Local delivery methods of therapeutic agents in the treatment of diffuse intrinsic brainstem gliomas

Clinical Neurology and Neurosurgery 142 (2016) 120–127

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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro

Local delivery methods of therapeutic agents in the treatment of diffuse intrinsic brainstem gliomas C. Rory Goodwin, Risheng Xu, Rajiv Iyer, Eric W. Sankey, Ann Liu, Nancy Abu-Bonsrah, Rachel Sarabia-Estrada, James L. Frazier, Daniel M. Sciubba, George I. Jallo ∗ The Johns Hopkins University School of Medicine, Department of Neurosurgery, Baltimore, MD, USA

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Article history: Received 10 December 2015 Accepted 5 January 2016 Available online 11 January 2016 Keywords: Brainstem glioma Convection-enhanced delivery Chemotherapy Tumor Interstitial continuous infusion Intranasal delivery

a b s t r a c t Brainstem gliomas comprise 10–20% of all pediatric central nervous system (CNS) tumors and diffuse intrinsic pontine gliomas (DIPGs) account for the majority of these lesions. DIPG is a rapidly progressive disease with almost universally fatal outcomes and a median survival less than 12 months. Current standard-of-care treatment for DIPG includes radiation therapy, but its long-term survival effects are still under debate. Clinical trials investigating the efficacy of systemic administration of various therapeutic agents have been associated with disappointing outcomes. Recent efforts have focused on improvements in chemotherapeutic agents employed and in methods of localized and targeted drug delivery. This review provides an update on current preclinical and clinical studies investigating treatment options for brainstem gliomas. © 2016 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 Brainstem tumor models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 Small molecule delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 3.1. Convection-enhanced delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 3.1.1. Biologic compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 3.2. Intranasal delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 3.2.1. Biologic compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 3.3. Human neural and mesenchymal stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 3.4. Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 3.5. Other therapeutic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

1. Introduction Abbreviations: CNS, central nervous system; DIPG, diffuse intrinsic pontine gliomas; BBB, blood–brain barrier; CED, convection-enhanced delivery; HESC, human embryonic stem cells; NPC, neural progenitor cells; PDGFR, platelet-derived growth factor receptor; Gd, Gadolinium. ∗ Corresponding author at: Johns Hopkins Hospital, Division of Pediatric Neurosurgery, Phipps 556, 600 N. Wolfe Street, Baltimore, MD 21287, USA. Fax: +1 410 955 7862. E-mail address: [email protected] (G.I. Jallo). http://dx.doi.org/10.1016/j.clineuro.2016.01.007 0303-8467/© 2016 Elsevier B.V. All rights reserved.

Brainstem tumors are heterogeneous and arise from the midbrain, pons, medulla, and upper cervical spine. Comprising 10–20% of all pediatric central nervous system (CNS) tumors with an annual incidence of 200–300 cases in the United States, brainstem tumors have a mean age of diagnosis of 7–9 years with no gender predilection [1,2]. Earlier classification schemes for pediatric brainstem

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Table 1 Classification schemes for pediatric brainstem tumors. Author

Method utilized to create system

Classification system

Epstein [3]

CT

Epstein and McCleary [4]

CT, MRI, and surgical observation

Stroink et al. [5]

CT

Barkovich et al. [6]

MRI

Albright [7]

MRI

Fischbein et al. [8]

MRI

Choux et al. [9]

CT and MRI

Rubin et al. [89]

Clinical features and MRI

Intrinsic Diffuse Focal Cervicomedullary Exophytic Anterolateral into cerebellopontine angle Posterolateral and into brachium pontis Disseminated Positive cytology Positive myelography Diffuse Focal Cervicomedullary Group I—dorsal exophytic glioma Group IIa—intrinsic brainstem tumors, hypodense, no enhancement Group IIb—intrinsic brainstem tumors, hyperdense, contrast enhancing exophytic Group III—focal cystic tumor with contrast enhancement Group IV—focal intrinsic isodense contrast enhancement Location (midbrain, pons, medulla) Focality (diffuse or focal) Direction and extent of tumor growth Degree of brainstem enlargement Exophytic growth Hemorrhage or necrosis Evidence of hydrocephalus Focal (midbrain, pons, medulla) Diffuse Midbrain Diffuse Focal Tectal Pons Diffuse Focal Medulla Diffuse Focal Dorsal Exophytic Type I—diffuse Type II—intrinsic, focal Type III—exophytic, focal Type IV—cervicomedullary Cervicomedullary Exophytic Cystic Focal Diffuse

