Next-generation humanized patient-derived xenograft mouse model for pre-clinical antibody studies in neuroblastoma

AbstractFaithful tumor mouse models are fundamental research tools to advance the field of immuno-oncology (IO). This is particularly relevant in diseases with low incidence, as in the case of pediatric malignancies, that rely on pre-clinical therapeutic development. However, conventional syngeneic and genetically engineered mouse models fail to recapitulate the tumor heterogeneity and microenvironmental complexity of human pathology that are essential determinants of cancer-directed immunity. Here, we characterize a novel mouse model that supports human natural killer (NK) cell development and engraftment of neuroblastoma orthotopic patient-derived xenograft (O-PDX) for pre-clinical antibody and cytokine testing. Using cytotoxicity assays, single-cell RNA-sequencing, and multi-color flow cytometry, we demonstrate that NK cells that develop in the humanized mice are fully licensed to execute NK cell cytotoxicity, permit human tumor engraftment, but can be therapeutically redirected to induce antibody-dependent cell-mediated cytotoxicity (ADCC). Although these cells share phenotypic and molecular features with healthy controls, we noted that they lacked an NK cell subset, termed activated NK cells, that is characterized by differentially expressed genes that are induced by cytokine activation. Because this subset of genes is also downregulated in patients with neuroblastoma compared to healthy controls, we hypothesize that this finding could be due to tumor-mediated suppressiv...
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research

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Aberrant expression of glycosphingolipids (GSLs) is a unique feature of cancer and stromal cells in tumor microenvironments. Although the impact of GSLs on tumor progression remains largely unclear, anticancer immunotherapies directed against GSLs are attracting growing attention. Here, we focus on GD2, a disialoganglioside expressed in tumors of neuroectodermal origin, and Globo H ceramide (GHCer), the most prevalent cancer ‐associated GSL overexpressed in a variety of epithelial cancers. We first summarize recent advances on our understanding of GD2 and GHCer biology and then discuss the clinical development of the fir...
Source: FEBS Letters - Category: Biochemistry Authors: Tags: Review Article Source Type: research
Conditions:   Constitutional Mismatch Repair Deficiency Syndrome;   Hematopoietic and Lymphoid Cell Neoplasm;   Lynch Syndrome;   Recurrent Lymphoma;   Recurrent Malignant Solid Neoplasm;   Recurrent Neuroblastoma;   Recurrent Primary Central Nervous System Neoplasm;   Refractory Lympho ma;   Refractory Malignant Solid Neoplasm;   Refractory Neuroblastoma;   Refractory Primary Central Nervous System Neoplasm;   Xeroderma Pigmentosum Interventions:   Proced...
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
Contributors : Florida Voli ; Emanuele Valli ; Luigi Lerra ; Kathleen Kimpton ; Federica Saletta ; Federico M Giorgi ; Daniele Mercatelli ; Jourdin R Rouaen ; Sylvie Shen ; Jayne E Murray ; Aria Ahmed-Cox ; Giuseppe Cirillo ; Chelsea Mayoh ; Paul A Beavis ; Michelle Haber ; Joseph A Trapani ; Maria Kavallaris ; Orazio VittorioSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensTherapeutic checkpoint antibodies blocking PD1/PD-L1 signaling have radically improved clinical outcomes in cancer. However, the regulation of PD-L1 expression on tumor cells is still poorly understood. Here we show...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research
Abstract High-risk neuroblastoma, which is associated with regional and systemic metastasis, is a leading cause of cancer-related mortality in children. Responding to this need for novel therapies for high-risk patients, we have developed a "nanoimmunotherapy," which combines photothermal therapy (PTT) using CpG oligodeoxynucleotide-coated Prussian blue nanoparticles (CpG-PBNPs) combined with anti-CTLA-4 (aCTLA-4) immunotherapy. Our in vitro studies demonstrate that in addition to causing ablative tumor cell death, our nanoimmunotherapy alters the surface levels of co-stimulatory, antigen-presenting, and...
Source: Translational Oncology - Category: Cancer & Oncology Authors: Tags: Transl Oncol Source Type: research
ConclusionTMB is a novel biomarker guiding the classification of neoplasms in the emerging era of immunotherapy. The characterization of ONB as a low ‐TMB pathology contributes to the overall taxonomy of all cancers and suggests limited utility of immunotherapy treatment.
Source: International Forum of Allergy and Rhinology - Category: Allergy & Immunology Authors: Tags: ORIGINAL ARTICLE Source Type: research
AbstractPatients with pediatric cancers such as neuroblastoma (NB) are often unresponsive to checkpoint blockade immunotherapy. One major factor in pediatric tumor resistance to immunotherapy is considered to be the low mutation rate of pediatric tumors. Another factor may be the overexpression of additional inhibitory pathways. While analyzing the RNA-sequencing database TARGET, we found that human NB tumors overexpress immune checkpoint molecule CD200. To determine its significance and impact on tumor immune microenvironment, we analyzed 49 cases of previously untreated, surgically removed NB tumors using immunohistochem...
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research
Neuroblastoma (NB) is the most common extracranial solid tumor in children and, in the high-risk group, has a 5-year mortality rate of ~50%. The high mortality rate and significant treatment-related morbidities associated with current standard of care therapies belie the critical need for more tolerable and effective treatments for this disease. While the monoclonal antibody dinutuximab has demonstrated the potential for immunotherapy to improve overall NB outcomes, the 5-year overall survival of high-risk patients has not yet substantially changed. The frequency and type of invariant natural killer T cells (iNKTs) and nat...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
AbstractTargeted immunotherapy has improved the outcome of patients with high-risk neuroblastoma (NB). However, immune escape of tumor cells still occurs and about 40% of NB patients relapse and die from their disease. We previously showed that natural killer (NK) cell stimulation by Toll-like receptor (TLR)-activated plasmacytoid dendritic cells (pDC) increases the efficacy of dinutuximab-based immunotherapy against NB cell lines via the TRAIL death-receptor pathway. With the aim to translate our findings into a novel adoptive therapy of TLR-activated pDC, we investigated the pDC/NK cell axis in NB patients undergoing din...
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research
Dinutuximab, an immunotherapy targeting GD2, was delivered loacally in a lyophilized silk fibroin foam for the treatment of an orthotopic neuroblastoma mouse model. Silk fibroin foam allows for a sustained release of dinutuximab, causing significant tumor growth inhibition. AbstractImmunotherapy targeting GD2 is a primary treatment for patients with high ‐risk neuroblastoma. Dinutuximab is a monoclonal antibody with great clinical promise but is limited by side effects such as severe pain. Local delivery has emerged as a potential mechanism to deliver higher doses of therapeutics into the tumor bed, while limiting system...
Source: Cancer Medicine - Category: Cancer & Oncology Authors: Tags: ORIGINAL RESEARCH Source Type: research
ierkens Neuroblastoma (NBL) is the most common extracranial solid tumor in childhood. Despite intense treatment, children with this high-risk disease have a poor prognosis. Immunotherapy showed a significant improvement in event-free survival in high-risk NBL patients receiving chimeric anti-GD2 in combination with cytokines and isotretinoin after myeloablative consolidation therapy. However, response to immunotherapy varies widely, and often therapy is stopped due to severe toxicities. Objective markers that help to predict which patients will respond or develop toxicity to a certain treatment are lacking. Immunothera...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
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