Superselective intraarterial cerebral infusion of cetuximab after osmotic blood/brain barrier disruption for recurrent malignant glioma: phase I study

Chakraborty, Shamik; Filippi, Christopher G.; Wong, Tamika; Ray, Ashley; Fralin, Sherese; Tsiouris, Apostolos John; Praminick, Bidyut; Demopoulos, Alexis; McCrea, Heather J.; Bodhinayake, Imithri; Ortiz, Rafael; Langer, David; Boockvar, John A.

doi:10.1007/s11060-016-2099-8

Cited by 75 publications

(66 citation statements)

References 28 publications

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“…Preclinical analyses indicate that following EGFR vIII binding cetuximab induces receptor internalization, resulting in 50% reduction of its active form [197]. Nevertheless, there is a lack of clinical studies evaluating the impact of cetuximab monotherapy on patients with primary glioblastoma [198,199]. When tested in vitro on GB cell lines with EGFR overexpression or using in vivo GB models, cetuximab leads to decrease in proliferation rate and enhancement of apoptosis.…”

Section: Immunotherapy In Egfr VIII -Positive Tumorsmentioning

confidence: 99%

EGFR^vIII: An Oncogene with Ambiguous Role

Rutkowska

Stoczyńska-Fidelus

Janik

et al. 2019

Journal of Oncology

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Epidermal growth factor receptor variant III (EGFRvIII) seems to constitute the perfect therapeutic target for glioblastoma (GB), as it is specifically present on up to 28–30% of GB cells. In case of other tumor types, expression and possible role of this oncogene still remain controversial. In spite of EGFRvIII mechanism of action being crucial for the design of small active anticancer molecules and immunotherapies, i.e., CAR-T technology, it is yet to be precisely defined. EGFRvIII is known to be resistant to degradation, but it is still unclear whether it heterodimerizes with EGF-activated wild-type EGFR (EGFRWT) or homodimerizes (including covalent homodimerization). Constitutive kinase activity of this mutated receptor is relatively low, and some researchers even claim that a nuclear, but not a membrane function, is crucial for its activity. Based on the analyses of recurrent tumors that are often lacking EGFRvIII expression despite its initial presence in corresponding primary foci, this oncogene is suggested to play a marginal role during later stages of carcinogenesis, while even in primary tumors EGFRvIII expression is detected only in a small percentage of tumor cells, undermining the rationality of EGFRvIII-targeting therapies. On the other hand, EGFRvIII-positive cells are resistant to apoptosis, more invasive, and characterized with enhanced proliferation rate. Moreover, expression of this oncogenic receptor was also postulated to be a marker of cancer stem cells. Opinions regarding the role that EGFRvIII plays in tumorigenesis and for tumor aggressiveness are clearly contradictory and, therefore, it is crucial not only to determine its mechanism of action, but also to unambiguously define its role at early and advanced cancer stages.

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Section: Immunotherapy In Egfr VIII -Positive Tumorsmentioning

confidence: 99%

EGFR^vIII: An Oncogene with Ambiguous Role

Rutkowska

Stoczyńska-Fidelus

Janik

et al. 2019

Journal of Oncology

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“…The first and most important is maintenance of sustained levels of low barrier permeability similar to those observed in human brain for more than 2 weeks in vitro. We also showed that the BBB Chip can be used to study reversible opening of the BBB using hypertonic solutions in vitro, as is done in vivo; this technique may be used to develop improved therapeutic delivery strategies in the future, as demonstrated here by delivery of an FDA approved therapeutic antibody, mimicking a clinically relevant drug delivery strategy 61 .…”

Section: Discussionmentioning

confidence: 86%

“…4b). To our knowledge, this is the first demonstration of delivery of a clinically approved antibody drug by reversible osmotic opening of the human BBB in vitro, which mimics responses seen in human patients [61][62][63] .…”

Section: Reversible Osmotic Opening Of the Human Bbb On-chipmentioning

confidence: 96%

“…Hyperosmolar agents, such as high concentration mannitol solutions, are used clinically to overcome the BBB permeability limitation in order to increase delivery of drugs to the brain 60,61 . Intravenous infusion of a mannitol solution induces reversible opening of pores within the BBB with a radius of about 200Å in animals 60,62 and humans 62,63 , and this recovers due to bulk fluid flow from the blood to the brain 63 .…”

Section: Reversible Osmotic Opening Of the Human Bbb On-chipmentioning

confidence: 99%

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Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function, drug penetration, and antibody shuttling properties

