Tejada-Solis, S. (Sonia)
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- 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.
- Hypofractionated radiation therapy and temozolomide in patients with glioblastoma and poor prognostic factors. A prospective, single-institution experience(Public Library of Science (PLoS), 2019) Arbizu, J. (Javier); Garcia-de-Eulate, R. (Reyes); Aristu-Mendioroz, J.J. (José Javier); Domínguez-Echávarri, P.D. (Pablo Daniel); Arbea-Moreno, L. (Leire); Tejada-Solis, S. (Sonia); Jablonska, P.A. (Paola Anna); Diez-Valle, R. (Ricardo); Idoate, M.A. (Miguel Ángel); Ramos, L. (Luis); Gallego-Perez-Larraya, J. (Jaime); Moreno-Jimenez, M. (Marta)Background: Hypofractionated radiation therapy is a feasible and safe treatment option in elderly and frail patients with glioblastoma. The aim of this study was to evaluate the effectiveness of hypofractionated radiation therapy with concurrent temozolomide in terms of feasibility and disease control in primary glioblastoma patients with poor prognostic factors other than advanced age, such as post-surgical neurological complications, high tumor burden, unresectable or multifocal lesions, and potential low treatment compliance due to social factors or rapidly progressive disease. Material and methods: GTV included the surgical cavity plus disease visible in T1WI-MRI, FLAIR-MRI and in the MET-uptake. The CTV was defined as the GTV plus 1.5-2 cm margin; the PTV was the CTV+0.3 cm margin. Forty, fourty-five, and fifty grays in 15 fractions were prescribed to 95% of PTV, CTV, and GTV, respectively. Treatment was delivered using IMRT or the VMAT technique. Simultaneously, 75 mg/m2/day of temozolomide were administered. Results: Between January 2010 and November 2017, we treated a total of 17 patients. The median age at diagnosis was 68-years; median KPS was 50-70%. MGMT-methylation status was negative in 5 patients, and 8 patients were IDH-wildtype. Eight of 18 patients were younger than 65-years. Median tumor volume was 26.95cc; median PTV volume was 322cc. Four lesions were unresectable; 6 patients underwent complete surgical resection. Median residual volume was 1.14cc. Progression-free survival was 60% at 6 months, 33% at 1-year and 13% at 2-years (median OS = 7 months). No acute grade 3-5 toxicities were documented. Symptomatic grade 3 radiation necrosis was observed in one patient. Conclusions: Patients with poor clinical factors other than advanced age can be selected for hypofractionated radiotherapy. The OS and PFS rates obtained in our series are similar to those in patients treated with standard fractionation, assuring good treatment adherence, low rates of toxicity and probable improved cost-effectiveness.
- A phase II trial of autologous dendritic cell vaccination and radiochemotherapy following fuorescence-guided surgery in newly diagnosed glioblastoma patients(BMC, 2017) Espinos, J. (Jaime); Garcia-de-Eulate, R. (Reyes); Alonso-Roldán, M.M. (Marta María); Pastor, F. (Fernando); Aristu-Mendioroz, J.J. (José Javier); Domínguez-Echávarri, P.D. (Pablo Daniel); Lopez-Diaz-de-Cerio, A. (Ascensión); Tejada-Solis, S. (Sonia); Diez-Valle, R. (Ricardo); Andreu, E.J. (Enrique José); Inoges, S. (Susana); Idoate, M.A. (Miguel Ángel); Bendandi, M. (Maurizio); Gallego-Perez-Larraya, J. (Jaime); Prosper-Cardoso, F. (Felipe)Background: Prognosis of patients with glioblastoma multiforme (GBM) remains dismal, with median overall survival (OS) of about 15 months. It is therefore crucial to search alternative strategies that improve these results obtained with conventional treatments. In this context, immunotherapy seems to be a promising therapeutic option. We hypoth‐ esized that the addition of tumor lysate-pulsed autologous dendritic cells (DCs) vaccination to maximal safe resection followed