Martinez-Velez, N. (Naiara)
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- The oncolytic adenovirus VCN01 promotes anti tumor effect in primitive neuroectodermal tumor models(Springer Science and Business Media LLC, 2019) Patiño-García, A. (Ana); Alonso-Roldán, M.M. (Marta María); Martinez-Velez, N. (Naiara); Gonzalez-Huarriz, M. (Marisol); Marrodán, L. (Lucía); Garcia-Moure, M. (Marc); Alemany-Güell, R. (Ramón); Cascallo, M. (Manel)Last advances in the treatment of pediatric tumors has led to an increase of survival rates of children affected by primitive neuroectodermal tumors, however, still a significant amount of the patients do not overcome the disease. In addition, the survivors might suffer from severe side effects caused by the current standard treatments. Oncolytic virotherapy has emerged in the last years as a promising alternative for the treatment of solid tumors. In this work, we study the anti-tumor effect mediated by the oncolytic adenovirus VCN-01 in CNS-PNET models. VCN-01 is able to infect and replicate in PNET cell cultures, leading to a cytotoxicity and immunogenic cell death. In vivo, VCN-01 increased significantly the median survival of mice and led to long-term survivors in two orthotopic models of PNETs. In summary, these results underscore the therapeutic effect of VCN-01 for rare pediatric cancers such as PNETs, and warrants further exploration on the use of this virus to treat them.
- Oncolytic adenoviruses as a therapeutic approach for osteosarcoma: A new hope(Elsevier, 2016) Patiño-García, A. (Ana); Alonso-Roldán, M.M. (Marta María); Martinez-Velez, N. (Naiara); Garcia-Moure, M. (Marc)Osteosarcoma is the most common bone cancer among those with non-hematological origin and affects mainly pediatric patients. In the last 50 years, refinements in surgical procedures, as well as the introduction of aggressive neoadjuvant and adjuvant chemotherapeutic cocktails, have increased to nearly 70% the survival rate of these patients. Despite the initial therapeutic progress the fight against osteosarcoma has not substantially improved during the last three decades, and almost 30% of the patients do not respond or recur after the standard treatment. For this group there is an urgent need to implement new therapeutic approaches. Oncolytic adenoviruses are conditionally replicative viruses engineered to selectively replicate in and kill tumor cells, while remaining quiescent in healthy cells. In the last years there have been multiple preclinical and clinical studies using these viruses as therapeutic agents in the treatment of a broad range of cancers, including osteosarcoma. In this review, we summarize some of the most relevant published literature about the use of oncolytic adenoviruses to treat human osteosarcoma tumors in subcutaneous, orthotopic and metastatic mouse models. In conclusion, up to date the preclinical studies with oncolytic adenoviruses have demonstrated that are safe and efficacious against local and metastatic osteosarcoma. Knowledge arising from phase I/II clinical trials with oncolytic adenoviruses in other tumors have shown the potential of viruses to awake the patient´s own immune system generating a response against the tumor. Generating osteosarcoma immune-competent adenoviruses friendly models will allow to better understand this potential. Future clinical trials with oncolytic adenoviruses for osteosarcoma tumors are warranted.
