E Antonio Chiocca

Dana-Farber Cancer Institute, Boston, Massachusetts, United States

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Publications (367)1921.86 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite the challenge of implementing oncolytic viral therapy into mainstream clinical use, the obstacles of early clinical trials have outlined numerous areas requiring additional investigation. In particular, the role of innate and adaptive immunity has received significant attention in this context. It is increasingly clear that a one-sided approach of either immune suppression or robust immune cell activation is not the answer for clinical success. Rather, recent studies are increasingly demonstrating the delicate balance between both anti-viral immune suppression and immune mediated tumor killing. In this review we focus on aspects of innate immune cell activation following oncolytic viral infection and how this response has the potential of bridging to the broader goal of viral mediated immunotherapy. Copyright © 2015. Published by Elsevier B.V.
    Current Opinion in Virology 08/2015; 13. DOI:10.1016/j.coviro.2015.03.015 · 6.06 Impact Factor
  • Mohammad Abolfotoh · Peleg M Horowitz · E Antonio Chiocca
    Neurosurgery 08/2015; DOI:10.1227/NEU.0000000000000966 · 3.62 Impact Factor
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    ABSTRACT: We report the indications and outcomes of awake right hemispheric brain surgery, as well as a rare patient with crossed aphasia. Awake craniotomies are often performed to protect eloquent cortex. We reviewed the medical records for 35 of 96 patients, in detail, who had awake right hemisphere brain operations. Intraoperative cortical mapping of motor and/or language function was performed in 29 of the 35 patients. A preoperative speech impairment and left hand dominance were the main indicators for awake right-sided craniotomies in patients with right hemisphere lesions. Four patients with lesion proximity to eloquent areas underwent awake craniotomies without cortical mapping. In addition, one patient had a broncho-pulmonary fistula, and another had a recent major cardiac procedure that precluded awake surgery. An eloquent cortex representation was identified in 14 patients (48.3%). Postoperatively, seven of 17 patients (41.1%) who presented with weakness, experienced improvements in their motor functions, 11 of 16 (68.7%) with seizures became seizure-free, and seven of nine (77.7%) with moderate to severe headaches and one of two with a visual field deficit improved significantly. There were also improvements in speech and language functions in all patients who presented with speech difficulties. A right sided awake craniotomy is an excellent option for left handed patients, or those with right sided cortical lesions that result in preoperative speech impairments. When combined with intraoperative cortical mapping, both speech and motor function can be well preserved. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of Clinical Neuroscience 08/2015; DOI:10.1016/j.jocn.2015.06.009 · 1.38 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):299-299. DOI:10.1158/1538-7445.AM2015-299 · 9.33 Impact Factor
  • Sean E Lawler · E Antonio Chiocca
    Journal of Clinical Oncology 07/2015; 33(25). DOI:10.1200/JCO.2015.62.5244 · 18.43 Impact Factor
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    ABSTRACT: Oncolytic viruses (OV) have broad potential as an adjuvant for the treatment of solid tumors. The present study addresses the feasibility of clinically applicable drugs to enhance the oncolytic potential of the OV Delta24-RGD in glioblastoma. In total, 446 drugs were screened for their viral sensitizing properties in glioblastoma stem-like cells (GSCs) in vitro. Validation was done for ten drugs to determine synergy based on the Chou Talalay assay. Mechanistic studies were undertaken to assess viability, replication efficacy, viral infection enhancement and cell death pathway induction in a selected panel of drugs. Four viral sensitizers (fluphenazine, indirubin, lofepramine and ranolazine) were demonstrated to reproducibly synergize with Delta24-RGD in multiple assays. After validation we underscored general applicability by testing candidate drugs in a broader context of a panel of different GSCs, various solid tumor models and multiple OVs. Overall this study identified four viral sensitizers which synergize with Delta24-RGD and two other strains of oncolytic viruses. The viral sensitizers interact with infection, replication and cell death pathways to enhance efficacy of the OV.Gene Therapy accepted article preview online, 21 July 2015. doi:10.1038/gt.2015.72.
