Alia Hdeib

Dendritic cell immunotherapy for solid tumors: evaluation of the DCVax® platform in the treatment of glioblastoma multiforme

DCVax(®) (Northwest Biotherapeutics, Inc., MD, USA) is a platform technology for delivering dendritic cell based therapeutic vaccines for a variety of cancers, including glioblastoma multiforme (GBM). DCVax(®)-L, one of the implementations of the DCVax platform, provides personalized active immunotherapy composed of autologous dendritic cells pulsed with autologous whole tumor lysate. Clinical trials with DCVax-L for GBM included previous Phase I/II clinical trials and an ongoing Phase III trial. Preliminary reports of patient outcomes after administration of the DCVax-L vaccine provide a promising therapeutic paradigm for patients with both initially diagnosed and recurrent GBM. Here we evaluate the current literature and clinical experience with the DCVax platform, with a particular focus on GBM treatment.

Convection-enhanced delivery of 131I-chTNT-1/B mAB for treatment of high-grade adult gliomas

Introduction: Despite treatment advances for malignant gliomas in adults, prognosis remains poor, largely due to the infiltrative and heterogeneous biology of these tumors. Response to adjuvant therapy is not always uniform and the blood–brain barrier prevents the majority of chemotherapeutics from adequately reaching primary tumor sites. These obstacles necessitate development of novel delivery methods and agents. Areas covered: 131I-chTNT-1/B mAB (Cotara) is a genetically engineered chimeric monoclonal antibody that binds to the DNA–histone H1 complex. It carries 131I, which delivers sufficient energy to kill adjacent tumor cells. Through convection-enhanced delivery (CED) it provides radioimmunotherapy directly to the resection cavity. We review the pharmacology and clinical experience with 131I-chTNT-1/B mAB, detailing results of completed Phase I and II trials. Expert opinion: Novel agents and therapeutic modalities, such as 131I-chTNT-1/B mAB, are of interest for treatment of malignant glioma, for which the prognosis continues to be dismal. 131I-chTNT-1/B mAB targets tumor cells and radioisotope labeling allows radiation delivery to the tumor with sharp fall-off. Data from Phase I and II trials of CED delivery of 131I-chTNT-1/B mAB shows it is well tolerated. Phase II trial data suggests it could be promising therapeutically, though conclusions about efficacy require further trials and clinical experience. The compound is currently in a Phase II trial for dose confirmation in patients with malignant gliomas.

Targeted radioimmunotherapy: the role of 131I-chTNT-1/B mAb (Cotara®) for treatment of high-grade gliomas

The prognosis for patients with malignant gliomas remains poor, and novel treatment paradigms are needed. Radioimmunotherapeutic drugs have been studied in clinical trials as adjuncts to treatment for these tumors. One such agent is (131)I-chTNT-1/B mAb (Cotara(®)), a compound locally delivered to the tumor site through convection-enhanced delivery. It is a genetically engineered chimeric monoclonal antibody that binds to the DNA-histone H1 complex, and carries (131)I, which locally delivers its radioactive payload to kill adjacent tumor cells. Clinical experience with Cotara is emerging; completed Phase I and II trials with a total of 51 patients helped to define dosing regimens for the drug. A recent Phase II dose-confirmation trial with Cotara for patients with glioblastoma multiforme at first relapse has demonstrated promising overall survival results of 41 weeks. This review explores the clinical experience of radioimmunotherapy and describes the role of Cotara for treatment of patients with malignant gliomas.

Depths and grids in brain tumors: Implantation strategies, techniques, and complications

Patients with intracranial mass lesions are at increased risk of intractable epilepsy even after tumor resection due to the potential epileptogenicity of lesional and perilesional tissue. Risk factors for tumoral epilepsy include tumor location, histology, and extent of tumor resection. In epilepsy that occurs after tumor resection, the epileptogenic zone often does not correspond precisely with the area of abnormality on imaging, and seizures often arise from a relatively restricted area despite widespread changes on imaging. Invasive monitoring via subdural grids and/or depth electrodes can therefore be helpful to delineate areas of eloquence and localize the epileptogenic zone for subsequent resection. Subdural grids offer excellent contiguous coverage of superficial cortex and allow resection using the same craniotomy, facilitating understanding of anatomic relationships. Depth electrodes offer superior coverage of deep structures, are easier to use in cases where a previous craniotomy is present, are not associated with anatomic distortion due to brain shift, and may be associated with a lower complication rate. We review the biology of focal postoperative epilepsy and invasive diagnostic strategies for the surgical evaluation of medically refractory epilepsy in patients who have undergone resection of intracranial mass lesions.

