Journal of Personalized Medicine

Research

11 pages, 1596 KiB

Open AccessFeature PaperArticle

αβ-T Cells Engineered to Express γδ-T Cell Receptors Can Kill Neuroblastoma Organoids Independent of MHC-I Expression

by Josephine G. M. Strijker, Ronja Pscheid, Esther Drent, Jessica J. F. van der Hoek, Bianca Koopmans, Kimberley Ober, Sander R. van Hooff, Waleed M. Kholosy, Annelisa M. Cornel, Chris Coomans, Andrea Bisso, Marleen M. van Loenen, Jan J. Molenaar and Judith Wienke

J. Pers. Med. 2021, 11(9), 923; https://doi.org/10.3390/jpm11090923 - 17 Sep 2021

Cited by 9 | Viewed by 4129

Abstract

Currently ~50% of patients with a diagnosis of high-risk neuroblastoma will not survive due to relapsing or refractory disease. Recent innovations in immunotherapy for solid tumors are highly promising, but the low MHC-I expression of neuroblastoma represents a major challenge for T cell-mediated [...] Read more.

Currently ~50% of patients with a diagnosis of high-risk neuroblastoma will not survive due to relapsing or refractory disease. Recent innovations in immunotherapy for solid tumors are highly promising, but the low MHC-I expression of neuroblastoma represents a major challenge for T cell-mediated immunotherapy. Here, we propose a novel T cell-based immunotherapy approach for neuroblastoma, based on the use of TEG002, αβ-T cells engineered to express a defined γδ-T cell receptor, which can recognize and kill target cells independent of MHC-I. In a co-culture killing assay, we showed that 3 out of 6 neuroblastoma organoids could activate TEG002 as measured by IFNγ production. Transcriptional profiling showed this effect correlates with an increased activity of processes involved in interferon signaling and extracellular matrix organization. Analysis of the dynamics of organoid killing by TEG002 over time confirmed that organoids which induced TEG002 activation were efficiently killed independent of their MHC-I expression. Of note, efficacy of TEG002 treatment was superior to donor-matched untransduced αβ-T cells or endogenous γδ-T cells. Our data suggest that TEG002 may be a promising novel treatment option for a subset of neuroblastoma patients. Full article

(This article belongs to the Special Issue Precision Medicine for Neuroblastoma)

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14 pages, 2117 KiB

Open AccessArticle

Neuroblastoma Risk Assessment and Treatment Stratification with Hybrid Capture-Based Panel Sequencing

by Annabell Szymansky, Louisa-Marie Kruetzfeldt, Lukas C. Heukamp, Falk Hertwig, Jessica Theissen, Hedwig E. Deubzer, Eva-Maria Willing, Roopika Menon, Steffen Fuchs, Theresa Thole, Stefanie Schulte, Karin Schmelz, Annette Künkele, Peter Lang, Jörg Fuchs, Angelika Eggert, Cornelia Eckert, Matthias Fischer, Anton G. Henssen, Elias Rodriguez-Fos and Johannes H. Schulte Show full author list Hide full author list

J. Pers. Med. 2021, 11(8), 691; https://doi.org/10.3390/jpm11080691 - 22 Jul 2021

Cited by 2 | Viewed by 3712

Abstract

For many years, the risk-based therapy stratification of children with neuroblastoma has relied on clinical and molecular covariates. In recent years, genome analysis has revealed further alterations defining risk, tumor biology, and therapeutic targets. The implementation of a robust and scalable method for [...] Read more.

