Successful intracranial delivery of trastuzumab by gene-therapy for treatment of HER2-positive breast cancer brain metastases

Zafir-Lavie, Inbal; Sherbo, Shay; Goltsman, Haim; Badinter, Felix; Yeini, Eilam; Ofek, Paula; Miari, Reem; Tal, Osnat; Liran, Atar; Shatil, Tamar; Krispel, Simi; Shapir, Nir; Neil, Garry A.; Benhar, Itai; Panet, Amos; Satchi‐Fainaro, Ronit

doi:10.1016/j.jconrel.2018.10.017

Cited by 30 publications

(29 citation statements)

References 54 publications

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“…Yet, for solid cancers, the vectors can be directly injected into tumors to enhance their efficacy locally [28]. For instance, intracranial delivery was efficient to treat breast cancer brain metastases [29,30]. Furthermore, oncolytic viruses that have tropism toward tumors and that exhibit a lytic effect against tumor cells can also be suitably engineered to both deliver transgenes in restricted locations and concomitantly exploit their antitumoral properties.…”

Section: General Notions Of Vector Designmentioning

confidence: 99%

Towards Physiologically and Tightly Regulated Vectored Antibody Therapies

Page

Fusil

Cosset

2020

Cancers

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Cancers represent highly significant health issues and the options for their treatment are often not efficient to cure the disease. Immunotherapy strategies have been developed to modulate the patient’s immune system in order to eradicate cancerous cells. For instance, passive immunization consists in the administration at high doses of exogenously produced monoclonal antibodies directed either against tumor antigen or against immune checkpoint inhibitors. Its main advantage is that it provides immediate immunity, though during a relatively short period, which consequently requires frequent injections. To circumvent this limitation, several approaches, reviewed here, have emerged to induce in vivo antibody secretion at physiological doses. Gene delivery vectors, such as adenoviral vectors or adeno-associated vectors, have been designed to induce antibody secretion in vivo after in situ cell modification, and have driven significant improvements in several cancer models. However, anti-idiotypic antibodies and escape mutants have been detected, probably because of both the continuous expression of antibodies and their expression by unspecialized cell types. To overcome these hurdles, adoptive transfer of genetically modified B cells that secrete antibodies either constitutively or in a regulated manner have been developed by ex vivo transgene insertion with viral vectors. Recently, with the emergence of gene editing technologies, the endogenous B cell receptor loci of B cells have been modified with the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated endonuclease (Cas-9) system to change their specificity in order to target a given antigen. The expression of the modified BCR gene hence follows the endogenous regulation mechanisms, which may prevent or at least reduce side effects. Although these approaches seem promising for cancer treatments, major questions, such as the persistence and the re-activation potential of these engineered cells, remain to be addressed in clinically relevant animal models before translation to humans.

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Section: General Notions Of Vector Designmentioning

confidence: 99%

Towards Physiologically and Tightly Regulated Vectored Antibody Therapies

Page

Fusil

Cosset

2020

Cancers

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“…effectively diffuse through the surrounding extracellular space to reach the brain parenchyma. Current brain delivery strategies about BBB transport mainly focus on transiently opening the BBB using focused ultrasound 94 and hyperosmotic agents 95 , on bypassing the barriers through local delivery 96 , or receptor-mediated transport. These studies address either transport across the BBB or circumventing the BBB to study diffusive transport through the ECS.…”

Section: L O N E S ( P E P T I D E P R E S E N T I N G M 1 3 K E P mentioning

confidence: 99%

Brain-Penetrating Peptide Shuttles Across the Blood-Brain Barrier and Extracellular-like Space

Peng¹,

Liu²,

Liu³

et al. 2019

Preprint

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Here, we describe a combinatorial approach to identify peptide shuttles that successfully traverse the multiple barriers to systemic drug delivery to the brain--1. the blood-brain barrier (BBB) and the 2. extracellular space (ECS) of the brain. Leveraging the excellent molecular diversity of M13 phage libraries, we identified peptides that actively transport across the BBB and diffuse through the extracellular matrix of the ECS in cell culture and in mice. These peptides demonstrate higher accumulation in the brain than gold standard peptides used in clinical trials. Importantly, these findings suggest that different sized therapeutics that were previous poorly permeable into the brain can accumulate at higher concentrations, thereby improving the therapeutic index and ultimate efficacy of drugs into the brain.

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“…Current brain delivery strategies about BBB transport mainly focus on transiently opening the BBB using focused ultrasound 94 and hyperosmotic agents 95 , on bypassing the barriers through local delivery 96 , or receptor-mediated transport. These studies address either transport across the BBB or circumventing the BBB to study diffusive transport through the ECS.…”

Section: L O N E S ( P E P T I D E P R E S E N T I N G M 1 3 K E P mentioning

confidence: 99%

Brain-Penetrating Peptide Shuttles Across the Blood-Brain Barrier and Extracellular-like Space

Peng¹,

Liu²,

Liu³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

Successful intracranial delivery of trastuzumab by gene-therapy for treatment of HER2-positive breast cancer brain metastases

Cited by 30 publications

References 54 publications

Towards Physiologically and Tightly Regulated Vectored Antibody Therapies

Towards Physiologically and Tightly Regulated Vectored Antibody Therapies

Brain-Penetrating Peptide Shuttles Across the Blood-Brain Barrier and Extracellular-like Space

Brain-Penetrating Peptide Shuttles Across the Blood-Brain Barrier and Extracellular-like Space

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