tumors are based on CT imaging and observation, while more recent ones rely on a combination of both CT and MR imaging. All schema differentiate tumors into focal or diffuse growth patterns, with further subdivisions based on their origin within the brainstem, the presence or absence of an exophytic component, and the presence of hydrocephalic or hemorrhagic features. The basis for these classification schemes is to help guide operative vs. nonoperative management of these lesions. In general, tumors with well-defined borders and focality are considered more surgically amenable, while those with diffuse, infiltrating patterns are less likely to benefit from surgery (Table 1) [3–9]. Of all pediatric brainstem tumors, diffuse intrinsic pontine gliomas (DIPGs) comprise the vast majority of cases (60–75%). Children with these infiltrating tumors often present with progressive symptoms such as weakness, ataxia and multiple cranial nerves deficits [10,11]. Prognosis is dismal with a median survival less than 12 months, and the surgical role is limited to diagnostic biopsy in some cases. Even the role for stereotactic or open biopsy in these patients has been controversial. In patients with classic DIPG diagnosed through radiographic and clinical criteria, decreased morbidity without biopsy has been shown [12]. In recent years, however, reconsideration of surgical biopsy has been

advocated by some to rule out masquerading diagnoses, obtain definitive histopathological diagnosis for clinical trial entry and/or to obtain tissue for molecular genotyping [13,14]. The mainstay of treatment of DIPG has been radiation therapy (54 Gy in daily fractions of 1.8 Gy) [15–17]. Outcomes have not shown a clear survival benefit, but improved progression-free survival and transient improvements in neurological function with radiotherapy, as well a relative lack of other therapeutic options have led to its widespread use in the treatment of DIPG. Varied radiation treatment doses have also been attempted with both hypo- and hyper-fractionated regimens demonstrating disappointing clinical responses similar to conventional strategies [18–21]. Treatment of childhood brainstem gliomas with chemotherapeutic agents has been particularly challenging given the lack of tumor-specific targets and the difficulty in delivering systemic, clinically relevant drug volumes due to limitation by the blood–brain barrier (BBB). To date, systemic administration of chemotherapeutic regimens in a variety of temporal combinations with radiotherapy have been assessed in clinical trials for patients diagnosed with brainstem gliomas [22–31]. Unfortunately, these multimodal therapeutic studies have not demonstrated a significant prolongation in survival. Therefore, treatment modalities such

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Table 2 Studies investigating delivery modalities for brainstem tumors. Author

Delivery method

Subject

Compound

Carson et al. [43] Sandberg et al. [41] Lonser et al. [61] Storm et al. [55] Occhiogrosso et al. [42] Degen et al. [44] Strege et al. [54] Wu et al. [30] Souweidane et al. [45] Souweidane et al. [64] Lonser et al. [52] Murad et al. [56] Hashizume et al. [60] Lee et al. [72] Tange et al. [59] Thomale et al. [46] Thomale et al. [52] Saito et. al. [57] Yoshimura et. [48] Anderson et al. [58] Luther et. al. [87] Sewing et. al. [49] Zhou et. al. [50]

CED CED CED CED CED CED CED CED CED CED CED CED Intranasal Human neural & mesenchymal stem cells ICI CED CED (multiple cannulas) CED CED CED CED CED CED

Rat Rat Primate Primate Rat Rat Primate Rat Rat Rat Human Primate Rat Rat Rat Rat Rat Human Rat Human Rat and Primate Mouse Mouse

