Henry Brem

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (285)1344.37 Total impact

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    ABSTRACT: Cell-free DNA shed by cancer cells has been shown to be a rich source of putative tumor-specific biomarkers. Because cell-free DNA from brain and spinal cord tumors cannot usually be detected in the blood, we studied whether the cerebrospinal fluid (CSF) that bathes the CNS is enriched for tumor DNA, here termed CSF-tDNA. We analyzed 35 primary CNS malignancies and found at least one mutation in each tumor using targeted or genome-wide sequencing. Using these patient-specific mutations as biomarkers, we identified detectable levels of CSF-tDNA in 74% [95% confidence interval (95% CI) = 57-88%] of cases. All medulloblastomas, ependymomas, and high-grade gliomas that abutted a CSF space were detectable (100% of 21 cases; 95% CI = 88-100%), whereas no CSF-tDNA was detected in patients whose tumors were not directly adjacent to a CSF reservoir (P < 0.0001, Fisher's exact test). These results suggest that CSF-tDNA could be useful for the management of patients with primary tumors of the brain or spinal cord.
    Proceedings of the National Academy of Sciences 08/2015; 112(31):9704-9. DOI:10.1073/pnas.1511694112 · 9.67 Impact Factor
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    ABSTRACT: We examined the relationship between the O(6)-methylguanine-methyltransferase (MGMT) methylation status and clinical outcomes in newly diagnosed glioblastoma multiforme (GBM) patients who were treated with Gliadel wafers (Eisai, Tokyo, Japan). MGMT promoter methylation has been associated with increased survival among patients with GBM who are treated with various alkylating agents. MGMT promoter methylation, in DNA from 122 of 160 newly diagnosed GBM patients treated with Gliadel, was determined by a quantitative methylation-specific polymerase chain reaction, and was correlated with overall survival (OS) and recurrence-free survival (RFS). The MGMT promoter was methylated in 40 (32.7%) of 122 patients. The median OS was 13.5 months (95% confidence interval [CI] 11.0-14.5) and RFS was 9.4 months (95% CI 7.8-10.2). After adjusting for age, Karnofsky performance score, extent of resection, temozolomide (TMZ) and radiation therapy (RT), the newly diagnosed GBM patients with MGMT methylation had a 15% reduced mortality risk, compared to patients with unmethylated MGMT (hazard ratio 0.85; 95% CI 0.56-1.31; p=0.46). The patients aged over 70years with MGMT methylation had a significantly longer median OS of 13.5months, compared to 7.6months in patients with unmethylated MGMT (p=0.027). A significant difference was also found in older patients, with a median RFS of 13.1 versus 7.6months for methylated and unmethylated MGMT groups, respectively (p=0.01). Methylation of the MGMT promoter in newly diagnosed GBM patients treated with Gliadel, RT and TMZ, was associated with significantly improved OS compared to the unmethylated population. In elderly patients, methylation of the MGMT promoter was associated with significantly better OS and RFS. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of Clinical Neuroscience 08/2015; DOI:10.1016/j.jocn.2015.07.003 · 1.38 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):3839-3839. DOI:10.1158/1538-7445.AM2015-3839 · 9.33 Impact Factor