    Gene therapy 07/2015; DOI:10.1038/gt.2015.72 · 3.10 Impact Factor
  • Agnieszka Bronisz · E Antonio Chiocca · Jakub Godlewski
    Oncotarget 07/2015; 6(20):17851-2. DOI:10.18632/oncotarget.4606 · 6.36 Impact Factor
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    ABSTRACT: Glioblastoma (GB) remains the most aggressive primary brain malignancy. Adoptive transfer of chimeric antigen receptor (CAR)-modified immune cells has emerged as a promising anti-cancer approach, yet the potential utility of CAR-engineered natural killer (NK) cells to treat GB has not been explored. Tumors from approximately 50% of GB patients express wild-type EGFR (wtEGFR) and in fewer cases express both wtEGFR and the mutant form EGFRvIII; however, previously reported CAR T cell studies only focus on targeting EGFRvIII. Here we explore whether both wtEGFR and EGFRvIII can be effectively targeted by CAR-redirected NK cells to treat GB. We transduced human NK cell lines NK-92 and NKL, and primary NK cells with a lentiviral construct harboring a second generation CAR targeting both wtEGFR and EGFRvIII and evaluated the anti-GB efficacy of EGFR-CAR-modified NK cells. EGFR-CAR-engineered NK cells displayed enhanced cytolytic capability and IFN-γ production when co-cultured with GB cells or patient-derived GB stem cells in an EGFR-dependent manner. In two orthotopic GB xenograft mouse models, intracranial administration of NK-92-EGFR-CAR cells resulted in efficient suppression of tumor growth and significantly prolonged the tumor-bearing mice survival. These findings support intracranial administration of NK-92-EGFR-CAR cells represents a promising clinical strategy to treat GB.
    Scientific Reports 07/2015; 5:11483. DOI:10.1038/srep11483 · 5.58 Impact Factor
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    ABSTRACT: Despite a high symptom burden, little is known about the incidence or predictors of hospitalization among glioblastoma patients, including risks during chemoradiation (CRT). We studied 196 consecutive newly diagnosed glioblastoma patients treated at our institution from 2006-2010. Toxicity data were reviewed during and after the CRT phase, defined as the period between diagnosis and 6 weeks after radiotherapy completion. Logistic regression and proportional hazards modeling identified predictors of hospitalization and overall survival (OS). Median age was 59 years (range, 23-90) and 83 % had Karnofsky performance status (KPS) score ≥ 70. Twenty-six percent of patients underwent gross total resection, 77 % received ≥ 59.4 Gy of radiotherapy, and 89 % received concurrent temozolomide. Median OS was 15.6 months (IQR, 8.5-26.8 months). Forty-three percent of patients were hospitalized during the CRT phase; OS was 10.7 vs. 17.8 months for patients who were vs. were not hospitalized, respectively (P P = .034) and KPS (OR, 0.95; 95 % CI, 0.93-0.97; P Hospitalization during the CRT phase was associated with decreased OS (adjusted hazard ratio, 1.47; 95 % CI, 1.01-2.13; P = .043), after adjustment for known prognostic factors. Hospitalization during the CRT phase is common among glioblastoma patients in the temozolomide era and is associated with shorter overall survival.
    Journal of Neuro-Oncology 06/2015; 124(1). DOI:10.1007/s11060-015-1820-3 · 3.07 Impact Factor
  • David A Reardon · Keith L Ligon · E Antonio Chiocca · Patrick Y Wen
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    ABSTRACT: Over the past few years, understanding the genetic abnormalities associated with glioblastoma, the most common malignant primary tumor of the central nervous system, has increased dramatically. Mutation types and frequencies have been comprehensively assessed, glioblastoma subclasses have been defined based on gene expression and methylation analyses, and novel mutations implicated in gliomagenesis have been identified. Nonetheless, a critical disconnect exists between achieved scientific advances and failure to improve patient outcome. Currently, standard therapy incorporating surgery, cranial irradiation, and temozolomide chemotherapy is uniformly applied for all patients. With this approach, median survival remains unacceptably poor including fewer than 10% of patients surviving 5 years after diagnosis. Salvage therapies are ineffective with PFS-6 rates under 10% for non-bevacizumab regimens and 40% for bevacizumab. Furthermore, all patients ultimately progress on bevacizumab, and then typically die from rapidly progressive tumor. Innovative treatment strategies directed to distinct patient subsets defined by specific genetic and gene expression analyses represent an attractive therapeutic paradigm shift for this highly challenging complex tumor, offering promise to ultimately improve outcome.
