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Neuroblastoma immunotherapy

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https://www.readbyqxmd.com/read/29123953/pd-1-blockade-augments-anti-neuroblastoma-immune-response-induced-by-anti-gd2-antibody-ch14-18-cho
#1
Nikolai Siebert, Maxi Zumpe, Madlen Jüttner, Sascha Troschke-Meurer, Holger N Lode
Immunotherapy with anti-GD2 antibody (Ab) ch14.18/CHO is effective for treatment of high-risk neuroblastoma (NB) patients and is mainly based on GD2-specific Ab-dependent cellular cytotoxicity (ADCC). Strategies to further enhance the efficacy are important and currently explored in prospective clinical trials randomizing ch14.18/CHO ± IL-2. Recently, expression of programmed death 1 (PD-1) inhibitory receptor by effector cells and its ligand (PD-L1) by tumor cells has been shown. Here, we report for the first time effects of PD-1 blockade on ch14...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29120699/tolerability-response-and-outcome-of-high-risk-neuroblastoma-patients-treated-with-long-term-infusion-of-anti-gd2-antibody-ch14-18-cho
#2
Ina Mueller, Karoline Ehlert, Stefanie Endres, Lena Pill, Nikolai Siebert, Silke Kietz, Penelope Brock, Alberto Garaventa, Dominique Valteau-Couanet, Evelyne Janzek, Norbert Hosten, Andreas Zinke, Winfried Barthlen, Emine Varol, Hans Loibner, Ruth Ladenstein, Holger N Lode
Immunotherapy with short term infusion (STI) of monoclonal anti-GD2 antibody (mAb) ch14.18 (4 × 25mg/m(2)/d; 8-20h) in combination with cytokines and 13-cis retinoic acid (RA) prolonged survival in high-risk neuroblastoma (NB) patients. Here, we investigated long-term infusion (LTI) of ch14.18 produced in Chinese hamster ovary cells (ch14.18/CHO; 10 × 10mg/m(2); 24h) in combination with subcutaneous (s.c.) interleukin-2 (IL-2) in a single center program and report clinical response, toxicity and survival...
November 9, 2017: MAbs
https://www.readbyqxmd.com/read/29103425/cancer-and-autoimmunity-paraneoplastic-neurological-disorders-associated-with-neuroblastic-tumors
#3
Wendy G Mitchell, Franz Blaes
Cancer and autoimmunity come together in paraneoplastic syndromes (PNS), which reflect the remote, not direct, effects of cancer. In the pediatric population, a variety of PNS have been described, but the most common of these rare disorders are instigated by neuroblastic tumors, such as neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. The main pediatric-onset neurological PNS are ROHHAD syndrome, anti-ANNA1 (anti-Hu), and opsoclonus-myoclonus syndrome. They manifest distinctive neurological features, which aid the diagnosis, though under-recognition still poses serious challenges and risks...
August 2017: Seminars in Pediatric Neurology
https://www.readbyqxmd.com/read/29070883/combined-immunotherapy-with-anti-pdl-1-pd-1-and-anti-cd4-antibodies-cures-syngeneic-disseminated-neuroblastoma
#4
Valentina Rigo, Laura Emionite, Antonio Daga, Simonetta Astigiano, Maria Valeria Corrias, Concetta Quintarelli, Franco Locatelli, Silvano Ferrini, Michela Croce
Anti-PD-1 or anti-PD-L1 blocking monoclonal antibodies (mAbs) have shown potent anti-tumor effects in adult cancer patients and clinical studies have recently been started in pediatric cancers, including high-risk/relapsing neuroblastoma (NB). Therefore, we studied the effects of anti-PD-1/PD-L1 mAbs in two syngeneic models of disseminated NB generated by the injection of either Neuro2a or NXS2 cells, which express PD-L1. In addition, we tested the combination of these agents with the immune-enhancing cytokine IL-21, the Ecto-NTPDase inhibitor POM-1, an anti-CD25 mAb targeting Treg cells, or an anti-CD4 mAb...
October 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29067879/expression-of-disialoganglioside-gd2-in-neuroblastic-tumors-a-prognostic-value-for-patients-treated-with-anti-gd2-immunotherapy
#5
Tatjana Terzic, Martine Cordeau, Sabine Herblot, Pierre Teira, Sonia Cournoyer, Mona Beaunoyer, Michel Peuchmaur, Michel Duval, Herve Sartelet
Neuroblastoma, a malignant neoplasm of the sympathetic nervous system, is one of the most aggressive pediatric cancers. Patients with stage IV high-risk neuroblastoma receive an intensive multimodal therapy ending with an immunotherapy based on a chimeric monoclonal antibody ch14.18. Although the use of ch14.18 monoclonal antibody has significantly increased the survival rate of high-risk neuroblastoma patients, about 33% of these patients still relapse and die from their disease. Ch14.18 targets the disialoganglioside, GD2, expressed on neuroblastic tumor (NT) cells...