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    ABSTRACT: Checkpoint molecules like programmed death-1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM-3) act as negative regulators of the immune system and can be upregulated in the setting of glioblastoma multiforme (GBM). Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model. However, tumor-infiltrating lymphocytes can express multiple checkpoints (including TIM-3), and expression of 2 or more checkpoints corresponds to a more exhausted T-cell phenotype. Here, we hypothesized that the addition of a second checkpoint-blocking antibody could achieve additive or synergistic antitumor effects. C57BL/6 mice were implanted with mouse glioma cell line GL261 transfected with luciferase and randomized into 8 treatment arms: (1) control, (2) SRS, (3) anti-PD-1 antibody, (4) anti-TIM-3 antibody, (5) anti-PD-1 + SRS, (6) anti-TIM-3 + SRS, (7) anti-PD-1 + anti-TIM-3, and (8) anti-PD-1 + anti-TIM-3 + SRS. Overall survival was measured. Brain, cervical lymph nodes, and peripheral blood were harvested on day 21 to assess immune activation. Survival benefits were demonstrated with combined anti-TIM-3 antibody + SRS compared with anti-TIM-3 antibody alone with a median survival (MS) of 92 vs 25 days and overall survival (OS) of 50% vs 0%, respectively (P < .001 by log-rank Mantel-Cox). Dual blockade with anti-TIM-3 + anti-PD-1 antibody also improved survival compared with TIM-3 blockade alone (MS of 146 vs 25 days, OS 60% vs 0%, respectively, P < .05). Notably, the triple-modality treatment (anti-PD-1 + anti-TIM-3 + SRS) provided a significant improvement in survival compared with all other treatment arms with an OS of 100% by day 146 (P < .05). Flow cytometry of organs harvested on day 21 showed that, compared with dual-therapy groups, mice treated with the triple-modality treatment had increased tumor infiltration by interferon-gamma+ (IFN-γ) and tumor necrosis factor-alpha+ (TNF-α)-producing CD4 T cells, as well as IFN-γ+ CD8 lymphocytes. Combining anti-TIM-3 with anti-PD-1 and radiation was synergistic and conferred a significant survival benefit.
    Neurosurgery 08/2015; 62 Suppl 1, CLINICAL NEUROSURGERY:212. DOI:10.1227/01.neu.0000467105.60300.04 · 3.62 Impact Factor
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    ABSTRACT: Craniectomy defects following resection of calvarial lesions are most often reconstructed using on-table manufacturing. With the advent of computer-aided design/manufacturing and customized craniofacial implants (CCIs), there seems to be more suited alternatives. In this study, the authors report their institutional experience and outcome using immediate, single-stage, CCI-based reconstruction for benign and malignant skull neoplasm defects. A retrospective review of a prospectively maintained database of all implant cranioplasties performed between 2011 and 2014, by a single craniofacial surgeon at a tertiary academic medical institution was performed. Preoperative and postoperative computed tomography scans with 3D reconstruction were performed for the purpose of assessing adequate resection and reconstructive outcomes. Primary endpoints included length of surgery, predicted defect versus postoperative implant surface area, contour irregularities, and complications. Of the 108 patients with cranioplasty identified, 7 patients were found to undergo immediate CCI-based reconstruction for calvarial neoplasms; 4 patients (4/7, 57%) presented with malignant pathology. All defects were >5 cm. As compared with their original size, all implants were modified intraoperatively between 0.2% and 40.8%, with a mean of 13.8%. With follow-up ranging between 1 and 16 months, there were no implant-related complications identified. The immediate and long-term aesthetic results, as well as patient satisfaction, were ideal. With this preliminary experience, the authors have successfully demonstrated that immediate customized implant reconstructive techniques, by way of intraoperative modification, are both safe and feasible for benign and malignant skull neoplasms. The authors believe that with wider acceptance of this multidisciplinary approach and increased surgeon familiarity, this technique will soon become the reconstructive standard of care.