- Assessment of metabolic patterns and new antitumoral treatment in osteosarcoma xenograft models by [18F]FDG and sodium [18F]fluoride PET(2018) Patiño-García, A. (Ana); Alonso-Roldán, M.M. (Marta María); Zalacain, M. (Marta); Martinez-Velez, N. (Naiara); Collantes, M. (María); Peñuelas-Sanchez, I. (Ivan); Marrodán, L. (Lucía); Garcia-Velloso, M. J. (María José); Ecay, M. (Margarita)BACKGROUND: Osteosarcoma is the most common malignant bone tumor in children and young adults that produces aberrant osteoid. The aim of this study was to assess the utility of 2-deoxy-2-[18F-] fluoro-D-glucose ([18F] FDG) and sodium [18F] Fluoride (Na [18F] F) PET scans in orthotopic murine models of osteosarcoma to describe the metabolic pattern of the tumors, to detect and diagnose tumors and to evaluate the efficacy of a new treatment based in oncolytic adenoviruses. METHODS: Orthotopic osteosarcoma murine models were created by the injection of 143B and 531MII cell lines. [18F]FDG and Na [18F] F PET scans were performed 30 days (143B) and 90 days (531MII) post-injection. The antitumor effect of two doses (107 and 108 pfu) of the oncolytic adenovirus VCN-01 was evaluated in 531 MII model by [18F] FDG PET studies. [18F] FDG uptake was quantified by SUVmax and Total Lesion Glycolysis (TLG) indexes. For Na [18F] F, the ratio tumor SUVmax/hip SUVmax was calculated. PET findings were confirmed by histopathological techniques. RESULTS: The metabolic pattern of tumors was different between both orthotopic models. All tumors showed [18F] FDG uptake, with a sensitivity and specificity of 100%. The [18F] FDG uptake was significantly higher for the 143B model (p < 0.001). Sensitivity for Na [18F] F was around 70% in both models, with a specificity of 100%. 531MII tumors showed a heterogeneous Na [18F] F uptake, significantly higher than 143B tumors (p < 0.01).
- RNU6-1 in circulating exosomes differentiates GBM from non-neoplastic brain lesions and PCNSL but not from brain metastases.(Society for NeuroOncology (SNO), 2020) Patiño-García, A. (Ana); Alonso-Roldán, M.M. (Marta María); Martinez-Velez, N. (Naiara); Marigil, M. (Miguel); Zandio, B. (Beatriz); Bruna, J. (Jordi); Gonzalez-Huarriz, M. (Marisol); Tejada-Solis, S. (Sonia); Esparragosa-Vázquez, I. (I.); Diez-Valle, R. (Ricardo); Garcia-Moure, M. (Marc); Gállego-Culleré, J. (Jaime); Agirre, A. (Amaia); Puigdelloses-Vallcorba, M. (Montserrat); Martinez-Vila, E. (Eduardo); Gallego-Perez-Larraya, J. (Jaime); Petrirena, G. (Gregorio); Nuñez-Cordoba, J.M. (Jorge M.)Background. Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Circulating biomarkers may assist in the processes of differential diagnosis and response assessment. GBM cells release extracellular vesicles containing a subset of proteins and nucleic acids. We previously demonstrated that exosomes isolated from the serum of GBM patients had an increased expression of RNU6-1 compared to healthy subjects. In this exploratory study, we investigated the role of this small noncoding RNA as a diagnostic biomarker for GBM versus other brain lesions with some potential radiological similarities. Methods. We analyzed the expression of RNU6-1 in circulating exosomes of GBM patients (n = 18), healthy controls (n = 30), and patients with subacute stroke (n = 30), acute/subacute hemorrhage (n = 30), acute demyelinating lesions (n = 18), brain metastases (n = 21), and primary central nervous system lymphoma (PCNSL; n = 12) using digital droplet PCR. Results. Expression of RNU6-1 was significantly higher in GBM patients than in healthy controls (P = .002). RNU6-1 levels were also significantly higher in exosomes from GBM patients than from patients with nonneoplastic lesions (stroke [P = .05], hemorrhage [P = .01], demyelinating lesions [P = .019]) and PCNSL (P = .004). In contrast, no significant differences were found between patients with GBM and brain metastases (P = .573). Receiver operator characteristic curve analyses supported the role of this biomarker in differentiating GBM from subacute stroke, acute/subacute hemorrhage, acute demyelinating lesions, and PCNSL (P < .05), but again not from brain metastases (P = .575).