For many years, the risk-based therapy stratification of children with neuroblastoma has relied on clinical and molecular covariates. In recent years, genome analysis has revealed further alterations defining risk, tumor biology, and therapeutic targets. The implementation of a robust and scalable method for analyzing traditional and new molecular markers in routine diagnostics is an urgent clinical need. Here, we investigated targeted panel sequencing as a diagnostic approach to analyze all relevant genomic neuroblastoma risk markers in one assay. Our “neuroblastoma hybrid capture sequencing panel” (NB-HCSP) assay employs a technology for the high-coverage sequencing (>1000×) of 55 selected genes and neuroblastoma-relevant genomic regions, which allows for the detection of single nucleotide changes, structural rearrangements, and copy number alterations. We validated our assay by analyzing 15 neuroblastoma cell lines and a cohort of 20 neuroblastomas, for which reference routine diagnostic data and genome sequencing data were available. We observed a high concordance for risk markers identified by the NB-HSCP assay, clinical routine diagnostics, and genome sequencing. Subsequently, we demonstrated clinical applicability of the NB-HCSP assay by analyzing routine clinical samples. We conclude that the NB-HCSP assay may be implemented into routine diagnostics as a single assay that covers all essential covariates for initial neuroblastoma classification, extended risk stratification, and targeted therapy selection. Full article

(This article belongs to the Special Issue Precision Medicine for Neuroblastoma)

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14 pages, 1878 KiB

Open AccessArticle

Low Expression of IL-15 and NKT in Tumor Microenvironment Predicts Poor Outcome of MYCN-Non-Amplified Neuroblastoma

by Yu-Mei Liao, Tsai-Hsien Hung, John K. Tung, John Yu, Ya-Ling Hsu, Jung-Tung Hung and Alice L. Yu

J. Pers. Med. 2021, 11(2), 122; https://doi.org/10.3390/jpm11020122 - 13 Feb 2021

Cited by 10 | Viewed by 2306

Abstract

Immune tumor microenvironment (TME) in neuroblastoma (NBL) contributes to tumor behavior and treatment response. T cells and natural killer (NK) cells have been shown to play important roles in the neuroblastoma TME. However, few reports address the clinical relevance of natural killer T [...] Read more.

Immune tumor microenvironment (TME) in neuroblastoma (NBL) contributes to tumor behavior and treatment response. T cells and natural killer (NK) cells have been shown to play important roles in the neuroblastoma TME. However, few reports address the clinical relevance of natural killer T cells (NKTs) and interleukin-15 (IL-15), one of the crucial cytokines controlling the activation and expansion of NK/NKT cells, in NBL. In this study, we examined NKT immunoscores and IL-15 expression in both MYCN-amplified and MYCN-non-amplified NBL to correlate with clinical outcomes such as event-free survival (EFS) and overall survival (OS). From Gene Expression Omnibus (GEO) datasets GSE45480 (n = 643) and GSE49711 (n = 493), we found that NKT immunoscore and IL-15 expression were both significantly lower in MYCN-amplified NBL, and similar results were observed using our clinical NBL samples (n = 53). Moreover, NBL patients (GEO dataset GSE49711 and our clinical samples) with both lower NKT immunoscore and IL-15 expression exhibited decreased EFS and OS regardless of MYCN gene amplification status. Multivariate analysis further showed that the combination of low NKT immunoscore and low IL-15 expression level was an independent prognostic factor for poor EFS and OS in our NBL patients. These findings provide the rationale for the development of strategy to incorporate IL-15 and NKT cell therapy into the treatment regimen for neuroblastoma. Full article

(This article belongs to the Special Issue Precision Medicine for Neuroblastoma)

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Review

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25 pages, 3622 KiB

Open AccessFeature PaperReview

From DNA Copy Number Gains and Tumor Dependencies to Novel Therapeutic Targets for High-Risk Neuroblastoma

by Bieke Decaesteker, Kaat Durinck, Nadine Van Roy, Bram De Wilde, Christophe Van Neste, Stéphane Van Haver, Stephen Roberts, Katleen De Preter, Vanessa Vermeirssen and Frank Speleman

J. Pers. Med. 2021, 11(12), 1286; https://doi.org/10.3390/jpm11121286 - 3 Dec 2021

Cited by 3 | Viewed by 3385

Abstract

Neuroblastoma is a pediatric tumor arising from the sympatho-adrenal lineage and a worldwide leading cause of childhood cancer-related deaths. About half of high-risk patients die from the disease while survivors suffer from multiple therapy-related side-effects. While neuroblastomas present with a low mutational burden, [...] Read more.