    The Journal of craniofacial surgery 07/2015; 26(5):1456-1462. DOI:10.1097/SCS.0000000000001816 · 0.68 Impact Factor
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    ABSTRACT: Effective blood-brain tumor barrier penetration and uniform solid tumor distribution can significantly enhance therapeutic delivery to brain tumors. Hydroxyl-functionalized, generation-4 poly(amidoamine) (PAMAM) dendrimers, with their small size, near-neutral surface charge, and the ability to selectively localize in cells associated with neuroinflammation may offer new opportunities to address these challenges. In this study we characterized the intracranial tumor biodistribution of systemically delivered PAMAM dendrimers in an intracranial rodent gliosarcoma model using fluorescence-based quantification methods and high resolution confocal microscopy. We observed selective and homogeneous distribution of dendrimer throughout the solid tumor (∼6 mm) and peritumoral area within fifteen minutes after systemic administration, with subsequent accumulation and retention in tumor associated microglia/macrophages (TAMs). Neuroinflammation and TAMs have important growth promoting and pro-invasive effects in brain tumors. The rapid clearance of systemically administered dendrimers from major organs promises minimal off-target adverse effects of conjugated drugs. Therefore, selective delivery of immunomodulatory molecules to TAM, using hydroxyl PAMAM dendrimers, may hold promise for therapy of glioblastoma. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Biomaterials 06/2015; 52(1):507-16. DOI:10.1016/j.biomaterials.2015.02.053 · 8.56 Impact Factor
  • Plastic and Reconstructive Surgery 05/2015; 135(5S Suppl):36-37. DOI:10.1097/01.prs.0000465489.84283.e6 · 2.99 Impact Factor
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    ABSTRACT: Patients with glioblastoma (GBM) have an inherently shortened survival because of their disease. It has been recently shown that carmustine wafers in addition to other therapies (surgery, temozolomide, and radiation) can further extend survival. There is concern, however, that these therapies may increase infection risk. The goals of this study were to calculate the incidence of postoperative infection, evaluate if carmustine wafers changes the risk of infection and identify factors independently associated with an infection following GBM surgery. All patients who underwent non-biopsy, surgical resection of an intracranial GBM from 2007 to 2011 at a single institution were retrospectively reviewed. Stepwise multivariate proportional hazards regression analysis was used to identify factors associated with infection, including the use of carmustine wafers. Variables with P < 0.05 were considered statistically significant. Four hundred and one patients underwent resection of an intracranial GBM during the reviewed period, and 21 (5%) patients developed an infection at a median time of 40 [28-286] days following surgery. The incidence of infection was not higher in patients who had carmustine wafers, and this remained true in multivariate analyses to account for differences in treatment cohorts. The factors that remained significantly associated with an increased risk of infection were prior surgery [RR (95% CI); 2.026 (1.473-4.428), P = 0.01], diabetes mellitus [RR (95% CI); 6.090 (1.380-9.354)], P = 0.02], and increasing duration of hospital stay [RR (95% CI); 1.048 (1.006-1.078); P = 0.02], where the greatest risk occurred with hospital stays >5 days [RR (95% CI); 3.904 (1.003-11.620), P = 0.05]. These findings may help guide treatment regimens aimed at minimizing infection for patients with GBM.
    Neurological Research 04/2015; 37(8):1743132815Y0000000042. DOI:10.1179/1743132815Y.0000000042 · 1.44 Impact Factor
  • Neuro-Oncology 04/2015; 17(suppl 3):iii38-iii38. DOI:10.1093/neuonc/nov061.154 · 5.56 Impact Factor
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    ABSTRACT: High-grade gliomas, glioblastomas (GB), are refractory to conventional treatment combining surgery, chemotherapy, mainly temozolomide, and radiotherapy. This highlights an urgent need to develop novel therapies and increase the efficacy of radio/chemotherapy for these very aggressive and malignant brain tumors. Recently, tumor metabolism became an interesting potential therapeutic target in various cancers. Accordingly, combining drugs targeting cell metabolism with appropriate chemotherapeutic agents or radiotherapy has become attractive. In light of these perspectives, we were particularly interested in the anti-cancer properties of a biguanide molecule used for type 2 diabetes treatment, metformin. In our present work, we demonstrate that metformin decreases mitochondrial-dependent ATP production and oxygen consumption and increases lactate and glycolytic ATP production. We show that metformin induces decreased proliferation, cell cycle arrest, autophagy, apoptosis and cell death in vitro with a concomitant activation of AMPK, Redd1 and inhibition of the mTOR pathway. Cell sensitivity to metformin also depends on the genetic and mutational backgrounds of the different GB cells used in this study, particularly their PTEN status. Interestingly, knockdown of AMPK and Redd1 with siRNA partially, but incompletely, abrogates the induction of apoptosis by metformin suggesting both AMPK/Redd1-dependent and -independent effects. However, the primary determinant of the effect of metformin on cell growth is the genetic and mutational backgrounds of the glioma cells. We further demonstrate that metformin treatment in combination with temozolomide and/or irradiation induces a synergistic anti-tumoral response in glioma cell lines. Xenografts performed in nude mice demonstrate in vivo that metformin delays tumor growth. As current treatments for GB commonly fail to cure, the need for more effective therapeutic options is overwhelming. Based on these results, metformin could represent a potential enhancer of the cytotoxic effects of temozolomide and/or radiotherapy.
