistance" characterized by the de-novo expression of Programmed Death Ligands (PD-Ls). Tumor cells can also constitutively express PD-Ls in response to oncogenic signaling. Here, we analyze the constitutive and the inducible surface expression of PD-Ls in NB cells...
2016: Oncoimmunology
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