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Topic: Neuroimmunology and Cancer

Targeting glioblastoma with oncolytic adenovirus

delta 24

Konstantinos I. Tsamis, George A. Alexiou, Athanassios P. Kyritsis
Department of Neurology, Medical School, University of Ioannina, 45500 Ioannina, Greece.

ONCOLYTIC VIRUSES the modulation of vessel permeability for viruses and
[8]
degradation of extracellular matrix. [12]
Oncolytic viruses have been introduced in cancer
treatment in the last two decades, offering new DEVELOPMENT OF ONCOLYTIC ADENOVIRUS
opportunities and hopes for ultimate therapy. Earlier DELTA 24
studies had also tried to take advantage of the
antineoplastic activity of natural viral species, but Among tens or even hundreds of different viruses that
it was genetic engineering that led to the production have been used to produce oncolytic viral vectors with
of modified viral strains selectively infecting and different genetic manipulations, oncolytic adenovirus
[1]
killing neoplastic cells. The two major characteristics delta 24 (Ad-Δ24) stands out due to its high specificity
of oncolytic viruses are their tropism for malignant and toxicity for malignant cells accomplished with
cells and their augmented cytotoxicity. The strategies simple genetic engineering. Ad-Δ24 is a mutant
employed to achieve oncotropism involve mainly replication-competent adenovirus containing a 24 base
genetic manipulation of viral vectors in order to pair deletion in early region 1A gene (E1A), expressing
either turn them against cells expressing specific a mutant E1A protein which cannot form complex with
surface markers or make them capable to multiply the retinoblastoma protein (Rb). [13,14] Thus Ad-Δ24,
only using the machinery of malignant cells. Despite unlike wild-type adenovirus, is unable to force the
[2]
the capability of specifically targeting neoplastic progression of infected normal cells in S phase that
cells, oncolytic viruses are, usually, not capable to is required for its replication. On the other hand, the
completely demise all malignant cells neither in vivo mutant virus can replicate in cells with disrupted Rb
nor in vitro. [3-5] This inherent limitation of oncolytic cell cycle control, like glioma cells. [15] In 2000, the
viruses is caused principally by restrictions in viral production of Ad-Δ24 was described for the first time
infection due to differential expression of surface viral along with a detailed description of its cytopathic effect
[6]
receptors on different types of malignant cells, by on different glioma cell-lines. [13] But despite its potent
barriers in viral infection in the organism [7,8] as well antiglioma effect, it was obvious even from the first
as by the proliferation of noninfected malignant cells studies that Ad-Δ24 would need further improvements
and the development of resistance. In this content, for optimal therapeutic effect. [16]
[9]
significant effort has been invested to increase the viral
cytotoxicity. Thus, genetic engineering has been used ADENOVIRUS DELTA 24 DERIVATIVES
to modify viral genome in order to produce molecules
toxic for cancer cells, in order to increase the cytopathic A significant number of modifications have been
effect. [10] Furthermore, genes have been employed, applied on the initial Ad-Δ24 system trying to enhance
causing an augmented immune response against virally its specific targeting or to augment its oncolytic potency.
infected cells, [11] meanwhile other strategies involve The most important effort that has been made to enhance
glioma targeting was the insertion of an Arg-Gly-Asp
Access this article online peptide (RGD) in the Ad-Δ24 fiber knob, increasing
Quick Response Code: its affinity with integrins that are highly expressed
Website: in gliomas and other tumor cells. [17] Adenovirus
www.nnjournal.net
infection in general depends on the initial binding
DOI: to the coxsackievirus and adenovirus receptor (CAR)
10.4103/2347-8659.149392 on the cell surface, followed by a secondary binding
to cell surface integrins. Thus, the effect of Ad-Δ24
[6]
Corresponding Author: Dr. Konstantinos I. Tsamis, Department of Neurology, Medical School, University of Ioannina, 45500
Ioannina, Greece. E‑mail: ktsamis1981@yahoo.gr

Neuroimmunol Neuroinflammation | Volume 2 | Issue 1 | January 15, 2015 1