    PLoS ONE 04/2015; 10(4):e0123721. DOI:10.1371/journal.pone.0123721 · 3.23 Impact Factor
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    ABSTRACT: Malignant gliomas, including glioblastoma and anaplastic astrocytomas, are characterized by their propensity to invade surrounding brain parenchyma, making curative resection difficult. These tumors typically recur within two centimeters of the resection cavity even after gross total removal. As a result, there has been an emphasis on developing therapeutics aimed at achieving local disease control. In this review, we will summarize the current developments in the delivery of local therapeutics, namely direct injection, convection-enhanced delivery and implantation of drug-loaded polymers, as well as the application of these therapeutics in future methods including microchip drug delivery and local gene therapy.
    Therapeutic delivery 04/2015; 6(3):353-69. DOI:10.4155/tde.14.114
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    ABSTRACT: The advent of interstitial chemotherapy has significantly increased therapeutic options for patients with malignant glioma. Interstitial chemotherapy can deliver high concentrations of chemotherapeutic agents, directly at the site of the brain tumor while bypassing systemic toxicities. Gliadel, a locally implanted polymer that releases the alkylating agent carmustine, given alone and in combination with various other antitumor and resistance modifying therapies, has significantly increased the median survival for patients with malignant glioma. Convection enhanced delivery, a technique used to directly infuse drugs into brain tissue, has shown promise for the delivery of immunotoxins, monoclonal antibodies, and chemotherapeutic agents. Preclinical studies include delivery of chemotherapeutic and immunomodulating agents by polymer and microchips. Interstitial chemotherapy was shown to maximize local efficacy and is an important strategy for the efficacy of any multimodal approach.
    Surgical Neurology International 02/2015; 6(Suppl 1):S78-84. DOI:10.4103/2152-7806.151345 · 1.18 Impact Factor
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    ABSTRACT: Biodegradable polymeric nanoparticles have the potential to be safer alternatives to viruses for gene delivery; however, their use has been limited by poor efficacy in vivo. In this work, we synthesize and characterize polymeric gene delivery nanoparticles and evaluate their efficacy for DNA delivery of herpes simplex virus type I thymidine kinase (HSVtk) combined with the prodrug ganciclovir (GCV) in a malignant glioma model. We investigated polymer structure for gene delivery in two rat glioma cell lines, 9L and F98, to discover nanoparticle formulations more effective than the leading commercial reagent Lipofectamine 2000. The lead polymer structure, poly(1,4-butanediol diacrylate-co-4-amino-1-butanol) end-modified with 1-(3-aminopropyl)-4-methylpiperazine, is a poly(beta-amino ester) (PBAE) and formed nanoparticles with HSVtk DNA that were 138 ± 4 nm in size and 13 ± 1 mV in zeta potential. These nanoparticles containing HSVtk DNA showed 100% cancer cell killing in vitro in the two glioma cell lines when combined with GCV exposure, while control nanoparticles encoding GFP maintained robust cell viability. For in vivo evaluation, tumor-bearing rats were treated with PBAE/HSVtk infusion via convection-enhanced delivery (CED) in combination with systemic administration of GCV. These treated animals showed a significant benefit in survival (p=0.0012 vs. control). Moreover, following a single CED infusion, labeled PBAE nanoparticles spread completely throughout the tumor. This study highlights a nanomedicine approach that is highly promising for the treatment of malignant glioma.