Carboplatin Fluorescein isothiocyanate-dextran Gd-bound albumin Carboplatin Fluorescein isothiocyanate-dextran Carboplatin, Gemcitabine Carboplatin Carboplatin Carmustine, O6-benzylguanine IL13-PE38QQR IL13-PE38QQR, Glucocerbrosidase Gemcitabine Telemorase inhibitor GRN163 IFN-ß, CD, 5-FC Carboplatin, oxaliplatin Carboplatin Carboplatin Nimustine hydrochloride Temozolomide Topotecan Theragnostic 131 I-8H9 Carmustine Small molecule kinase inhibitors: combinations of dasatinib, everolimus, perifosine

Note: CED: convection-enhanced delivery; ICI: interstitial continuous infusion; Gd: gadolinium; IL 13-PE38QQR: IL 13 and modified pseudomonas exotoxin moiety PEA fusion protein; IFN-␤: interferon-␤; CD: cytosine deaminase; 5-FC: 5-fluorocytosine.

as convection-enhanced delivery (CED) that bypass the BBB have been investigated (Table 2). With these prior studies in mind, orthotopic xenograft murine models have been examined to improve the treatment options available for patients diagnosed with brainstem tumors. Here, we present a review of previous and ongoing pre-clinical and clinical studies focused on the local delivery of therapeutic agents for the treatment of diffuse intrinsic brainstem gliomas. 2. Brainstem tumor models In order to develop new treatment strategies, reliable experimental animal models for brainstem tumors are a necessity to simulate the human disease process. In 2002, Wu et al. described the successful stereotactic brainstem implantation of multiple cell lines, including breast carcinoma, 9L rat-derived gliosarcoma, and F98 rat-derived glioma cells, confirmed by light microscopy and MRI [32]. Jallo et al. reported an experimental tumor model in neonatal rat pups by injecting cell suspensions into the brainstem. Both F98 and 9L cell lines were injected in 82 rodent pups. After correcting for maternal elimination of pups, brainstem tumor production occurred in 80–90% of animals [33]. Although these studies provided a guide for rodent brainstem tumor generation, a more comprehensive animal model was still lacking. An ideal brainstem tumor model should have a reproducible course of paraparesis onset, a predictable pattern of tumor infiltration that mimics human brainstem tumors, the ability to be monitored radiographically, and an adequate therapeutic window for experimental intervention. With these criteria in mind, Lee et al. published a report on the development of a novel brainstem tumor model in which a cannulated guide screw system was attached to the skull of rats with subsequent stereotactic tumor cell inoculation into the pontine tegmentum [34]. In this model, all tumor-injected rats experienced a consistent progression to hemiparesis with a predictable onset of symptoms. Additionally, FDG-PET studies fused with CT scans demonstrated brainstem lesions, confirmed by histological studies. While prior models used nonhuman glioma cell lines, in 2010, Siu et al. established a novel multipotent human glioblastoma stemlike neurosphere line, 060919, and implanted those into rat

brainstem. The authors were able to successfully produce invasive, vascular lesions with confirmed histological features of human glioblastoma. The median survival of animals injected with the neurospheres (31 days) was longer than the survival of animals injected with nonhuman glioma cells (15 days), which may allow a longer therapeutic window for experimental treatments [35]. Overall, prior human xenograft brainstem tumor models have been questioned for their ability to accurately recapitulate the molecular and genetic characteristics of DIPG. Genetic studies of DIPG have shown that over 70% of tumors carry somatic mutations in the gene H3F3A, which is associated with poorer prognosis and decreased survival. Using this information, Funato et al. used human embryonic stem cells (HESCs) to induce this unique heterozygous mutation intrinsic to DIPG and study resultant tumorigenesis in a mouse model. After deriving neural progenitor cells (NPCs) from HESCs, they co-transduced the cells with lentiviruses encoding several oncogenes with a high frequency of expression and/or mutation in DIPGs. The transduced NPCs had confirmed features of neoplastic cells including a high proliferative rate, increased cell migration, and invasion. When injected into the brainstem of immunocompromised mice, transduced NPCs developed into extensive, infiltrating pontine tumors and exhibited encasement of the basilar artery, microcystic change, as well as subarachnoid and subventricular spread. Confirmed by immunohistochemistry, these characteristic histological findings of DIPG suggest that this may be a useful representative murine model for the disease [36]. Further attempts have been made to generate mouse models of brainstem gliomas. Using early postmortem human DIPG samples, a neurosphere-xenograft model was created by Monje et al. that implicated the hedgehog (Hh) pathway in the oncogenic processes associated with DIPG formation [37]. Becher et al. based on observations that platelet-derived growth factor receptor (PDGFR) was overexpressed in biopsy and autopsy specimens of brainstem gliomas, utilized the RCAS/tv-a system to overexpress PDGF in nestin-positive cells lining the fourth ventricle. This produced lowgrade brainstem gliomas, which demonstrated high-grade features when crossed with Ink4A-ARF-null mice. Thus, a murine model was generated in which preclinical testing could be utilized with possible characteristics classically found in human brainstem gliomas.