Neuroblastoma is a pediatric tumor arising from the sympatho-adrenal lineage and a worldwide leading cause of childhood cancer-related deaths. About half of high-risk patients die from the disease while survivors suffer from multiple therapy-related side-effects. While neuroblastomas present with a low mutational burden, focal and large segmental DNA copy number aberrations are highly recurrent and associated with poor survival. It can be assumed that the affected chromosomal regions contain critical genes implicated in neuroblastoma biology and behavior. More specifically, evidence has emerged that several of these genes are implicated in tumor dependencies thus potentially providing novel therapeutic entry points. In this review, we briefly review the current status of recurrent DNA copy number aberrations in neuroblastoma and provide an overview of the genes affected by these genomic variants for which a direct role in neuroblastoma has been established. Several of these genes are implicated in networks that positively regulate MYCN expression or stability as well as cell cycle control and apoptosis. Finally, we summarize alternative approaches to identify and prioritize candidate copy-number driven dependency genes for neuroblastoma offering novel therapeutic opportunities. Full article

(This article belongs to the Special Issue Precision Medicine for Neuroblastoma)

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16 pages, 283 KiB

Open AccessFeature PaperReview

Personalized Medicine for Neuroblastoma: Moving from Static Genotypes to Dynamic Simulations of Drug Response

by Jeremy Z. R. Han, Jordan F. Hastings, Monica Phimmachanh, Dirk Fey, Walter Kolch and David R. Croucher

J. Pers. Med. 2021, 11(5), 395; https://doi.org/10.3390/jpm11050395 - 11 May 2021

Cited by 6 | Viewed by 4027

Abstract

High-risk neuroblastoma is an aggressive childhood cancer that is characterized by high rates of chemoresistance and frequent metastatic relapse. A number of studies have characterized the genetic and epigenetic landscape of neuroblastoma, but due to a generally low mutational burden and paucity of [...] Read more.

High-risk neuroblastoma is an aggressive childhood cancer that is characterized by high rates of chemoresistance and frequent metastatic relapse. A number of studies have characterized the genetic and epigenetic landscape of neuroblastoma, but due to a generally low mutational burden and paucity of actionable mutations, there are few options for applying a comprehensive personalized medicine approach through the use of targeted therapies. Therefore, the use of multi-agent chemotherapy remains the current standard of care for neuroblastoma, which also conceptually limits the opportunities for developing an effective and widely applicable personalized medicine approach for this disease. However, in this review we outline potential approaches for tailoring the use of chemotherapy agents to the specific molecular characteristics of individual tumours by performing patient-specific simulations of drug-induced apoptotic signalling. By incorporating multiple layers of information about tumour-specific aberrations, including expression as well as mutation data, these models have the potential to rationalize the selection of chemotherapeutics contained within multi-agent treatment regimens and ensure the optimum response is achieved for each individual patient. Full article

(This article belongs to the Special Issue Precision Medicine for Neuroblastoma)

18 pages, 3330 KiB

Open AccessReview

The Promise of Patient-Derived Preclinical Models to Accelerate the Implementation of Personalised Medicine for Children with Neuroblastoma

by Elizabeth R. Tucker, Sally George, Paola Angelini, Alejandra Bruna and Louis Chesler

J. Pers. Med. 2021, 11(4), 248; https://doi.org/10.3390/jpm11040248 - 30 Mar 2021

Cited by 15 | Viewed by 3321

Abstract

Patient-derived preclinical models are now a core component of cancer research and have the ability to drastically improve the predictive power of preclinical therapeutic studies. However, their development and maintenance can be challenging, time consuming, and expensive. For neuroblastoma, a developmental malignancy of [...] Read more.