    ACS Nano 02/2015; 9(2). DOI:10.1021/nn504905q · 12.88 Impact Factor
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    ABSTRACT: We assessed the antiangiogenic effects of subconjunctival injection of Fc-endostatin (FcE) using a human vascular endothelial growth factor-induced rabbit corneal neovascularization model. Angiogenesis was induced in rabbit corneas through intrastromal implantations of VEGF polymer implanted 2 mm from the limbus. NZW rabbits were separated into groups receiving twice weekly subconjunctival injections of either saline; 25 mg/mL bevacizumab; 2 mg/mL FcE; or 20 mg/mL FcE. Corneas were digitally imaged at 5 time points. An angiogenesis index (AI) was calculated (vessel length (mm) × vessel number score) for each observation. All treatment groups showed a significant decrease in the vessel length and AI compared to saline on all observation days (í µí±ƒ < 0.001). By day 15, FcE 2 inhibited angiogenesis significantly better than FcE 20 (í µí±ƒ < 0.01). There was no significant difference between FcE 2 and BV, although the values trended towards significantly increased inhibition by BV. BV was a significantly better inhibitor than FcE 20 by day 8 (í µí±ƒ < 0.01). FcE was safe and significantly inhibited new vessel growth in a rabbit corneal neovascularization model. Lower concentration FcE 2 exhibited better inhibition than FcE 20, consistent with previous FcE studies referencing a biphasic dose-response curve. Additional studies are necessary to further elucidate the efficacy and clinical potential of this novel angiogenesis inhibitor.
    Journal of Ophthalmology 01/2015; In Press(Article ID 137136). DOI:10.1155/2015/137136 · 1.43 Impact Factor
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    ABSTRACT: Preoperative anemia may affect postoperative mortality and morbidity following elective cranial operations. The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was used to identify elective cranial neurosurgical cases (2006-2012). Morbidity was defined as wound infection, systemic infection, cardiac, respiratory, renal, neurologic, and thromboembolic events, and unplanned returns to the operating room. For 30-day postoperative mortality and morbidity, adjusted odds ratios (ORs) were estimated with multivariable logistic regression. Of 8015 patients who underwent elective cranial neurosurgery, 1710 patients (21.4%) were anemic. Anemic patients had an increased 30-day mortality of 4.1% versus 1.3% in non-anemic patients (P < 0.001) and an increased 30-day morbidity rate of 25.9% versus 14.14% in non-anemic patients (P < 0.001). The 30-day morbidity rates for all patients undergoing cranial procedures were stratified by diagnosis: 26.5% aneurysm, 24.7% sellar tumor, 19.7% extra-axial tumor, 14.8% intra-axial tumor, 14.4% arteriovenous malformation, and 5.6% pain. Following multivariable regression, the 30-day mortality in anemic patients was threefold higher than in non-anemic patients (4.1% vs 1.3%; OR = 2.77; 95% CI: 1.65-4.66). The odds of postoperative morbidity in anemic patients were significantly higher than in non-anemic patients (OR = 1.29; 95% CI: 1.03-1.61). There was a significant difference in postoperative morbidity event odds with a hematocrit level above (OR = 1.07; 95% CI: 0.78-1.48) and below (OR = 2.30; 95% CI: 1.55-3.42) 33% [hemoglobin (Hgb) 11 g/dl]. Preoperative anemia in elective cranial neurosurgery was independently associated with an increased risk of 30-day postoperative mortality and morbidity when compared to non-anemic patients. A hematocrit level below 33% (Hgb 11 g/dl) was associated with a significant increase in postoperative morbidity.
    Surgical Neurology International 11/2014; 5:156. DOI:10.4103/2152-7806.143754 · 1.18 Impact Factor
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    ABSTRACT: The NCCN Guidelines for Central Nervous System Cancers provide multidisciplinary recommendations for the clinical management of patients with cancers of the central nervous system. These NCCN Guidelines Insights highlight recent updates regarding the management of metastatic brain tumors using radiation therapy. Use of stereotactic radiosurgery (SRS) is no longer limited to patients with 3 or fewer lesions, because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique. SRS is increasingly becoming an integral part of management of patients with controlled, low-volume brain metastases.