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Fig. 1. Radiograph of a rat after placement of a cannula into the brainstem.

This model assumes, however, that nestin-expressing ependymal cells from the fourth ventricular are the main cells of origin for these tumors [38]. Recently, Aoki et al. demonstrated an experimental murine DIPG model through orthotopic implantation of human glioma cells lines GS2 and AM-38 into athymic mice [39]. Cell lines were transduced with a luciferase-encoding vector, allowing for bioluminescence imaging of implanted tumor cells. The authors examined response to therapy in implanted mice who received temozolomide treatment, or no treatment, and demonstrated a decrease in tumor burden within murine pons. With this technique, the authors demonstrate a unique, reproducible murine model for humanxenografted brainstem tumors in which treatment effect can be quantified. One caveat to this model’s use, however, is that the cell line of choice recapitulates high-grade adult human glioma, rather than pediatric DIPG. Further applications of this model using DIPG cell line implantation could be of utility in preclinical DIPG investigations.

3. Small molecule delivery 3.1. Convection-enhanced delivery Convection-enhanced delivery (CED) utilizes the properties of bulk flow to achieve clinically relevant, homogeneously distributed infusions within brain parenchyma [40]. Held under a low positive pressure gradient, stereotactically guided cannula placement allows for the delivery of molecules of a wide range of sizes to various areas of the CNS, thus bypassing the BBB [41] (Fig. 1). By directly bypassing the BBB, local drug concentrations are several orders of magnitude higher than can be achieved via systemic administration. The distribution also occurs preferentially along white matter tracts, similar to patterns of glioma cell invasion [42,43]. These features make CED an ideal method in the investigation of drug delivery for pediatric brainstem gliomas. Iterations of improvement in the properties of inner cannula catheters and outer guide catheters have led to the successful utility of CED for many CNS applications. Studies have demonstrated that high infusion rates into normal brain may increase intracranial pressure and disrupt normal tissue architecture, which has led to the utilization of slow infusion rates [44,45]. In addition, studies have compared flexible and rigid cannulas to overcome backflow leakage along the cannulas in brain parenchyma [46,47]. Advances in cannulae distal ends have led to minimal parenchymal trauma. Additionally, the use of inner and outer step-cannulae have minimized back-flow along the catheter tract [48,49] CED models are