by radiotherapy and concomitant and adjuvant temozolomide could improve patients’ survival. Methods: We conducted a phase-II clinical trial of autologous DCs vaccination in patients with newly diagnosed patients GBM who were candidates to complete or near complete resection. Candidates were fnally included if residual tumor volume was lower than 1 cc on postoperative radiological examination. Autologous DCs were generated from peripheral blood monocytes and pulsed with autologous whole tumor lysate. The vaccination calendar started before radiotherapy and was continued during adjuvant chemotherapy. Progression free survival (PFS) and OS were analyzed with the Kaplan–Meier method. Immune response were assessed in blood samples obtained before each vaccines. Results: Thirty-two consecutive patients were screened, one of which was a screening failure due to insufcient resection. Median age was 61 years (range 42–70). Karnofsky performance score (KPS) was 90–100 in 29%, 80 in 35.5% and 60–70 in 35.5% of cases. MGMT (O6 -methylguanine-DNA-methyltransferase) promoter was methylated in 45.2% of patients. No severe adverse efects related to immunotherapy were registered. Median PFS was 12.7 months (CI 95% 7–16) and median OS was 23.4 months (95% CI 16–33.1). Increase in post-vaccination tumor specifc immune response after vaccines (proliferation or cytokine production) was detected in 11/27 evaluated patients. No correla‐ tion between immune response and survival was found. Conclusions: Our results suggest that the addition of tumor lysate-pulsed autologous DCs vaccination to tumor resection and combined radio-chemotherapy is feasible and safe. A multicenter randomized clinical trial is warranted to evaluate the potential survival beneft of this therapeutic approach.
- Development of a DIPG Orthotopic Model in Mice Using an Implantable Guide-Screw System(Public Library of Science - Green Policies in RoMEO, 2017) Patiño-García, A. (Ana); Alonso-Roldán, M.M. (Marta María); El-Habr, E. (Elías); Chneiweiss, H. (Hervé); Martinez-Velez, N. (Naiara); Marigil, M. (Miguel); Domínguez-Echávarri, P.D. (Pablo Daniel); Garcia-Maure, M. (Marc); Gonzalez-Huarriz, M. (Marisol); Tejada-Solis, S. (Sonia); Xipell, E. (Enric); Diez-Valle, R. (Ricardo); Junier, M.P. (Marie Pierre); Idoate, M.A. (Miguel Ángel)Objective In this work we set to develop and to validate a new in vivo frameless orthotopic Diffuse Intrinsic Pontine Glioma (DIPG) model based in the implantation of a guide-screw system. Methods It consisted of a guide-screw also called bolt, a Hamilton syringe with a 26-gauge needle and an insulin-like 15-gauge needle. The guide screw is 2.6 mm in length and harbors a 0.5 mm central hole which accepts the needle of the Hamilton syringe avoiding a theoretical displacement during insertion. The guide-screw is fixed on the mouse skull according to the coordinates: 1mm right to and 0.8 mm posterior to lambda. To reach the pons the Hamilton syringe is adjusted to a 6.5 mm depth using a cuff that serves as a stopper. This system allows delivering not only cells but also any kind of intratumoral chemotherapy, antibodies or gene/viral therapies. Results The guide-screw was successfully implanted in 10 immunodeficient mice and the animals were inoculated with DIPG human cell lines during the same anesthetic period. All the mice developed severe neurologic symptoms and had a median overall survival of 95 days ranging the time of death from 81 to 116 days. Histopathological analysis confirmed tumor into the pons in all animals confirming the validity of this model. Conclusion Here we presented a reproducible and frameless DIPG model that allows for rapid evaluation of tumorigenicity and efficacy of chemotherapeutic or gene therapy products delivered intratumorally to the pons.