- The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models(Springer Science and Business Media LLC, 2019) Mackay, A. (Alan); Patiño-García, A. (Ana); Aldave, G. (Guillermo); Alonso-Roldán, M.M. (Marta María); El-Habr, E. (Elías); Gomez-Manzano, C. (Candelaria); Chneiweiss, H. (Hervé); Zalacain, M. (Marta); Martinez-Velez, N. (Naiara); Marigil, M. (Miguel); Raabe, E. (Eric); Aristu-Mendioroz, J.J. (José Javier); García-Barchino, M.J. (María José); Martinez-Climent, J.A. (José Ángel); Gonzalez-Huarriz, M. (Marisol); Tejada-Solis, S. (Sonia); Monje, M. (Michelle); Marrodán, L. (Lucía); Ramos, L.I. (Luis Isaac); Diez-Valle, R. (Ricardo); Garcia-Moure, M. (Marc); Junier, M.P. (Marie Pierre); Varela-Guruceaga, M. (Maider); Puigdelloses-Vallcorba, M. (Montserrat); Laspidea, V. (Virginia); Fueyo, J. (Juan); Gallego-Perez-Larraya, J. (Jaime); Becher, O.J. (Oren J.); Jiang, H. (Hong); Jones, C. (Chris)Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).
- Delta-24-RGD combined with radiotherapy exerts a potent antitumor effect in diffuse intrinsic pontine glioma and pediatric high grade glioma models(Springer Science and Business Media LLC, 2019) Patiño-García, A. (Ana); Alonso-Roldán, M.M. (Marta María); Gomez-Manzano, C. (Candelaria); Martinez-Velez, N. (Naiara); Marigil, M. (Miguel); Aristu-Mendioroz, J.J. (José Javier); Gonzalez-Huarriz, M. (Marisol); Tejada-Solis, S. (Sonia); Ramos, L.I. (Luis Isaac); Diez-Valle, R. (Ricardo); Garcia-Moure, M. (Marc); Fueyo, J. (Juan); Becher, O.J. (Oren J.)Pediatric high grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPGs), are aggressive tumors with a dismal outcome. Radiotherapy (RT) is part of the standard of care of these tumors; however, radiotherapy only leads to a transient clinical improvement. Delta-24-RGD is a genetically engineered tumor-selective adenovirus that has shown safety and clinical efficacy in adults with recurrent gliomas. In this work, we evaluated the feasibility, safety and therapeutic efficacy of Delta-24-RGD in combination with radiotherapy in pHGGs and DIPGs models. Our results showed that the combination of Delta-24-RGD with radiotherapy was feasible and resulted in a synergistic anti-glioma effect in vitro and in vivo in pHGG and DIPG models. Interestingly, Delta-24-RGD treatment led to the downregulation of relevant DNA damage repair proteins, further sensitizing tumors cells to the effect of radiotherapy. Additionally, Delta-24-RGD/radiotherapy treatment significantly increased the trafficking of immune cells (CD3, CD4+ and CD8+) to the tumor niche compared with single treatments. In summary, administration of the Delta-24-RGD/radiotherapy combination to pHGG and DIPG models is safe and significantly increases the overall survival of mice bearing these tumors. Our data offer a rationale for the combination Delta-24-RGD/radiotherapy as a therapeutic option for children with these tumors. SIGNIFICANCE: Delta-24-RGD/radiotherapy administration is safe and significantly increases the survival of treated mice. These positive data underscore the urge to translate this approach to the clinical treatment of children with pHGG and DIPGs.