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still under active investigation as a potential treatment modality for brainstem gliomas [32]. An initial study was conducted in 2002 to evaluate the safety and distribution parameters of CED within the rat pons under stereotactic guidance with no postoperative neurologic deficits [50]. A second group underwent the same operation but had fluorescein isothiocyanate-dextran infused through the cannulas, which showed that the volumes of infusion correlated with the volumes of distribution in the rat brainstem. Sandberg et al. demonstrated that CED could be safely applied to the rat brainstem and chronic brainstem infusions may enhance the potential application of this modality in the treatment of diffuse brainstem gliomas [51]. Feasibility studies have shown that chemotherapeutic compounds and small molecule kinase inhibitors can be safely delivered using CED within rodent brainstem [52–59]. Degen et al. investigated the safety and efficacy of CED of carboplatin and gemcitabine at therapeutic concentrations, into the brainstems of rats without associated toxicity [53]. Rats containing tumors implanted in the brainstem experienced a significant prolongation in survival when treated with intratumoral CED of either drug in comparison to intratumoral saline and systemic chemotherapy. Mini-osmotic pumps and intratumoral delivery of carboplatin to brainstem tumors in rats also demonstrated a significantly prolonged survival compared to control rats [55,56]. The Berlin-Baltimore brainstem neurological grading scale correlated with survival. Kroin and Penn demonstrated that inoperable CNS tumors with diameter sizes of ∼2 cm warrant multiple cannula systems for sufficient local therapy, and distribution studies with CED demonstrate that carboplatin can reach therapeutic levels in the brainstem up to 4 mm around the tip of the cannula, which would be insufficient for larger tumors [52,60]. Thus, a study was conducted to assess the feasibility of multiple cannula placement in the rat brainstem, and it was shown that the unilateral application of up to three cannulas in the brainstem of rats was both safe and feasible with a more homogenous drug distribution [61]. Souweidane et al. evaluated the clinical tolerance of the interstitial infusion of carmustine into the rat brainstem in combination with the systemic administration of O6-benzylguanine, an O(6)-alkylguanine DNA alkyltransferase inhibitor (blocks the DNA repair proteins O(6)-alkylguanine DNA alkyltransferase that confer resistance to O(6)-alkylating agents) [54,62]. They were able to demonstrate that this treatment combination is safe in rats as there were no detrimental neurological changes. A few studies have shown that cannulas can be safely and feasibly placed in the brainstem of primates and the infusion of carboplatin results in a demonstrable dose-dependent toxicity [63,64]. Murad et al. studied the CED of gemcitabine and Gadoliniumdiethylenetriamine, to track the distribution of gemcitabine by MRI in the primate brainstem and demonstrate that gemcitabine can be delivered safely at therapeutic concentrations [65]. Finally, CED of small molecule therapeutic agents has recently been demonstrated in humans. In 2011, Saito et al. reported the use of nimustine hydrochloride and CED in a 13-year-old boy with a recurrence of glioblastoma in the right cerebellum despite surgical resection, systemic chemotherapy, and radiotherapy. An infusion cannula was inserted via the left frontal lobe with stereotactic assistance and nimustine hydrochloride was infused over 2.5 days at a rate of 1.0–4.0 ␮L/min. Simultaneously, the patient received 200 mg/m2 /day of oral temozolomide for five days as well as IV dexamethasone. Although the patient developed short-term mild hemiparesis after termination of the infusion, he recovered fully in a week and MR imaging revealed shrinkage of the brainstem lesion [66]. In another pilot feasibility study by Anderson et al. two pediatric patients were treated with CED of topotecan. They found that a total volume of infusion greater than 2.7 mL with flow rates greater than 0.12 mL/h led to new neurological deficits, which improved with lower flow rates. Serial MRI demonstrated an initial

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reduction in tumor size, although this treatment ultimately did not prolong survival in either patient [67]. Further studies are needed to determine the optimal flow rates to maximize safety and efficacy in patients. 3.1.1. Biologic compounds Lonser et al. investigated the safety of locally infused Gadolinium(Gd)-bound albumin via stereotactically implanted cannulas into large areas of the primate pons [68]. Infusate volume, homogeneity, and anatomical distribution were visualized and quantified using MRI. The study demonstrated that the primate brainstem could be perfused safely with macromolecules and that a large molecular weight imaging tracer can be used to deliver, monitor in vivo, and control the distribution of small- and largemolecular-weight therapeutic agents in the brainstem. Two patients were reported to have undergone the frameless stereotactic placement of cannulas into the brainstem for CED [69]. One patient had a diffuse pontine glioma that was diagnosed 10 months earlier, and underwent an infusion of the recombinant cytotoxin IL13-PE38QQR with GD-diethylenetriamine for tracking of the tissue distribution. Tumor progression was seen after eight weeks. The second patient had progressive Gaucher’s disease and received glucocerebrosidase with Gd-diethylenetriamine. This report documented the feasibility of CED delivery of biologic therapeutics for patients with intrinsic brainstem lesions, but further rigorous and long-term studies are needed to assess its efficacy. Real-time CED imaging and tracking is of key importance when infusing therapeutic compounds to the brainstem. Chittiboina et al. demonstrated the ability to surrogately track therapeutic drug delivery with real-time MR imaging with Gd-DTPA coinfusate [70]. Important technical notes were reported in this study, including the entrainment of air within the inner cannula upon stylet removal, thus impeding infusate distribution beyond the area of pneumocephalus and prompting further infusions to be performed with primed catheters. Additionally, multiple catheter tracts and re-infusion led to infusate patterns down old catheter tracts. Finally, greater than 10 ␮L/min infusion rates were associated with catheter leak back. Importantly, these studies in humans demonstrate the ability to bypass the BBB and deliver clinically relevant volumes of distribution of therapeutic compounds to brainstem gliomas. 3.2. Intranasal delivery The nasal passages have been investigated as a mode of drug delivery to the brain that bypasses the BBB and is noninvasive. Daily intranasal administration of fluorescein-labeled GRN163, a telomerase inhibitor has been studied in rats harboring intracerebral human tumor xenografts and demonstrated 75.5 day and 35 day survival in the treatment and control groups, respectively [71]. Histopathologic examination of the brains demonstrated selective killing of tumor cells with no significant toxicity shown in normal brain tissue. Further studies investigating the utility of intranasal drug delivery in the rodent brainstem model are needed to determine whether this delivery strategy provides a viable alternative to intravenous injection and/or CED. 3.2.1. Biologic compounds While no study has directly measured the efficacy of biologic agents in a brainstem glioma model, a number of high molecular weight therapeutics have been successfully delivered to the brainstem via intranasal delivery [72,73]. Currently, proteins are hypothesized to traverse the BBB intranasally via two mechanisms—a slow intraneuronal route, or a fast extraneuronal pathway. The extraneuronal pathway involves drug trafficking across the nasal olfactory epithelium, followed by passage within