- Infratentorial hygroma secondary to decompressive craniectomy after cerebellar infarction(Sociedad Española de Neurocirugía, 2009) Gomez-Ibañez, A. (Asier); Garcia-de-Eulate, R. (Reyes); Domínguez-Echávarri, P.D. (Pablo Daniel); Tejada-Solis, S. (Sonia); Diez-Valle, R. (Ricardo)We present a case of expansive CSF collection in the cerebellar convexity. The patient was a 74 years old lady who one month before had suffered a cerebellar infarct complicated with acute hydrocephalus. She had good evolution after decompressive craniectomy without shunting. Fifteen days after surgery, the patient started with new positional vertigo, nausea and vomiting and a wound CSF fistula that needed ventriculoperitoneal shunt (medium pressure) because conservative treatment failed. After shunting, the fistula closed, but the patient symptoms worsened. The MRI showed normal ventricular size with a cerebellar hygroma, extending to the posterior interhemispheric fissure. The collection had no blood signal and expanded during observation. A catheter was implanted in the collection and connected to the shunt. The patient became asymptomatic after surgery, and the hygromas had disappeared in control CT at one month. This case shows an infrequent problem of CSF circulation at posterior fossa that resulted in vertigo of central origin. A higroma-ventricle-peritoneal shunt solved the symptoms of the patient.
- 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. (Inés); 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.).
- Involvement of miRNAs in the differentiation of human glioblastoma multiforme stem-like cells(Public Library of Science, 2013) Grande, L. (Lara); Huse, J.T. (Jason T.); Alonso-Roldán, M.M. (Marta María); Nogueira, L. (Lorena); Martinez-Climent, J.A. (José Ángel); Tejada-Solis, S. (Sonia); Aznar, M.A. (María Ángela); Aldaz-Arrieta, B. (Beatriz); Diez-Valle, R. (Ricardo); Fernandez-Luna, J.L. (J.L.); Raquel; Sagardoy, A. (Ainara); Guruceaga, E. (Elizabeth)Glioblastoma multiforme (GBM)-initiating cells (GICs) represent a tumor subpopulation with neural stem cell-like properties that is responsible for the development, progression and therapeutic resistance of human GBM. We have recently shown that blockade of NFκB pathway promotes terminal differentiation and senescence of GICs both in vitro and in vivo, indicating that induction of differentiation may be a potential therapeutic strategy for GBM. MicroRNAs have been implicated in the pathogenesis of GBM, but a high-throughput analysis of their role in GIC differentiation has not been reported. We have established human GIC cell lines that can be efficiently differentiated into cells expressing astrocytic and neuronal lineage markers. Using this in vitro system, a microarray-based high-throughput analysis to determine global expression changes of microRNAs during differentiation of GICs was performed. A number of changes in the levels of microRNAs were detected in differentiating GICs, including over-expression of hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222, and down-regulation of hsa-miR-93 and hsa-miR-106a. Functional studies showed that miR-21 over-expression in GICs induced comparable cell differentiation features and targeted SPRY1 mRNA, which encodes for a negative regulator of neural stem-cell differentiation. In addition, miR-221 and miR-222 inhibition in differentiated cells restored the expression of stem cell markers while reducing differentiation markers. Finally, miR-29a and miR-29b targeted MCL1 mRNA in GICs and increased apoptosis. Our study uncovers the microRNA dynamic expression changes occurring during differentiation of GICs, and identifies miR-21 and miR-221/222 as key regulators of this process.
- Oncolytic viruses as therapeutic tools for pediatric brain tumors(MDPI AG, 2018) Patiño-García, A. (Ana); Alonso-Roldán, M.M. (Marta María); Gomez-Manzano, C. (Candelaria); Tejada-Solis, S. (Sonia); Garcia-Moure, M. (Marc); Varela-Guruceaga, M. (Maider); Fueyo, J. (Juan)In recent years, we have seen an important progress in our comprehension of the molecular basis of pediatric brain tumors (PBTs). However, they still represent the main cause of death by disease in children. Due to the poor prognosis of some types of PBTs and the long-term adverse effects associated with the traditional treatments, oncolytic viruses (OVs) have emerged as an interesting therapeutic option since they displayed safety and high tolerability in pre-clinical and clinical levels. In this review, we summarize the OVs evaluated in different types of PBTs, mostly in pre-clinical studies, and we discuss the possible future direction of research in this field. In this sense, one important aspect of OVs antitumoral effect is the stimulation of an immune response against the tumor which is necessary for a complete response in preclinical immunocompetent models and in the clinic. The role of the immune system in the response of OVs needs to be evaluated in PBTs and represents an experimental challenge due to the limited immunocompetent models of these diseases available for pre-clinical research.
- Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma(Nature Publishing Group, 2019) Berraondo, P. (Pedro); Perez-Gracia, J.L. (Jose Luis); Rodriguez-Ruiz, M.E. (María Esperanza); Lopez-Diaz-de-Cerio, A. (Ascensión); Tejada-Solis, S. (Sonia); Diez-Valle, R. (Ricardo); Goicoechea, I. (Iosune); Inoges, S. (Susana); Gurpide, A. (Alfonso); Melero, I. (Ignacio); Choi, J. (Jungmin); Porciuncula, A. (Angelo); Idoate, M.A. (Miguel Ángel); Andrea, C.E. (Carlos Eduardo) de; López-Janeiro, Á. (Álvaro); Gallego-Perez-Larraya, J. (Jaime); Villarroel-Espindola, F. (Franz); Schalper, K.A. (Kurt A.); Giraldez, M. (Miriam); Fernandez-Sanmamed, M. (Miguel)Glioblastoma is the most common primary central nervous system malignancy and has a poor prognosis. Standard first-line treatment, which includes surgery followed by adjuvant radio-chemotherapy, produces only modest benefits to survival1,2. Here, to explore the feasibility, safety and immunobiological effects of PD-1 blockade in patients undergoing surgery for glioblastoma, we conducted a single-arm phase II clinical trial (NCT02550249) in which we tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients (27 salvage surgeries for recurrent cases and 3 cases of primary surgery for newly diagnosed patients). Availability of tumor tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumor immune microenvironment using multiple molecular and cellular analyses. Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented TCR clonal diversity among tumor-infiltrating T lymphocytes, supporting a local immunomodulatory effect of treatment. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later.
- Factors associated with a higher rate of distant failure after primary treatment for glioblastoma(Springer, 2014) Aldave, G. (Guillermo); Marigil, M. (Miguel); Domínguez-Echávarri, P.D. (Pablo Daniel); Tejada-Solis, S. (Sonia); Diez-Valle, R. (Ricardo); Gallego-Perez-Larraya, J. (Jaime)Our purpose was to analyze the pattern of failure in glioblastoma (GBM) patients at first recurrence after radiotherapy and temozolomide and its relationship with different factors. From 77 consecutive GBM patients treated at our institution with fluorescence guided surgery and standard radiochemotherapy, 58 first recurrences were identified and included in a retrospective review. Clinical data including age, Karnofsky performance score, preoperative tumor volume and location, extend of resection, MGMT promoter methylation status, time to progression (PFS), overall survival (OS) and adjuvant therapies were reviewed for every patient. Recurrent tumor location respect the original lesion was the end point of the study. The recurrence pattern was local only in 65.5% of patients and non-local in 34.5%. The univariate and multivariate analysis showed that greater preoperative tumor volume in T1 gadolinium enhanced sequences, was the only variable with statistical signification (p < 0.001) for increased rate of non-local recurrences, although patients with MGMT methylation and complete resection of enhancing tumor presented non-local recurrences more frequently. PFS was longer in patients with non-local recurrences (13.8 vs. 6.4 months; p = 0.019, log-rank). However, OS was not significantly different in both groups (24.0 non-local vs. 19.3 local; p = 0.9). Rate of non-local recurrences in our series of patients treated with fluorescence guided surgery and standard radiochemotherapy was higher than previously published in GBM, especially in patients with longer PFS. Greater preoperative enhancing tumor volume was associated with increased rate of non-local recurrences.