- CD137 and PD-L1 targeting with immunovirotherapy induces a potent and durable antitumor immune response in glioblastoma models(2021) Ausejo-Mauleón, I. (Iker); Patiño-García, A. (Ana); Alonso-Roldán, M.M. (Marta María); Gomez-Manzano, C. (Candelaria); Zalacain, M. (Marta); Martinez-Velez, N. (Naiara); Gonzalez-Huarriz, M. (Marisol); Marrodán, L. (Lucía); Chen, Z. (ZhiHong); Garcia-Moure, M. (Marc); Hervas-Stubbs, S. (Sandra); Puigdelloses-Vallcorba, M. (Montserrat); Hambardzumyan, D. (Dolores); Labiano, S. (Sara); Laspidea, V. (Virginia); Fueyo, J. (Juan); Gallego-Perez-Larraya, J. (Jaime); Herrador-Cañete, G. (Guillermo); Jiang, H. (Hong); Nava-Martín, D. (Daniel) de laBackground Glioblastoma (GBM) is a devastating primary brain tumor with a highly immunosuppressive tumor microenvironment, and treatment with oncolytic viruses (OVs) has emerged as a promising strategy for these tumors. Our group constructed a new OV named Delta-24-ACT, which was based on the Delta-24-RGD platform armed with 4-1BB ligand (4-1BBL). In this study, we evaluated the antitumor effect of Delta-24-ACT alone or in combination with an immune checkpoint inhibitor (ICI) in preclinical models of glioma. Methods The in vitro effect of Delta-24-ACT was characterized through analyses of its infectivity, replication and cytotoxicity by flow cytometry, immunofluorescence (IF) and MTS assays, respectively. The antitumor effect and therapeutic mechanism were evaluated in vivo using several immunocompetent murine glioma models. The tumor microenvironment was studied by flow cytometry, immunohistochemistry and IF. Results Delta-24-ACT was able to infect and exert a cytotoxic effect on murine and human glioma cell lines. Moreover, Delta-24-ACT expressed functional 4-1BBL that was able to costimulate T lymphocytes in vitro and in vivo. Delta-24-ACT elicited a more potent antitumor effect in GBM murine models than Delta-24-RGD, as demonstrated by significant increases in median survival and the percentage of long-term survivors. Furthermore, Delta-24-ACT modulated the tumor microenvironment, which led to lymphocyte infiltration and alteration of their immune phenotype, as ...
- Tune up in situ autovaccination against solid tumors with oncolytic viruses(MDPI, 2018) Martinez-Velez, N. (Naiara); Avci, N.G. (Naze G.); Nguyen, T. (Teresa); Ho-Shin, D. (Dong); Jiang, H. (Hong)With the progress of immunotherapy in cancer, oncolytic viruses (OVs) have attracted more and more attention during the past decade. Due to their cancer-selective and immunogenic properties, OVs are considered ideal candidates to be combined with immunotherapy to increase both specificity and efficacy in cancer treatment. OVs preferentially replicate in and lyse cancer cells, resulting in in situ autovaccination leading to adaptive anti-virus and anti-tumor immunity. The main challenge in OV approaches is how to redirect the host immunity from anti-virus to anti-tumor and optimize the clinical outcome of cancer patients. Here, we summarize the conceptual updates on oncolytic virotherapy and immunotherapy in cancer, and the development of strategies to enhance the virus-mediated anti-tumor immune response, including: (1) arm OVs with cytokines to modulate innate and adaptive immunity; (2) combining OVs with immune checkpoint inhibitors to release T cell inhibition; (3) combining OVs with immune co-stimulators to enhance T cell activation. Future studies need to be enforced on developing strategies to augment the systemic effect on metastasized tumors.