    Discovery medicine 06/2015; 19(107):471-7. · 3.63 Impact Factor
  • Agnieszka Bronisz · E Antonio Chiocca
    Nature medicine 05/2015; 21(5):426-7. DOI:10.1038/nm.3857 · 27.36 Impact Factor
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    ABSTRACT: We present a 59-year-old woman who noted an enlarging lump on her forehead 6months after a left frontotemporal craniotomy for tumor resection and chemoradiation of her primary glioblastoma multiforme (GBM). GBM is a highly aggressive intracranial neoplasm associated with the shortest survival time of any primary central nervous system malignancy. Extracranial metastasis is rare, especially without previous surgical disruption of the dura and calvarium, which has been postulated to cause seeding of the extracranial space with tumor cells. This patient's MRI revealed tumor recurrence for which she underwent repeat resection. Histopathology confirmed GBM with unmethylated O-6-methylguanine-DNA methyltransferase and wildtype isocitrate dehydrogenase 1 status, as well as tumor invasion through the bone and subdermal space. The genetic and molecular factors that predict extracranial invasion remain unclear and require further investigation. Emerging data on circulating tumor cells in GBM patients indicate that extraaxial metastasis may be part of the disease course in some, particularly in long term survivors. Furthermore, the proximity of calvarial and scalp lesions to previous surgical sites and the time course in which they emerge after surgery suggests that iatrogenic seeding may also play a role in metastasis. With heightened awareness of the phenomenon, surgical strategies such as watertight approximation of the dura, bone flap replacement, or changing surgical instruments once the intradural component is complete may prove useful to prevent seeding. Prophylactic craniospinal irradiation may also be an appropriate tool in patients at high risk for metastasis, although this population is difficult to identify. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of Clinical Neuroscience 05/2015; 22(9). DOI:10.1016/j.jocn.2015.03.018 · 1.38 Impact Factor
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    ABSTRACT: In aggressive, rapidly growing solid tumors such as glioblastoma multiforme (GBM), cancer cells face frequent dynamic changes in their microenvironment, including the availability of glucose and other nutrients. These challenges require that tumor cells have the ability to adapt in order to survive periods of nutrient/energy starvation. We have identified a reciprocal negative feedback loop mechanism in which the levels of microRNA-451 (miR-451) are negatively regulated through the phosphorylation and inactivation of its direct transcriptional activator OCT1 by 5' AMP-activated protein kinase (AMPK), which is activated by glucose depletion-induced metabolic stress. Conversely, in a glucose-rich environment, unrestrained expression of miR-451 suppresses AMPK pathway activity. These findings uncover miR-451 as a major effector of glucose-regulated AMPK signaling, allowing tumor cell adaptation to variations in nutrient availability in the tumor microenvironment. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 11(6). DOI:10.1016/j.celrep.2015.04.016 · 8.36 Impact Factor
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    ABSTRACT: Older patients with newly diagnosed glioblastoma have poor outcomes, and optimal treatment is controversial. Hypofractionated radiation therapy (HRT) is frequently used but has not been compared to patients receiving standard fractionated radiation therapy (SRT) and temozolomide (TMZ). We conducted a retrospective analysis of patients ≥65 years of age who received radiation for the treatment of newly diagnosed glioblastoma from 1994 to 2013. The distribution of clinical covariates across various radiation regimens was analyzed for possible selection bias. Survival was calculated using the Kaplan-Meier method. Comparison of hypofractionated radiation (typically, 40 Gy/15 fractions) versus standard fractionation (typically, 60 Gy/30 fractions) in the setting of temozolomide was conducted using Cox regression and propensity score analysis. Patients received SRT + TMZ (n=57), SRT (n=35), HRT + TMZ (n=34), or HRT (n=9). Patients receiving HRT were significantly older (median: 79 vs 69 years of age; P<.001) and had worse baseline performance status (P<.001) than those receiving SRT. On multivariate analysis, older age (adjusted hazard ratio [AHR]: 1.06; 95% confidence interval [CI]: 1.01-1.10, P=.01), lower Karnofsky performance status (AHR: 1.02; 95% CI: 1.01-1.03; P=.01), multifocal disease (AHR: 2.11; 95% CI: 1.23-3.61, P=.007), and radiation alone (vs SRT + TMZ; SRT: AHR: 1.72; 95% CI: 1.06-2.79; P=.03; HRT: AHR: 3.92; 95% CI: 1.44-10.60, P=.007) were associated with decreased overall survival. After propensity score adjustment, patients receiving HRT with TMZ had similar overall survival compared with those receiving SRT with TMZ (AHR: 1.10, 95% CI: 0.50-2.4, P=.82). With no randomized data demonstrating equivalence between HRT and SRT in the setting of TMZ for glioblastoma, significant selection bias exists in the implementation of HRT. Controlling for this bias, we observed similar overall survival for HRT and SRT with concurrent TMZ among elderly patients, suggesting the need for a randomized trial to compare these regimens directly. Copyright © 2015 Elsevier Inc. All rights reserved.
    International journal of radiation oncology, biology, physics 04/2015; 92(2). DOI:10.1016/j.ijrobp.2015.01.017 · 4.26 Impact Factor
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    Richard Lee Price · Ennio Antonio Chiocca
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    ABSTRACT: The hypothesis that cytomegalovirus (CMV) modulates cancer is evolving. Originally discovered in glioblastoma in 2002, the number of cancers, where intratumoral CMV antigen is detected, has increased in recent years suggesting that CMV actively affects the pathobiology of certain tumors. These findings are controversial as several groups have also reported inability to replicate these results. Regardless, several clinical trials for glioblastoma are underway or have been completed that target intratumoral CMV with anti-viral drugs or immunotherapy. Therefore, a better understanding of the possible pathobiology of CMV in cancer needs to be ascertained. We have developed genetic, syngeneic, and orthotopic malignant glioma mouse models to study the role of CMV in cancer development and progression. These models recapitulate for the most part intratumoral CMV expression as seen in human tumors. Additionally, we discovered that CMV infection in Trp53(-/+) mice promotes pleomorphic rhabdomyosarcomas. These mouse models are not only a vehicle for studying pathobiology of the viral-tumor interaction but also a platform for developing and testing cancer therapeutics.
    Frontiers in Oncology 03/2015; 5:61. DOI:10.3389/fonc.2015.00061
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    ABSTRACT: Background: Multidimensional genotyping of formalin-fixed paraffin-embedded (FFPE) samples has the potential to improve diagnostics and clinical trials for brain tumors, but prospective use in the clinical setting is not yet routine. We report our experience with implementing a multiplexed copy number and mutation-testing program in a diagnostic laboratory certified by the Clinical Laboratory Improvement Amendments. Methods: We collected and analyzed clinical testing results from whole-genome array comparative genomic hybridization (OncoCopy) of 420 brain tumors, including 148 glioblastomas. Mass spectrometry-based mutation genotyping (OncoMap, 471 mutations) was performed on 86 glioblastomas. Results: OncoCopy was successful in 99% of samples for which sufficient DNA was obtained (n = 415). All clinically relevant loci for glioblastomas were detected, including amplifications (EGFR, PDGFRA, MET) and deletions (EGFRvIII, PTEN, 1p/19q). Glioblastoma patients ≤40 years old had distinct profiles compared with patients >40 years. OncoMap testing reliably identified mutations in IDH1, TP53, and PTEN. Seventy-seven glioblastoma patients enrolled on trials, of whom 51% participated in targeted therapeutic trials where multiplex data informed eligibility or outcomes. Data integration identified patients with complete tumor suppressor inactivation, albeit rarely (5% of patients) due to lack of whole-gene coverage in OncoMap. Conclusions: Combined use of multiplexed copy number and mutation detection from FFPE samples in the clinical setting can efficiently replace singleton tests for clinical diagnosis and prognosis in most settings. Our results support incorporation of these assays into clinical trials as integral biomarkers and their potential to impact interpretation of results. Limited tumor suppressor variant capture by targeted genotyping highlights the need for whole-gene sequencing in glioblastoma.