    Journal of the National Comprehensive Cancer Network: JNCCN 11/2014; 12(11):1517-23. · 4.18 Impact Factor
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    ABSTRACT: Metastases represent the most common brain tumors in adults. Surgical resection alone results in 45% recurrence and is usually accompanied by radiation and chemotherapy. Adequate chemotherapy delivery to the CNS is hindered by the blood-brain barrier. Efforts at delivering chemotherapy locally to gliomas have shown modest increases in survival, likely limited by the infiltrative nature of the tumor. Temozolomide (TMZ) is first-line treatment for gliomas and recurrent brain metastases. Doxorubicin (DOX) is used in treating many types of breast cancer, although its use is limited by severe cardiac toxicity. Intracranially implanted DOX and TMZ microcapsules are compared with systemic administration of the same treatments in a rodent model of breast adenocarcinoma brain metastases. Outcomes were animal survival, quantified drug exposure, and distribution of cleaved caspase 3. Intracranial delivery of TMZ and systemic DOX administration prolong survival more than intracranial DOX or systemic TMZ. Intracranial TMZ generates the more robust induction of apoptotic pathways. We postulate that these differences may be explained by distribution profiles of each drug when administered intracranially: TMZ displays a broader distribution profile than DOX. These microcapsule devices provide a safe, reliable vehicle for intracranial chemotherapy delivery and have the capacity to be efficacious and superior to systemic delivery of chemotherapy. Future work should include strategies to improve the distribution profile. These findings also have broader implications in localized drug delivery to all tissue, because the efficacy of a drug will always be limited by its ability to diffuse into surrounding tissue past its delivery source.
    Proceedings of the National Academy of Sciences 10/2014; 111(45). DOI:10.1073/pnas.1313420110 · 9.67 Impact Factor
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    ABSTRACT: Background: 3-bromopyruvate (3-BrPA) and dichloroacetate (DCA) are inhibitors of cancer-cell specific aerobic glycolysis. Their application in glioma is limited by 3-BrPA's inability to cross the blood-brain-barrier and DCA's dose-limiting toxicity. The safety and efficacy of intracranial delivery of these compounds were assessed. Methods: Cytotoxicity of 3-BrPA and DCA were analyzed in U87, 9L, and F98 glioma cell lines. 3-BrPA and DCA were incorporated into biodegradable pCPP:SA wafers, and the maximally tolerated dose was determined in F344 rats. Efficacies of the intracranial 3-BrPA wafer and DCA wafer were assessed in a rodent allograft model of high-grade glioma, both as a monotherapy and in combination with temozolomide (TMZ) and radiation therapy (XRT). Results: 3-BrPA and DCA were found to have similar IC50 values across the 3 glioma cell lines. 5% 3-BrPA wafer-treated animals had significantly increased survival compared with controls (P = .0027). The median survival of rats with the 50% DCA wafer increased significantly compared with both the oral DCA group (P = .050) and the controls (P = .02). Rats implanted on day 0 with a 5% 3-BrPA wafer in combination with TMZ had significantly increased survival over either therapy alone. No statistical difference in survival was noted when the wafers were added to the combination therapy of TMZ and XRT, but the 5% 3-BrPA wafer given on day 0 in combination with TMZ and XRT resulted in long-term survivorship of 30%. Conclusion: Intracranial delivery of 3-BrPA and DCA polymer was safe and significantly increased survival in an animal model of glioma, a potential novel therapeutic approach. The combination of intracranial 3-BrPA and TMZ provided a synergistic effect.
    Neuro-Oncology 07/2014; 17(1). DOI:10.1093/neuonc/nou143 · 5.56 Impact Factor
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    ABSTRACT: There is great promise that ongoing advances in the delivery of therapeutics to the central nervous system (CNS) combined with rapidly expanding knowledge of brain tumor patho-biology will provide new, more effective therapies. Brain tumors that form from brain cells, as opposed to those that come from other parts of the body, rarely metastasize outside of the CNS. Instead, the tumor cells invade deep into the brain itself, causing disruption in brain circuits, blood vessel and blood flow changes, and tissue swelling. Patients with the most common and deadly form, glioblastoma (GBM) rarely live more than 2 years even with the most aggressive treatments and often with devastating neurological consequences. Current treatments include maximal safe surgical removal or biopsy followed by radiation and chemotherapy to address the residual tumor mass and invading tumor cells. However, delivering effective and sustained treatments to these invading cells without damaging healthy brain tissue is a major challenge and focus of the emerging fields of nanomedicine and viral and cell-based therapies. New treatment strategies, particularly those directed against the invasive component of this devastating CNS disease, are sorely needed. In this review, we (1) discuss the history and evolution of treatments for GBM, (2) define and explore three critical barriers to improving therapeutic delivery to invasive brain tumors, specifically, the neuro-vascular unit as it relates to the blood brain barrier, the extra-cellular space in regard to the brain penetration barrier, and the tumor genetic heterogeneity and instability in association with the treatment efficacy barrier, and (3) identify promising new therapeutic delivery approaches that have the potential to address these barriers and create sustained, meaningful efficacy against GBM.