Patient-derived preclinical models are now a core component of cancer research and have the ability to drastically improve the predictive power of preclinical therapeutic studies. However, their development and maintenance can be challenging, time consuming, and expensive. For neuroblastoma, a developmental malignancy of the neural crest, it is possible to establish patient-derived models as xenografts in mice and zebrafish, and as spheroids and organoids in vitro. These varied approaches have contributed to comprehensive packages of preclinical evidence in support of new therapeutics for neuroblastoma. We discuss here the ethical and technical considerations for the creation of patient-derived models of neuroblastoma and how their use can be optimized for the study of tumour evolution and preclinical therapies. We also discuss how neuroblastoma patient-derived models might become avatars for personalised medicine for children with this devastating disease. Full article

(This article belongs to the Special Issue Precision Medicine for Neuroblastoma)

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23 pages, 976 KiB

Open AccessReview

The Potential of Mesenchymal Stromal Cells in Neuroblastoma Therapy for Delivery of Anti-Cancer Agents and Hematopoietic Recovery

by Caroline Hochheuser, Nina Y. Kunze, Godelieve A. M. Tytgat, Carlijn Voermans and Ilse Timmerman

J. Pers. Med. 2021, 11(3), 161; https://doi.org/10.3390/jpm11030161 - 25 Feb 2021

Cited by 10 | Viewed by 3141

Abstract

Neuroblastoma is one of the most common pediatric cancers and a major cause of cancer-related death in infancy. Conventional therapies including high-dose chemotherapy, stem cell transplantation, and immunotherapy approach a limit in the treatment of high-risk neuroblastoma and prevention of relapse. In the [...] Read more.

Neuroblastoma is one of the most common pediatric cancers and a major cause of cancer-related death in infancy. Conventional therapies including high-dose chemotherapy, stem cell transplantation, and immunotherapy approach a limit in the treatment of high-risk neuroblastoma and prevention of relapse. In the last two decades, research unraveled a potential use of mesenchymal stromal cells in tumor therapy, as tumor-selective delivery vehicles for therapeutic compounds and oncolytic viruses and by means of supporting hematopoietic stem cell transplantation. Based on pre-clinical and clinical advances in neuroblastoma and other malignancies, we assess both the strong potential and the associated risks of using mesenchymal stromal cells in the therapy for neuroblastoma. Furthermore, we examine feasibility and safety aspects and discuss future directions for harnessing the advantageous properties of mesenchymal stromal cells for the advancement of therapy success. Full article

(This article belongs to the Special Issue Precision Medicine for Neuroblastoma)

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Other

Jump to: Research, Review

26 pages, 8585 KiB

Open AccessSystematic Review

Differentiating Neuroblastoma: A Systematic Review of the Retinoic Acid, Its Derivatives, and Synergistic Interactions

by Nadiya Bayeva, Erin Coll and Olga Piskareva

J. Pers. Med. 2021, 11(3), 211; https://doi.org/10.3390/jpm11030211 - 16 Mar 2021

Cited by 38 | Viewed by 9030

Abstract

A neuroblastoma (NB) is a solid paediatric tumour arising from undifferentiated neuronal cells. Despite the recent advances in disease management and treatment, it remains one of the leading causes of childhood cancer deaths, thereby necessitating the development of new therapeutic agents and regimens. [...] Read more.

A neuroblastoma (NB) is a solid paediatric tumour arising from undifferentiated neuronal cells. Despite the recent advances in disease management and treatment, it remains one of the leading causes of childhood cancer deaths, thereby necessitating the development of new therapeutic agents and regimens. Retinoic acid (RA), a vitamin A derivative, is a promising agent that can induce differentiation in NB cells. Its isoform, 13-cis RA or isotretinoin, is used in NB therapy; however, its effectiveness is limited to treating a minimal residual disease as maintenance therapy. As such, research focuses on RA derivatives that might increase the anti-NB action or explores the potential synergy between RA and other classes of drugs, such as cellular processes mediators, epigenetic modifiers, and immune modulators. This review summarises the in vitro, in vivo, and clinical data of RA, its derivatives, and synergising compounds, thereby establishing the most promising RA derivatives and combinations of RA for further investigation. Full article

(This article belongs to the Special Issue Precision Medicine for Neuroblastoma)

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