perineural/lymphatic channels or through perivascular spaces directly into the brain parenchyma and the cerebrospinal fluid. Intranasal delivery of a variety of biologics have been demonstrated to be effective in multiple disease models, including nerve degeneration, memory loss, and allergic encephalomyelitis [74–77]. Furrer et al. described the delivery of ESBA105, a TNF-alpha inhibitory single-chain antibody fragment (26.3 kDa) to the brain [78]. Pharmacokinetic parameters such as drug concentration were determined for the olfactory bulb, cerebrum, cerebellum, brain stem, and for serum, following both intranasal and intravenous administrations of 400 ␮g and 40 ␮g drug, respectively. Between one and two hours post-administration, the maximum drug concentration in the brain was 1.1–12.2 ␮g/mg of total protein. A second peak was observed after 8 h (cerebellum), 10 h (brainstem) and 12 h (olfactory bulb), reflecting the slower intraneuronal route of drug delivery. Although a 10-fold higher dose was given intranasally, systemic peripheral exposure was about 33-fold lower in the intranasal delivery group. Preliminary data available suggests that intranasal delivery of biologic compounds could be a potential treatment modality for brainstem gliomas. 3.3. Human neural and mesenchymal stem cells Recently, Lee et al. demonstrated the potential utilization of stem cells for the targeting of brainstem gliomas with therapeutic agents [79]. Human neural stem cells, derived from the human fetal ventricular zone, and various human mesenchymal stem cells were used to compare their respective tumor-tropic migratory capacities toward and therapeutic potential against F98 glioma cells with a human fibroblast cell line as a control. The migratory capacities were assessed in vitro and in an established in vivo rat brainstem glioma model (stem cells injected into the right forebrain) and 29.7% of neural stem cells and 20–29% of mesenschymal stem cells migrated from the right forebrain to the brainstem glioma cells. Using an in vivo rat brainstem glioma model, neural stem cells containing a fusion gene (cytosine deaminase (CD) and interferon-␤ proinflammatory cytokine (IFN-␤)) injected intratumorally followed by systemic administration of 5-FC resulted in a 59.1% reduction in size of the tumor in comparison to controltreated animals in their model. This initial study showed promise for the potential use of neural stem cells in the fight against brainstem gliomas but further studies are needed. 3.4. Immunotherapy Another promising and evolving avenue of research involves the administration of immunotherapy agents targeted to neoplastic cells. The identification and cloning of genes which encode various cytokines, coupled with a polymer-based local delivery system provided another strategy to treat malignant brain tumors [80–82]. Immunotherapy uses white blood cell secreted or exogenously administered cytokines such as interleukins, interferons and colony stimulating factors to activate the host’s immune system. Cytokines exert their immunomodulatory activity in a paracrine fashion producing a strong local inflammatory response specific to each cytokine in the area directly adjacent to potential neoplastic antigens recruiting active effector cells and inducing long-term immune memory [83]. To generate an appropriate immune response, foreign antigen must be presented to lymphocytes in the presence of a co-stimulatory molecule such as a cytokine. The paracrine physiology of cytokines can alter the immunologic environment enhancing antigen presentation and activating specific lymphocytes. Thus, high local concentrations of cytokines delivered through polymer-based systems could activate the immune response to produce a localized attack on tumor cells.