- Oncolytic DNX-2401 virus for pediatric diffuse intrinsic pontine glioma(Massachusetts Medical Society, 2022) Tavira, B. (Beatriz); Patiño-García, A. (Ana); Stunnenberg, H. (Henk); Alonso-Roldán, M.M. (Marta María); Gomez-Manzano, C. (Candelaria); Zalacain, M. (Marta); Martinez-Velez, N. (Naiara); Robbins, J. (Joan); Lang, F.F. (Frederick F.); Ewald, B. (Brett); Gonzalez-Huarriz, M. (Marisol); Tejada-Solis, S. (Sonia); Cruz, O. (Ofelia); Esparragosa-Vázquez, I. (I.); Astigarraga, I. (Itziar); Marrodán, L. (Lucía); Villalba, M. (María); Alkorta-Aranburu, G. (Gorka); Oscoz-Lizarbe, M. (Miren); Diez-Valle, R. (Ricardo); Garcia-Moure, M. (Marc); Hervas-Stubbs, S. (Sandra); Dobbs, J. (Jessica); Lugt, J. (Jasper) van der; Puigdelloses-Vallcorba, M. (Montserrat); Idoate, M.A. (Miguel Ángel); Dharmadhikari, G. (Gitanjali); Lopez-Ibor, B. (Blanca); Andrea, C.E. (Carlos Eduardo) de; Labiano, S. (Sara); Hulleman, E. (Esther); Tamayo, I. (Ibon); Laspidea, V. (Virginia); Hernandez-Alcoceba, R. (Rubén); Fueyo, J. (Juan); Gallego-Perez-Larraya, J. (Jaime); Ruiz-Moreno, C. (Cristian); Nuñez-Cordoba, J.M. (Jorge M.); Jones, C. (Chris)Background: Pediatric patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis, with a median survival of less than 1 year. Oncolytic viral therapy has been evaluated in patients with pediatric gliomas elsewhere in the brain, but data regarding oncolytic viral therapy in patients with DIPG are lacking. Methods: We conducted a single-center, dose-escalation study of DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells, in patients with newly diagnosed DIPG. The patients received a single virus infusion through a catheter placed in the cerebellar peduncle, followed by radiotherapy. The primary objective was to assess the safety and adverse-event profile of DNX-2401. The secondary objectives were to evaluate the effect of DNX-2401 on overall survival and quality of life, to determine the percentage of patients who have an objective response, and to collect tumor-biopsy and peripheral-blood samples for correlative studies of the molecular features of DIPG and antitumor immune responses. Results: A total of 12 patients, 3 to 18 years of age, with newly diagnosed DIPG received 1×1010 (the first 4 patients) or 5×1010 (the subsequent 8 patients) viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetraparesis developed in 1 patient each. Over a median follow-up of 17.8 months (range, 5.9 to 33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, 1 of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from 1 patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire. Conclusions: Intratumoral infusion of oncolytic virus DNX-2401 followed by radiotherapy in pediatric patients with DIPG resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients but was associated with adverse events. (Funded by the European Research Council under the European Union's Horizon 2020 Research and Innovation Program and others; EudraCT number, 2016-001577-33; ClinicalTrials.gov number, NCT03178032.).
- Analysis of SOX2-regulated transcriptome in glioma stem cells(2016-09-16) Acanda-de-la-Rocha, A.M. (Arlet María); Alonso-Roldán, M.M. (Marta María); Gomez-Manzano, C. (Candelaria); Martinez-Velez, N. (Naiara); Gonzalez-Huarriz, M. (Marisol); Xipell, E. (Enric); Guruceaga, E. (Elizabeth); Fueyo, J. (Juan); Lopez-Bertoni, H. (Hernando)Introduction Glioblastoma is the most malignant brain tumor in adults and is associated with poor sur- vival despite multimodal treatments. Glioma stem-like cells (GSCs) are cells functionally defined by their self-renewal potential and the ability to reconstitute the original tumor upon orthotopic implantation. They have been postulated to be the culprit of glioma chemo- and radio-resistance ultimately leading to relapse. Understanding the molecular circuits govern- ing the GSC compartment is essential. SOX2, a critical transcription regulator of embryonic and neural stem cell function, is deregulated in GSCs however; the precise molecular path- ways regulated by this gene in GSCs remain poorly understood. Results We performed a genome-wide analysis of SOX2-regulated transcripts in GSCs, using a microarray. We identified a total of 2048 differentially expressed coding transcripts and 261 non-coding transcripts. Cell adhesion and cell-cell signaling are among the most enriched terms using Gene Ontology (GO) classification. The pathways altered after SOX2 down- modulation includes multiple cellular processes such as amino-acid metabolism and inter- cellular signaling cascades. We also defined and classified the set of non-coding transcripts differentially expressed regulated by SOX2 in GSCs, and validated two of them. Conclusions We present a comprehensive analysis of the transcriptome controlled by SOX2 in GSCs, gaining insights in the understanding of the potential roles of SOX2 in glioblastoma.