Mustafaoğlu

Herland

Hasselkus

et al. 2018

Preprint

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The highly specialized human brain microvascular endothelium forms a selective blood-brain barrier (BBB) with adjacent pericytes and astrocytes that restricts delivery of many pharmaceuticals and therapeutic antibodies to the central nervous system. Here, we describe an in vitro microfluidic 'organ-on-achip' (Organ Chip) model of the BBB lined by induced pluripotent stem cellderived human brain microvascular endothelium (iPS-BMVEC) interfaced with primary human brain astrocytes and pericytes that recapitulates the high level of barrier function of the in vivo human BBB for at least one week in culture. The endothelium expresses high levels of tight junction proteins, multiple functional efflux pumps, and displays selective transcytosis of peptides and anti-transferrin receptor antibodies previously observed in vivo. This increased level of barrier functionality was accomplished using a developmentally-inspired induction protocol that includes a period of differentiation under hypoxic conditions. This enhanced BBB Chip may therefore represent a new in vitro tool for development and validation of delivery systems that transport drugs and therapeutic antibodies across the human BBB.The human blood-brain barrier (BBB) is a unique and selective physiological barrier that controls transport between the blood and the central nervous system (CNS) to maintain homeostasis for optimal brain function. The BBB is composed of brain microvascular endothelial cells (BMVECs) that line the capillaries as well as surrounding extracellular matrix (ECM), pericytes, and astrocytes, which create a microenvironment that is crucial to BBB function 1 . The brain microvascular endothelium differs from that found in peripheral capillaries based on its complex tight junctions, which restrict 3 paracellular transit and instead, require that transcytosis be used to transport molecules from the blood through the endothelium and into the CNS 2 . BMVECs also express multiple broad-spectrum efflux pumps on their luminal surface that inhibit uptake of lipophilic molecules, including many drugs, into the brain 3,4 . The astrocytes and pericytes provide signals that are required for differentiation of the BMVECs 5,6 , and all three cell types are needed to maintain BBB integrity in vivo as well as in vitro 7-9 . The BBB is also of major clinical relevance because dysfunction of the BBB associated is observed in many neurological diseases, and the efficacy of drugs designed to treat neurological disorders is often limited by their inability to cross the BBB 10 . Unfortunately, neither animal models of the BBB nor in vitro cultures of primary or immortalized human BMVECs alone effectively mimic the barrier and transporter functions of the BBB observed in humans [11][12][13][14] . Thus, there is a great need for a human BBB model that could be used to develop new and more effective CNS-targeting therapeutics and delivery technologies as well as advance fundamental and translational research 8,9 .

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“…One potential hypothesis for the failure of mAbs and other proteins as therapeutics for the treatment of AD is their inefficiency in crossing the blood-brain barrier (BBB) to have a sufficient dose to exude their efficacies. Several efforts to improve delivery of mAbs and other proteins into the brain such as osmotic BBB disruption (BBBD), [19][20][21] "Trojan Horse" delivery method, 22 and ultrasound with microbubbles 23,24 have exhibited various levels of success. Our approach is to use cadherin peptides as BBB modulators (BBBM) to improve the delivery of molecules into the brain.…”

Section: Introduction and Epidemiologymentioning

confidence: 99%

Non-invasive Brain Delivery and Efficacy of BDNF in APP/PS1 Transgenic Mice

Kopec

Zhao

Rosa‐Molinar

et al. 2020

MRAJ

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Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) have been demonstrated for their potential as a neuroregenerative treatment of Alzheimer's disease (AD). Unfortunately, most proteins cannot be effectively delivered into the brain from the blood stream due to the presence of the blood-brain barrier (BBB). In this study, we delivered BDNF using ADTC5 as BBB modulator (BBBM) into the brains of transgenic APP/PS1 mice, a mouse model for AD. As controls, two groups of APP/PS1 mice were treated with BDNF alone and vehicle, respectively. All three groups were subjected to behavioral/cognitive assessments in Y-maze and novel object recognition (NOR) tests as well as evaluation of the brain markers activated by BDNF. The results showed that BDNF + ADTC5 group performed significantly better in both the Y-maze and NOR assessments compared to mice that received BDNF alone or vehicle. In addition, significant upregulations of NG2 receptors as well as EGR1 and ARC mRNA transcripts were observed in the brain cortex of mice treated with BDNF + ADTC5, further indicating the efficacy of delivered BDNF in the brain. There were high plaque loads in all groups of mice, suggesting no influence of BDNF on the plaque formation. In summary, ADTC5 can deliver BDNF into the brains of APP/ PS1 mice and the activity of BDNF in improving cognitive function was likely due to improvement in synaptic plasticity via NG2 glia cells and not by reducing the plaque load.

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Superselective intraarterial cerebral infusion of cetuximab after osmotic blood/brain barrier disruption for recurrent malignant glioma: phase I study

Cited by 75 publications

References 28 publications

EGFR^vIII: An Oncogene with Ambiguous Role

EGFR^vIII: An Oncogene with Ambiguous Role

Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function, drug penetration, and antibody shuttling properties

Non-invasive Brain Delivery and Efficacy of BDNF in APP/PS1 Transgenic Mice

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Superselective intraarterial cerebral infusion of cetuximab after osmotic blood/brain barrier disruption for recurrent malignant glioma: phase I study

Cited by 75 publications

References 28 publications

EGFRvIII: An Oncogene with Ambiguous Role

EGFRvIII: An Oncogene with Ambiguous Role

Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function, drug penetration, and antibody shuttling properties

Non-invasive Brain Delivery and Efficacy of BDNF in APP/PS1 Transgenic Mice

Contact Info

Product

Resources

About

EGFR^vIII: An Oncogene with Ambiguous Role

EGFR^vIII: An Oncogene with Ambiguous Role