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Local delivery of IL-2 has been studied and shown to have multiple effects on the treatment of malignant neoplasms—although not in brainstem specific lesions. Other immunotherapeutic agents, such as interferon, IL-12, and anti-glioma monoclonal antibody, have shown potential benefit in the treatment of malignant neoplasms and provide novel strategies yet to be investigated for brainstem gliomas. Luther et al. developed an anti-glioma monoclonal antibody, 8H9, conjugated to radioactive iodine (124 I or 131 I) to serve as a “theragnostic” agent delivered via CED to the pons in rats and primates. In this study, only one out of fifteen rats experienced toxicity and toxicity was not seen in any primates during the infusion, demonstrating feasibility and safety of theragnostic 124 I8H9 via CED for DIPG [84]. Currently, there is an ongoing Phase I clinical trial investigating the use of CED to deliver 124I-8H9, a monoclonal antibody, in patients with DIPG (NCT01502917) [85]. A recent pilot study investigated the use of subcutaneous vaccinations with glioma-associated antigen epitope peptides (EphA2, IL-13Ra3 and surviving) in HLA-A2 positive children with newly diagnosed DIPG and other high-grade gliomas [86,87]. The patients tolerated the vaccine with no dose-limiting CNS toxicity, with encouraging preliminary results. However, symptomatic pseudoprogression was present in a significant minority of patients. These studies provide avenues for further research, especially in light of a recent study assessing various pediatric brain tumors, which revealed distinct immunological signatures that may be potential therapeutic targets [85,88]. Ultimately, the use of immunotherapy in the treatment of patients with DIPG will require extensive experimental investigation. 3.5. Other therapeutic agents Malignant tumors can be characterized by a lack of apoptosis, angiogenesis, and uncontrolled cellular proliferation, which can all serve as potential targets for therapeutic agents. With advances in molecular engineering, retroviruses and virus-based immunotherapies may be used to locally deliver a variety of therapeutics. The development of small interfering RNA allows for the inhibition of the expression of specific genes. With the evolution of this technology, identification of genes involved in the pathogenesis of brainstem tumors may someday be used to target and optimally delivery these agents to treat diffuse brainstem tumors. 4. Conclusion Diffuse brainstem tumors continue to pose a formidable challenge to healthcare providers, and the prognosis continues to remain dismal because of the limited treatment options currently available. The complex neuroanatomic structure and location of the brainstem, along with the BBB, adds to the difficulty of experimentally investigating new therapeutic options. Laboratories have been intensively investigating local intracranial delivery methods, particularly CED, for the administration of therapeutic compounds at the tumor site in rodent models, in which CED via cannulas has been shown to be safe and feasible. CED of therapeutic agents for brainstem tumors is a process in evolution, and a reliable primate brainstem tumor model is in need of development, although cannula placement into the primate brainstem has been demonstrated to be safe and feasible. When CED has been optimized, the problem of finding an efficacious compound for brainstem gliomas will likely continue to be an area of intense research. Furthermore, other delivery modalities are being investigated, such as interstitial continuous infusion therapy, a modified version of CED, neural stem cells, and the intranasal delivery of CNS tumor-specific compounds. The experimental work reviewed in this report demonstrates the promising investigations that have been and continue to be

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undertaken in an attempt to discover an optimal local delivery method of therapeutic agents for brainstem tumors. Further experimental studies are necessary and the previously published reports have provided an initial platform for the launching of new ideas.

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