Development of the Neurological Institute: a strategic, improvement, and systems approach

The Neurological Institute at University Hospitals Case Medical Center is designed to be responsive to the ever-changing healthcare environment, aligning clinical services and goals in response to internal and external pressures for change. These goals are many, including the further development of system integration across disciplines and geographic locations, creation of a regional strategy, and research as well as education strategies that are aligned with clinical services, patient outcomes that demonstrate improved health status management, and improved financial strength. There are many details to the development of a strategic business unit such as the Neurological Institute, but this article focuses on the high-level strategies of developing the Neurological Institute and takes a closer look at the growth of one of its 16 centers of excellence.

Astroblastoma and Other Predominantly Pediatric Supratentorial Papillary/Epithelioid Gliomas

Abstract Astroblastomas are rare primary brain tumors with no currently assigned World Health Organization grade. In their classical presentation, they are well-circumscribed supratentorial solid-cystic tumors with minimal peritumoral T2 hyperintensity. They can be difficult to distinguish from other predominantly pediatric supratentorial papillary/epithelioid gliomas, such as ependymomas, choroid plexus tumors, papillary glioneuronal tumors, papillary tumors of the pineal region, and occasionally atypical teratoid/rhabdoid tumor of the central nervous system. Distinct morphologic, immunohistochemical, and ultrastructural features aid in reaching a definitive diagnosis. In this review, we present a case of pediatric astroblastoma with a unique course and discuss the key differences and similarities between astroblastomas and other predominantly pediatric supratentorial papillary/epithelioid gliomas.

Immunotherapy for malignant primary brain tumors with ICT-107, a dendritic cell vaccine

ABSTRACT Introduction: ICT-107 is a dendritic cell vaccine for the treatment of primary malignant brain tumors such as glioblastoma multiforme (GBM). For this immunotherapy treatment, autologous dendritic cells are pulsed with peptides from six tumor-associated antigens expressed on gliomas. Areas covered: Review of phase I and II clinical date is presented. In a phase I clinical trial with ICT-107 treatment in patients with malignant gliomas, the vaccine was found to be safe and tolerable, with encouraging results for overall survival and progression-free survival. A Phase II trial has completed enrollment, while a Phase III trial is currently opened to enrolling patients with newly diagnosed glioblastoma multiforme. Expert opinion: Immunotherapy with ICT-107 might present a therapeutic option for treatment in a subgroup of GBM patients.

Brachyury-targeting immunotherapy for chordomas: treatment with GI-6301, a Saccharomyces cerevisiae yeast-based cancer vaccine

ABSTRACT Introduction: Chordomas are slow growing rare tumors deriving from notochordal remnants, occurring in locations along the neuro-axis from the skull base to the sacro-coccygeal spine. Treatment includes surgery, with en bloc resection when feasible, photon/proton based radiation therapy, and molecularly targeted agents. However overall long-term prognosis remains guarded. Areas covered: We review the role of GI-6301, a yeast-brachyury based therapeutic cancer vaccine for immnotherapeutic treatment of patients with chordomas, and review it’s pharmacology and clinical efficacy demonstrated in a completed Phase I trial. Expert opinion: Brachyury is highly expressed in chordomas. GI-6301 immunotherapy aims to provide a therapeutic option for patients with chordoma, particularly for those who have failed conventional surgery and irradiation, and for whom treatment options are limited. A Phase I dose-escalation trial has shown promising results. A phase II study with GI-6301 in patients with locally advanced chroma is underway.