The combination was safe but, even at myelotoxic doses of cyclophosphamide, neither consistent modulation of NARA responses nor enhanced antitumor efficacy was achieved.
REALM ROYALE ERROR CODE 20006 TRIAL
Promising preclinical data 18–20 underpinned that phase I trial of escalating doses of cyclophosphamide with a primary endpoint of modulating neutralizing antireoviral antibody (NARA) responses. In particular, studies on cyclophosphamide were conducted with the premeditated intention of blunting antiviral antibody responses to allow more effective systemic delivery. 12–17 These phase I trials, which variously involved combinations with gemcitabine, platinum and taxanes, primarily looked for safety, tolerability and signals of efficacy, but data were also collected on the effect of chemotherapy on antiviral humoral immune responses. 11 Subsequently, preclinical and clinical studies combining reovirus with standard anticancer chemotherapies were conducted in an attempt to further improve responses. 8 9 No dose-limiting toxicities were observed, and clear signs of single-agent activity were observed, with a 37% response rate in the first trial of intratumoural administration 10 and a 45% response rate in the first trial of intravenous administration, improving to 67% in patients with confirmed viral shedding. Reovirus has been tested as a single agent in multiple clinical trials in patients with advanced cancers, initially intratumorally 7 and then intravenously. It is not known if this phenomenon occurs in patients. 5 6 This effect, which occurs after cotreatment with granulocyte-macrophage colony-stimulating factor, was predicated on enhanced monocyte/macrophage virus carriage and delivery to tumor.
4 More recently, preclinical data have suggested that the antireovirus neutralizing antibody response may, paradoxically, enhance therapy in mouse models. It has also been postulated that frequent, high doses of virus given before an antibody response peaks or cytotoxic chemotherapy-mediated attenuation of the antibody titer might enhance systemic delivery of virus to tumor tissue. It has been suggested that antireoviral antibody responses may hinder the antitumor efficacy of reovirus. Later research indicated that the oncolytic activity of reovirus may be contingent on a more complex and nuanced mechanism than simply being Ras enabled. While reovirus is non-pathogenic in humans, it has been shown to replicate selectively in cells that have an activated or mutated Ras signaling pathway 1 and this inspired research into its use as an oncolytic virus.
Mammalian orthoreovirus type 3 Dearing (hereafter referred to as reovirus) is a wild-type double-stranded RNA virus.
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