Single-chain antibodies: A therapeutic modality for cancer gene therapy (Review)

Efficient and Selective Gene Transfer into Primary Human Brain Tumors by Using Single-Chain Antibody-Targeted Adenoviral Vectors with Native Tropism Abolished

Journal of Virology ◽

10.1128/jvi.76.6.2753-2762.2002 ◽

2002 ◽

Vol 76 (6) ◽

pp. 2753-2762 ◽

Cited By ~ 56

Author(s):

Victor W. van Beusechem ◽

Jacques Grill ◽

D. C. Jeroen Mastenbroek ◽

Thomas J. Wickham ◽

Peter W. Roelvink ◽

...

Keyword(s):

Gene Therapy ◽

Gene Transfer ◽

Brain Tumors ◽

Human Brain ◽

Cancer Gene Therapy ◽

Adenoviral Vectors ◽

Receptor Expression ◽

Normal Brain ◽

Cancer Gene ◽

Single Chain

ABSTRACT The application of adenoviral vectors in cancer gene therapy is hampered by low receptor expression on tumor cells and high receptor expression on normal epithelial cells. Targeting adenoviral vectors toward tumor cells may improve cancer gene therapy procedures by providing augmented tumor transduction and decreased toxicity to normal tissues. Targeting requires both the complete abolition of native tropism and the addition of a new specific binding ligand onto the viral capsid. Here we accomplished this by using doubly ablated adenoviral vectors, lacking coxsackievirus-adenovirus receptor and αv integrin binding capacities, together with bispecific single-chain antibodies targeted toward human epidermal growth factor receptor (EGFR) or the epithelial cell adhesion molecule. These vectors efficiently and selectively targeted both alternative receptors on the surface of human cancer cells. Targeted doubly ablated adenoviral vectors were also very efficient and specific with primary human tumor specimens. With primary glioma cell cultures, EGFR targeting augmented the median gene transfer efficiency of doubly ablated adenoviral vectors 123-fold. Moreover, EGFR-targeted doubly ablated vectors were selective for human brain tumors versus the surrounding normal brain tissue. They transduced organotypic glioma and meningioma spheroids with efficiencies similar to those of native adenoviral vectors, while exhibiting greater-than-10-fold-reduced background levels on normal brain explants from the same patients. As a result, EGFR-targeted doubly ablated adenoviral vectors had a 5- to 38-fold-improved tumor-to-normal brain targeting index compared to native vectors. Hence, single-chain targeted doubly ablated adenoviral vectors are promising tools for cancer gene therapy. They should provide an improved therapeutic index with efficient tumor transduction and effective protection of normal tissue.

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Virotherapy: cancer gene therapy at last?

F1000Research ◽

10.12688/f1000research.8211.1 ◽

2016 ◽

Vol 5 ◽

pp. 2105 ◽

Cited By ~ 9

Author(s):

Alan E. Bilsland ◽

Pavlina Spiliopoulou ◽

T. R. Jeffry Evans

Keyword(s):

Gene Therapy ◽

Cancer Gene Therapy ◽

Phase Iii ◽

Therapeutic Modality ◽

Cancer Gene ◽

Pivotal Phase ◽

Phase Iii Trial ◽

New Class ◽

Anti Cancer ◽

Advanced Generation

For decades, effective cancer gene therapy has been a tantalising prospect; for a therapeutic modality potentially able to elicit highly effective and selective responses, definitive efficacy outcomes have often seemed out of reach. However, steady progress in vector development and accumulated experience from previous clinical studies has finally led the field to its first licensed therapy. Following a pivotal phase III trial, Imlygic (talimogene laherparepvec/T-Vec) received US approval as a treatment for cutaneous and subcutaneous melanoma in October 2015, followed several weeks later by its European authorisation. These represent the first approvals for an oncolytic virotherapy. Imlygic is an advanced-generation herpesvirus-based vector optimised for oncolytic and immunomodulatory activities. Many other oncolytic agents currently remain in development, providing hope that current success will be followed by other diverse vectors that may ultimately come to constitute a new class of clinical anti-cancer agents. In this review, we discuss some of the key oncolytic viral agents developed in the adenovirus and herpesvirus classes, and the prospects for further enhancing their efficacy by combining them with novel immunotherapeutic approaches.

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Cancer Gene Therapy

Technology in Cancer Research & Treatment ◽

10.1177/153303460500400402 ◽

2005 ◽

Vol 4 (4) ◽

pp. 315-330 ◽

Cited By ~ 23

Author(s):

Masato Yamamoto ◽

David T. Curiel

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Continuous Infusion ◽

Cancer Gene Therapy ◽

Therapeutic Modality ◽

Current Status ◽

Cancer Gene ◽

Gastrointestinal Cancers ◽

Delivery Method ◽

Promising Strategy

The prognosis of patients with some kinds of cancers whose patients are often found unresectable upon diagnosis is still dismal. In these fields, development of a new therapeutic modality is needed and gene therapy represents one promising strategy. So far, numerous cancer gene therapy clinical trials based on these principles have been carried out and have shown the safety of such modalities, but have fallen short of the initial expectations to cure cancers. In this review, we would like to make a problem-oriented discussion of current status of cancer gene therapy research by using mainly gastrointestinal cancers as an example. In order to overcome obstacles for full realization of cancer gene therapy, numerous researches have been conducted by many researchers. Various cancer-selective and non-selective genes, as well as lytic viruses themselves have been employed for gene therapy. In the context of gene delivery method, different kinds of viral and non-viral strategies have been utilized. In addition, surrogate assays, such as soluble markers and imaging, have been developed for safer and more informative clinical trials. Many experiments and clinical trials to date have figured out current obstacles for the realization of an effective cancer gene therapy modality. Tireless efforts to overcome such hurdles and continuous infusion of novel concepts into this field should lead to break through technologies and the cure of the patients.

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