January 1, 2017: Pediatric and Developmental Pathology
https://www.readbyqxmd.com/read/29062613/emerging-and-investigational-therapies-for-neuroblastoma
#6
Mark A Applebaum, Ami V Desai, Julia L Glade Bender, Susan L Cohn
INTRODUCTION: Treatment for children with clinically aggressive, high-risk neuroblastoma remains challenging. Less than 50% of patients with high-risk neuroblastoma will survive long-term with current therapies, and survivors are at risk for serious treatment-related late toxicities. Here, we review new and evolving treatments that may ultimately improve outcome for children with high-risk neuroblastoma with decreased potential for late adverse events. AREAS COVERED: New strategies for treating high-risk neuroblastoma are reviewed including: radiotherapy, targeted cytotoxics, biologics, immunotherapy, and molecularly targeted agents...
2017: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/29061769/therapeutic-innovations-for-targeting-childhood-neuroblastoma-implications-of-the-neurokinin-1-receptor-system
#7
REVIEW
Michael Berger, Dietrich VON Schweinitz
Neuroblastoma is the most common solid extracranial malignant tumor in children. Despite recent advances in the treatment of this heterogenous tumor with surgery and chemotherapy, the prognosis in advanced stages remains poor. Interestingly, neuroblastoma is one of the few solid tumors, to date, in which an effect for targeted immunotherapy has been proven in controlled clinical trials, giving hope for further advances in the treatment of this and other tumors by targeted therapy. A large array of novel therapeutic options for targeted therapy of neuroblastoma is on the horizon...
November 2017: Anticancer Research
https://www.readbyqxmd.com/read/29039999/treatment-and-survival-of-childhood-neuroblastoma-evidence-from-a-population-based-study-in-the-united-states
#8
Diarmuid Coughlan, Matthew Gianferante, Charles F Lynch, Jennifer L Stevens, Linda C Harlan
BACKGROUND: Childhood neuroblastoma describes a heterogeneous group of extracranial solid tumors, that are treated per risk profile. We sought to describe treatment patterns and survival using population-based data from throughout the United States. MATERIALS AND METHODS: Using the National Cancer Institute (NCI)'s Patterns of Care data, we analyzed treatment provided to newly diagnosed, histologically confirmed neuroblastoma patients in 2010 and 2011, registered to one of 14 Surveillance, Epidemiology, and End Results (SEER) cancer registries...
October 17, 2017: Pediatric Hematology and Oncology
https://www.readbyqxmd.com/read/28972044/neuroblastoma-patients-kir-and-kir-ligand-genotypes-influence-clinical-outcome-for-dinutuximab-based-immunotherapy-a-report-from-the-children-s-oncology-group
#9
Amy K Erbe, Wei Wang, Lakeesha Carmichael, KyungMann Kim, Eneida A Mendonca, Yiqiang Song, Dustin Hess, Patrick K Reville, Wendy B London, Arlene Naranjo, Jacquelyn A Hank, Mitchell B Diccianni, Ralph A Reisfeld, Stephen D Gillies, Katherine K Matthay, Susan L Cohn, Michael D Hogarty, John M Maris, Julie R Park, Mehmet Fevzi Ozkaynak, Andrew Gilman, Alice L Yu, Paul M Sondel
PURPOSE: In 2010, a Children's Oncology Group (COG) phase III randomized trial for high-risk neuroblastoma patients (ANBL0032) demonstrated improved event-free survival (EFS) and overall survival (OS) following treatment with an immunotherapy regimen of dinutuximab, GM-CSF, IL-2, and isotretinoin compared to treatment with isotretinoin alone. Dinutuximab, a chimeric anti-GD2 monoclonal antibody, acts in part via NK cells. Killer Immunoglobulin-like Receptors (KIRs) on NK cells and their interactions with KIR-ligands can influence NK cell function...