    Neuro-Oncology 03/2015; DOI:10.1093/neuonc/nov015 · 5.56 Impact Factor
  • Kaith Almefty · E. Antonio Chiocca
    World Neurosurgery 02/2015; 84(1). DOI:10.1016/j.wneu.2015.02.019 · 2.88 Impact Factor
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    ABSTRACT: MicroRNA-10b (miR-10b) is commonly elevated in glioblastoma (GBM), while not expressed in normal brain tissues. Targeted inhibition of miR-10b has pleiotropic effects on GBM derived cell lines, it reduces GBM growth in animal models, but does not affect normal neurons and astrocytes. This data raises the possibility of developing miR-10b-targeting GBM therapy. However, the mechanisms contributing to miR-10b-mediated glioma cell survival and proliferation are unexplored. We found that inhibition of miR-10b has distinct effects on specific glioma cell lines. In cells expressing high levels of tumor suppressor p21WAF1/Cip1, it represses E2F1-mediated transcription, leading to down-regulation of multiple E2F1 target genes encoding for S-phase specific proteins, epigenetic modulators, and miRNAs (e.g. miR-15/16), and thereby stalling progression through the S-phase of cell cycle. Subsequently, miR-15/16 activities are reduced and many of their direct targets are de-repressed, including ubiquitin ligase FBXW7 that destabilizes Cyclin E. Conversely, GBM cells expressing low p21 level, or after p21 knock-down, exhibit weaker or no E2F1 response to miR-10b inhibition. Comparative analysis of The Cancer Genome Atlas revealed a strong correlation between miR-10b and multiple E2F target genes in GBM and low-grade glioma. Taken together, these findings indicate that miR-10b regulates E2F1-mediated transcription in GBM, in a p21-dependent fashion.
    Oncotarget 02/2015; 6(6). DOI:10.18632/oncotarget.3009 · 6.36 Impact Factor

Publication Stats

10k Citations
1,921.86 Total Impact Points


  • 2013–2015
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 2012–2015
    • Brigham and Women's Hospital
      • Department of Neurosurgery
      Boston, Massachusetts, United States
    • Northwestern University
      • Department of Neurological Surgery
      Evanston, Illinois, United States
  • 1990–2015
    • Harvard Medical School
      • • Department of Radiology
      • • Department of Neurology
      • • Department of Surgery
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 2004–2014
    • The Ohio State University
      • Department of Neurological Surgery
      Columbus, Ohio, United States
    • Okayama University
      • Department of Neurological Surgery
      Okayama, Okayama, Japan
  • 1998–2014
    • Harvard University
      Cambridge, Massachusetts, United States
    • Università degli Studi di Genova
      • Dipartimento di Medicina sperimentale (DIMES)
      Genova, Liguria, Italy
    • Cornell University
      Итак, New York, United States
  • 1992–2013
    • Massachusetts General Hospital
      • • Division of Surgical Oncology
      • • Molecular Neurobiology Laboratory
      • • Department of Neurosurgery
      • • Department of Neurology
      • • Department of Pathology
      Boston, MA, United States
  • 2007
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
  • 2005
    • Columbus State University
      Columbus, Georgia, United States
    • St. Jude Children's Research Hospital
      Memphis, Tennessee, United States
  • 2003
    • Partners HealthCare
      Boston, Massachusetts, United States
  • 2001
    • Brown University
      Providence, Rhode Island, United States
    • Barrow Neurological Institute
      Phoenix, Arizona, United States
  • 1999
    • Martin Luther University of Halle-Wittenberg
      Halle-on-the-Saale, Saxony-Anhalt, Germany