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Batich K.A.,Duke University | Choi B.D.,Duke University | Mitchell D.A.,Duke Brain Tumor Immunotherapy Program | Mitchell D.A.,Duke University
Neuromethods | Year: 2013

We have demonstrated that dendritic cells (DCs) loaded with total tumor RNA (ttRNA) represent a potent platform for the induction of antitumor immunity in preclinical murine glioma models. DCs are potent immunostimulatory cells that represent a promising contemporary biologic entity for realizing the potentials of immunotherapy. The use of RNA to encode tumor antigens for DCs was pioneered at our institution by Drs. Eli Gilboa and Smita Nair, but the ability of RNA-loaded DCs to stimulate potent antitumor immunity has been independently confirmed in several murine and human systems. In fact, there is accumulating evidence that RNA transfection represents a superior method for loading antigens onto DCs. In this chapter, we describe the methods involved in using DCs electroporated with ttRNA to potentiate the host immune response against infiltrating MGs. Furthermore, this chapter includes an in-depth review of the history of immunotherapy for high-grade gliomas using animal models as well as an overview of some of the more compelling immunotherapeutic strategies known to date. © 2013 Springer Science+Business Media New York.

Batich K.A.,Duke Brain Tumor Immunotherapy Program | Swartz A.M.,Duke Brain Tumor Immunotherapy Program | Sampson J.H.,Duke Brain Tumor Immunotherapy Program | Sampson J.H.,Duke University
Expert Opinion on Biological Therapy | Year: 2015

Introduction: Patients with primary glioblastoma (GBM) have a dismal prognosis despite standard therapy, which can induce potentially deleterious side effects. Arming the immune system is an alternative therapeutic approach, as its cellular effectors and inherent capacity for memory can be utilized to specifically target invasive tumor cells, while sparing collateral damage to otherwise healthy brain parenchyma.Areas covered: Active immunotherapy is aimed at eliciting a specific immune response against tumor antigens. Dendritic cells (DCs) are one of the most potent activators of de novo and recall immune responses and are thus a vehicle for successful immunotherapy. Currently, investigators are optimizing DC vaccines by enhancing maturation status and migratory potential to induce more potent antitumor responses. An update on the most recent DC immunotherapy trials is provided.Expert opinion: Targeting of unique antigens restricted to the tumor itself is the most important parameter in advancing DC vaccines. In order to overcome intrinsic mechanisms of immune evasion observed in GBM, the future of DC-based therapy lies in a multi-antigenic vaccine approach. Successful targeting of multiple antigens will require a comprehensive understanding of all immunologically relevant oncological epitopes present in each tumor, thereby permitting a rational vaccine design. © 2015 Informa UK, Ltd.

Choi B.D.,Duke Brain Tumor Immunotherapy Program | Gedeon P.C.,Duke Brain Tumor Immunotherapy Program | Sanchez-Perez L.,Duke Brain Tumor Immunotherapy Program | Bigner D.D.,Duke University | Sampson J.H.,Duke Brain Tumor Immunotherapy Program
OncoImmunology | Year: 2013

Regulatory T cells (Tregs) play a central role in in tumor escape from immunosurveillance. We report that a bispecific T-cell engager (BiTE) targeting a mutated form of the epidermal growth factor receptor, i.e., EGFRvIII, potently redirects Tregs to kill glioblastoma through the granzyme-perforin pathway. © 2013 Landes Bioscience.

Gedeon P.C.,Duke Brain Tumor Immunotherapy Program | Choi B.D.,Duke Brain Tumor Immunotherapy Program | Sampson J.H.,Duke Brain Tumor Immunotherapy Program | Sampson J.H.,Duke University | Bigner D.D.,Duke University
Drugs of the Future | Year: 2013

Glioblastoma, the most common primary malignant brain tumor, is among the most difficult cancers to treat. Despite the aggressive standard of care, including surgical removal followed by radiotherapy with concomitant and adjuvant chemotherapy, the often sudden onset, diffuse infiltrating nature and highly malignant features of the lesion result in a median overall survival of < 15 months. Currently employed standard- of-care therapy for glioblastoma is nonspecific, leading to premature withdrawal of treatment due to off-target toxicity. Rindopepimut is a peptide-based vaccine that elicits a potent humoral and cellular immune response specifically against cells expressing EGFRvIII, a rearranged, cell-surface tyrosine kinase receptor present exclusively in glioblastoma and other common neoplasms. Several phase I and phase II clinical trials have demonstrated that vaccination with rindopepimut is safe, well tolerated and produces a highly potent immune response that effectively eradicates EGFRvIII-expressing tumor cells, leading to a 73% increase in survival among patients with newly diagnosed glioblastoma. Furthermore, temozolomide-induced lymphopenia enhances the rindopepimut-induced immune response against EGFRvIII, allowing for enhanced vaccination responses in the context of standard-of-care chemotherapy. Rindopepimut is currently undergoing evaluation in a phase III international trial for newly diagnosed glioblastoma and is under clinical investigation for recurrent glioblastoma and pediatric brain stem gliomas. Copyright © 2013 Prous Science, S.A.U. or its licensors. All rights reserved.

Suryadevara C.,Duke Brain Tumor Immunotherapy Program | Suryadevara C.,Duke University | Verla T.,Duke Brain Tumor Immunotherapy Program | Verla T.,Duke University | And 9 more authors.
Surgical Neurology International | Year: 2015

Malignant gliomas (MG) are the most common type of primary malignant brain tumor. Most patients diagnosed with glioblastoma (GBM), the most common and malignant glial tumor, die within 12-15 months. Moreover, conventional treatment, which includes surgery followed by radiation and chemotherapy, can be highly toxic by causing nonspecific damage to healthy brain and other tissues. The shortcomings of standard-of-care have thus created a stimulus for the development of novel therapies that can target central nervous system (CNS)-based tumors specifically and efficiently, while minimizing off-target collateral damage to normal brain. Immunotherapy represents an investigational avenue with the promise of meeting this need, already having demonstrated its potential against B-cell malignancy and solid tumors in clinical trials. T-cell engineering with tumor-specific chimeric antigen receptors (CARs) is one proven approach that aims to redirect autologous patient T-cells to sites of tumor. This platform has evolved dramatically over the past two decades to include an improved construct design, and these modern CARs have only recently been translated into the clinic for brain tumors. We review here emerging immunotherapeutic platforms for the treatment of MG, focusing on the development and application of a CAR-based strategy against GBM. © 2015 Ene1 CI.

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