October 2, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28959231/demographic-clinical-and-immunologic-features-of-389-children-with-opsoclonus-myoclonus-syndrome-a-cross-sectional-study
#10
Michael R Pranzatelli, Elizabeth D Tate, Nathan R McGee
Pediatric-onset opsoclonus-myoclonus syndrome (OMS) is a devastating neuroinflammatory, often paraneoplastic, disorder. The objective was to characterize demographic, clinical, and immunologic aspects in the largest cohort reported to date. Cross-sectional data were collected on 389 children in an IRB-approved, observational study at the National Pediatric Myoclonus Center. Non-parametric statistical analysis was used. OMS manifested in major racial/ethnic groups, paralleling US population densities. Median onset age was 1...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28906153/investigational-drugs-in-phase-ii-clinical-trials-for-the-treatment-of-neuroblastoma
#11
REVIEW
Loredana Amoroso, Riccardo Haupt, Alberto Garaventa, Mirco Ponzoni
Neuroblastoma (NB) is an embryonal tumor originating from undifferentiated neural crest cell, highly heterogeneous ranging from spontaneous regression to progression despite multimodal treatments. Approximately, 20% of patients are refractory to frontline therapy and 50% will relapse/progress after an initial response. The overall five year survival for high-risk neuroblastoma ranges from 35-45%. Despite enhanced understanding of NB biology and the addition of myeloablative chemotherapy, isotretinoin and immunotherapy, survival for high risk NB remains less than 50%...
November 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28871274/paired-expression-analysis-of-tumor-cell-surface-antigens
#12
Rimas J Orentas, Sivasish Sindiri, Christine Duris, Xinyu Wen, Jianbin He, Jun S Wei, Jason Jarzembowski, Javed Khan
Adoptive immunotherapy with antibody-based therapy or with T cells transduced to express chimeric antigen receptors (CARs) is useful to the extent that the cell surface membrane protein being targeted is not expressed on normal tissues. The most successful CAR-based (anti-CD19) or antibody-based therapy (anti-CD20) in hematologic malignancies has the side effect of eliminating the normal B cell compartment. Targeting solid tumors may not provide a similar expendable marker. Beyond antibody to Her2/NEU and EGFR, very few antibody-based and no CAR-based therapies have seen broad clinical application for solid tumors...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28830878/constitutive-signaling-from-an-engineered-il7-receptor-promotes-durable-tumor-elimination-by-tumor-redirected-t-cells
#13
Thomas Shum, Bilal Omer, Haruko Tashiro, Robert L Kruse, Dimitrios L Wagner, Kathan Parikh, Zhongzhen Yi, Tim Sauer, Daofeng Liu, Robin Parihar, Paul Castillo, Hao Liu, Malcolm K Brenner, Leonid S Metelitsa, Stephen Gottschalk, Cliona M Rooney
Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes...
November 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28780888/anti-gd2-immunotherapy-for-neuroblastoma
#14
REVIEW
Sameer Sait, Shakeel Modak
Current therapeutic approaches for high-risk neuroblastoma (HR-NB) include high-dose chemotherapy, surgery and radiotherapy; interventions that are associated with long and short-term toxicities. Effective immunotherapy holds particular promise for improving survival and quality of life by reducing exposure to cytotoxic agents. GD2, a surface glycolipid is the most common target for immunotherapy. Areas covered: We review the status of anti-GD2 immunotherapies currently in clinical use for neuroblastomas and novel GD2-targeted strategies in preclinical development...
October 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/28748630/transverse-myelitis-as-an-unexpected-complication-following-treatment-with-dinutuximab-in-pediatric-patients-with-high-risk-neuroblastoma-a-case-series
#15
Yang-Yang Ding, Jessica Panzer, John M Maris, Alicia Castañeda, Marta Gomez-Chiari, Jaume Mora
Immunotherapy with the anti-GD2 monoclonal antibody ch14.18, or dinutuximab, represents an important therapeutic advance in the treatment of pediatric high-risk neuroblastoma and is now considered part of standard of care in this patient population. To date, transverse myelitis as a result of dinutuximab therapy has not been reported in clinical trials or in the published literature. We describe three patients with clinical symptoms of transverse myelitis, confirmed via magnetic resonance imaging, shortly following initiation of dinutuximab...
July 27, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28733263/consolidation-therapy-for-newly-diagnosed-pediatric-patients-with-high-risk-neuroblastoma-using-busulfan-melphalan-autologous-hematopoietic-cell-transplantation-anti-gd2-antibody-granulocyte-macrophage-colony-stimulating-factor-interleukin-2-and-haploidentical
#16
Aimee C Talleur, Brandon M Triplett, Sara Federico, Ewelina Mamcarz, William Janssen, Jianrong Wu, David Shook, Wing Leung, Wayne L Furman
The treatment of pediatric high-risk neuroblastoma is intensive and multimodal. Despite the introduction of immunotherapy for minimal residual disease, survival rates remain suboptimal and new therapies are needed. As part of a phase 2 trial, we are using a consolidation therapy regimen that combines a busulfan/melphalan conditioning schema, autologous hematopoietic cell transplantation (AHCT), and experimental immunotherapy with hu14.18K322A (a humanized anti-GD2 monoclonal antibody), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-2, with or without the adoptive transfer of haploidentical natural killer cells (NKs)...