    Frontiers in Oncology 07/2014; 4:126. DOI:10.3389/fonc.2014.00126
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    ABSTRACT: Background Glioblastoma (GBM) is the most common malignant brain tumor in adults and is associated with a poor prognosis. Cytotoxic T lymphocyte antigen -4 (CTLA-4) blocking antibodies have demonstrated an ability to generate robust antitumor immune responses against a variety of solid tumors. 4-1BB (CD137) is expressed by activated T lymphocytes and served as a co-stimulatory signal, which promotes cytotoxic function. Here, we evaluate a combination immunotherapy regimen involving 4-1BB activation, CTLA-4 blockade, and focal radiation therapy in an immune-competent intracranial GBM model. Methods GL261-luciferace cells were stereotactically implanted in the striatum of C57BL/6 mice. Mice were treated with a triple therapy regimen consisted of 4-1BB agonist antibodies, CTLA-4 blocking antibodies, and focal radiation therapy using a small animal radiation research platform and mice were followed for survival. Numbers of brain-infiltrating lymphocytes were analyzed by FACS analysis. CD4 or CD8 depleting antibodies were administered to determine the relative contribution of T helper and cytotoxic T cells in this regimen. To evaluate the ability of this immunotherapy to generate an antigen-specific memory response, long-term survivors were re-challenged with GL261 glioma en B16 melanoma flank tumors. Results Mice treated with triple therapy had increased survival compared to mice treated with focal radiation therapy and immunotherapy with 4-1BB activation and CTLA-4 blockade. Animals treated with triple therapy exhibited at least 50% long-term tumor free survival. Treatment with triple therapy resulted in a higher density of CD4+ and CD8+ tumor infiltrating lymphocytes. Mechanistically, depletion of CD4+ T cells abrogated the antitumor efficacy of triple therapy, while depletion of CD8+ T cells had no effect on the treatment response. Conclusion Combination therapy with 4-1BB activation and CTLA-4 blockade in the setting of focal radiation therapy improves survival in an orthotopic mouse model of glioma by a CD4+ T cell dependent mechanism and generates antigen-specific memory.
    PLoS ONE 07/2014; 9(7). DOI:10.1371/journal.pone.0101764. · 3.23 Impact Factor

Publication Stats

11k Citations
1,344.37 Total Impact Points


  • 1990–2015
    • Johns Hopkins University
      • • Department of Neurosurgery
      • • Department of Biomedical Engineering
      • • Department of Medicine
      Baltimore, Maryland, United States
  • 2014
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
  • 1988–2014
    • Johns Hopkins Medicine
      • • Department of Neurosurgery
      • • Division of General Surgery and Surgical Oncology
      • • Division of Neuroradiology
      • • Department of Pathology
      Baltimore, Maryland, United States
  • 2004
    • The University of Chicago Medical Center
      Chicago, Illinois, United States
  • 2003
    • University of San Francisco
      San Francisco, California, United States
  • 2002
    • Texas A&M University - Galveston
      Galveston, Texas, United States
  • 1994
    • The Children's Hospital of Philadelphia
      • Department of Neurology
      Philadelphia, PA, United States
  • 1991–1994
    • Massachusetts Institute of Technology
      • Department of Chemical Engineering
      Cambridge, Massachusetts, United States