Natural and genetically engineered viral agents for oncolysis and gene therapy of human cancers

Abstract

Based on personal acquaintances and experience dating back to the early 1950s, the senior author reviews the history of viral therapy of cancer. He points out the difficulties encountered in the treatment of human cancers, as opposed by the highly successful viral therapy of experimentally maintained tumors in laboratory animals, especially that of ascites carcinomas in mice. A detailed account of viral therapy of human tumors with naturally oncolytic viruses follows, emphasizing the first clinical trials with viral oncolysates. The discrepancy between the high success rates, culminating in cures, in the treatment of tumors of laboratory animals, and the moderate results, such as stabilizations of disease, partial responses, very rare complete remissions, and frequent relapses with virally treated human tumors is recognized. The preclinical laboratory testing against established human tumor cell lines that were maintained in tissue cultures for decades, and against human tumors extricated from their natural habitat and grown in xenografts, may not yield valid results predictive of the viral therapy applied against human tumors growing in their natural environment, the human host. Since the recent discovery of the oncosuppressive efficacy of bacteriophages, the colon could be regarded as the battlefield, where incipient tumor cells and bacteriophages vie for dominance. The inner environment of the colon will be the teaching ground providing new knowledge on the value of the anti-tumor efficacy of phage-induced innate anti-tumor immune reactions. Genetically engineered oncolytic viruses are reviewed next. The molecular biology of viral oncolysis is explained in details. Elaborate efforts are presented to elucidate how gene product proteins of oncolytic viruses switch off the oncogenic cascades of cancer cells. The facts strongly support the conclusion that viral therapy of human cancers will remain in the front lines of modern cancer therapeutics. It may be a combination of naturally oncolytic viruses and wild-type viruses rendered oncolytic and harmless by genetic engineering, that will induce complete remissions of human tumors. It may be necessary to co-administer certain chemotherapeutic agents, advanced cancer vaccines, or even immune lymphocytes, and targeted therapeuticals, to ascertain, that remissions induced by the viral agents will remain complete and durable; will co-operate with anti-tumor host immune reactions, and eventually will result in cures of advanced metastatic human cancers.

Current Advancements on the Significance of Oncolytic Viruses in the Treatment of Tumor Cells

“…These studies have resulted in the development of several patients which may contribute towards the advancement in future therapeutics [11].…”

“…Naturally occurring oncolytic viruses include Newcastle disease virus (NDV), Vesicular Stomatitis Virus (VSV), myxoma virus and reovirus. Engineered oncolytic viruses encompass backbones from adenoviruses, vaccina viruses and HSV [11].…”

Molecular biology of oncogenic inflammatory processes. I. Non-oncogenic and oncogenic pathogens, intrinsic inflammatory reactions without pathogens, and microRNA/DNA interactions (Review)

“…A genetically engineered oncolytic adenovirus was another choice (reviewed in ref. 164). The splice variant of the epidermal growth factor receptor EGFRvIII vaccine was already in its earliest clinical trials.…”

Apprivoiser nos ennemis pour en faire des alliés : la « virothérapie » anticancéreuse

“…> L'idée que les virus puissent agir comme agents anticancéreux n'est pas nouvelle et date essentiellement du début du XX e siècle ; l'historique du sujet a d'ailleurs fait l'objet d'une excellente revue [1]. Une compréhension limitée des virus et de leur mode de multiplication ne permit toutefois pas à cette approche d'être retenue, par rapport à d'autres méthodes jugées sans doute plus directes et faciles à maîtriser, telles que la radiothérapie et la chimiothérapie.…”

“…Alors qu'avant 1990 moins d'une centaine d'articles peuvent être trouvés dans PubMed en utilisant oncolytic virus comme termes de recherche, ce nombre atteint plus de 1 700 pour la période 2000-2010 et plus de 300 pour la seule année 2011 ! Depuis une douzaine d'années, des chercheurs du monde entier se réunissent ainsi tous les deux ans pour discuter des progrès dans la conception de ces virus dits « oncolytiques » (qui lysent ou détruisent les cellules cancéreuses) ; nous étions plus de 200 en 2011 1 . Les interrogations suscitées par l'utilisation de virus comme agents thérapeutiques ont évolué de façon importante au cours des dernières années.…”