November 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28680756/amplification-of-n-myc-is-associated-with-a-t-cell-poor-microenvironment-in-metastatic-neuroblastoma-restraining-interferon-pathway-activity-and-chemokine-expression
#17
Julian P Layer, Marie T Kronmüller, Thomas Quast, Debby van den Boorn-Konijnenberg, Maike Effern, Daniel Hinze, Kristina Althoff, Alexander Schramm, Frank Westermann, Martin Peifer, Gunther Hartmann, Thomas Tüting, Waldemar Kolanus, Matthias Fischer, Johannes Schulte, Michael Hölzel
Immune checkpoint inhibitors have significantly improved the treatment of several cancers. T-cell infiltration and the number of neoantigens caused by tumor-specific mutations are correlated to favorable responses in cancers with a high mutation load. Accordingly, checkpoint immunotherapy is thought to be less effective in tumors with low mutation frequencies such as neuroblastoma, a neuroendocrine tumor of early childhood with poor outcome of the high-risk disease group. However, spontaneous regressions and paraneoplastic syndromes seen in neuroblastoma patients suggest substantial immunogenicity...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680748/mycn-is-an-immunosuppressive-oncogene-dampening-the-expression-of-ligands-for-nk-cell-activating-receptors-in-human-high-risk-neuroblastoma
#18
Elisa Brandetti, Irene Veneziani, Ombretta Melaiu, Annalisa Pezzolo, Aurora Castellano, Renata Boldrini, Elisa Ferretti, Doriana Fruci, Lorenzo Moretta, Vito Pistoia, Franco Locatelli, Loredana Cifaldi
Neuroblastoma (NB) is the most common extracranial solid tumor occurring in childhood. Amplification of the MYCN oncogene is associated with poor prognosis. Downregulation on NB cells of ligands recognized by Natural Killer (NK) cell-activating receptors, involved in tumor cell recognition and lysis, may contribute to tumor progression and relapse. Here, we demonstrate that in human NB cell lines MYCN expression inversely correlates with that of ligands recognized by NKG2D and DNAM1 activating receptors in human NB cell lines...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28676342/tumor-antigen-and-receptor-densities-regulate-efficacy-of-a-chimeric-antigen-receptor-targeting-anaplastic-lymphoma-kinase
#19
Alec J Walker, Robbie G Majzner, Ling Zhang, Kelsey Wanhainen, Adrienne H Long, Sang M Nguyen, Paola Lopomo, Marc Vigny, Terry J Fry, Rimas J Orentas, Crystal L Mackall
We explored the utility of targeting anaplastic lymphoma kinase (ALK), a cell surface receptor overexpressed on pediatric solid tumors, using chimeric antigen receptor (CAR)-based immunotherapy. T cells expressing a CAR incorporating the single-chain variable fragment sequence of the ALK48 mAb linked to a 4-1BB-CD3ζ signaling domain lysed ALK-expressing tumor lines and produced interferon-gamma upon antigen stimulation but had limited anti-tumor efficacy in two xenograft models of human neuroblastoma. Further exploration demonstrated that cytokine production was highly dependent upon ALK target density and that target density of ALK on neuroblastoma cell lines was insufficient for maximal activation of CAR T cells...
September 6, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28659916/hla-bw4-i-80-isoform-differentially-influences-clinical-outcome-as-compared-to-hla-bw4-t-80-and-hla-a-bw4-isoforms-in-rituximab-or-dinutuximab-based-cancer-immunotherapy
#20
Amy K Erbe, Wei Wang, Patrick K Reville, Lakeesha Carmichael, KyungMann Kim, Eneida A Mendonca, Yiqiang Song, Jacquelyn A Hank, Wendy B London, Arlene Naranjo, Fangxin Hong, Michael D Hogarty, John M Maris, Julie R Park, M F Ozkaynak, Jeffrey S Miller, Andrew L Gilman, Brad Kahl, Alice L Yu, Paul M Sondel
Killer-cell immunoglobulin-like receptors (KIRs) are a family of glycoproteins expressed primarily on natural killer cells that can regulate their function. Inhibitory KIRs recognize MHC class I molecules (KIR-ligands) as ligands. We have reported associations of KIRs and KIR-ligands for patients in two monoclonal antibody (mAb)-based trials: (1) A Children's Oncology Group (COG) trial for children with high-risk neuroblastoma randomized to immunotherapy treatment with dinutuximab (anti-GD2 mAb) + GM-CSF + IL-2 + isotretinion or to treatment with isotretinoin alone and (2) An Eastern Cooperative Oncology Group (ECOG) trial for adults with low-tumor burden follicular lymphoma responding to an induction course of rituximab (anti-CD20 mAb) and randomized to treatment with maintenance rituximab or no-maintenance rituximab...
2017: Frontiers in Immunology
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