A phase I trial of Ad.hIFN-beta gene therapy for glioma.
ABSTRACT Interferon-beta (IFN-beta) is a pleiotropic cytokine with antitumoral activity. In an effort to improve the therapeutic index of IFN-beta by providing local, sustained delivery of IFN-beta to gliomas, the safety and biological activity of a human IFN-beta (hIFN-beta)-expressing adenovirus vector (Ad.hIFN-beta) was evaluated in patients with malignant glioma by stereotactic injection, followed 4-8 days later by surgical removal of tumor with additional injections of Ad.hIFN-beta into the tumor bed. Eleven patients received Ad.hIFN-beta in cohorts of 2 x 10(10), 6 x 10(10), or 2 x 10(11) vector particles (vp). The most common adverse events were considered by the investigator as being unrelated to treatment. One patient, who was enrolled in the cohort with the highest dose levels, experienced dose-limiting, treatment-related Grade 4 confusion following the post-operative injection. Ad.hIFN-beta DNA was detected within the tumor, blood, and nasal swabs in a dose-dependent fashion and hIFN-beta protein was detectable within the tumor. At the highest doses tested, a reproducible increase in tumor cell apoptosis in post-treatment versus pre-treatment biopsies with associated tumor necrosis was observed. Direct Ad.hIFN-beta injection into the tumor and the surrounding normal brain areas after surgical removal was feasible and associated with apoptosis induction.
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ABSTRACT: Replication-selective oncolytic adenoviruses are being developed for the treatment of cancer, but the safety and feasibility of repeated adenovirus delivery to tumors via the bloodstream was unknown, particularly in light of a patient death after hepatic artery infusion of a replication-defective adenovirus vector. We performed a Phase II trial of an oncolytic replication-selective adenovirus (dl1520, also known as Onyx-015) administered by hepatic artery infusion in patients with gastrointestinal carcinoma metastatic to the liver (n = 27). dl1520 was infused into the hepatic artery (2 x 10(12) particles) on days 1 and 8 as a single agent, and thereafter starting on day 22 in combination with i.v. 5-fluorouracil and leucovorin every 28 days. Repeated viral infusions were feasible, and no deaths occurred on study; reversible grade 3/4 hyperbilirubinemia occurred in 2 patients. Systemic inflammatory cytokine responses varied greatly between patients and even between cycles within a given patient. Proinflammatory cytokines [e.g., tumor necrosis factor, IFN-gamma, and interleukin (IL) 6] typically rose within 3 h and were followed at 18 h by a rise in IL-10. However, in the single patient who suffered a severe but reversible systemic inflammatory response, a unique cytokine profile was detected: marked acute increases of IL-6 (20-fold higher than average for all of the patients) and inhibition of IL-10 production. Delayed secondary peaks of viremia were reproducibly detected 3-6 days after treatment, even in the presence of high level neutralizing antibody titers and antiviral cytokines. Mathematical modeling was used to calculate the number of virus particles produced and shed into the blood with each replication cycle. The combination of virotherapy and chemotherapy had antitumoral activity in some chemotherapy-resistant colorectal tumors. The intra-arterial infusion of oncolytic adenoviruses warrants additional study.Cancer Research 12/2002; 62(21):6070-9. · 8.65 Impact Factor
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ABSTRACT: Oncolytic virotherapy is an emerging biotherapeutic platform based on genetic engineering of viruses capable of selectively infecting and replicating within cancer cells. Such viruses have been found to be both safe and to produce antitumour effects in a number of Phase I and II clinical trials. Early work in this field has been pioneered with strains of adenovirus which, although well suited to gene therapy approaches, have displayed certain limitations in their ability to directly destroy and spread through tumour tissues, particularly after systemic administration. Investigators have subsequently been examining the feasibility of using a variety of different viruses as oncolytic agents. Vaccinia virus is perhaps the most widely administered and successful medical product in history; it displays many of the qualities thought necessary for an effective antitumour agent and is particularly well characterised in people due to its role in the eradication of smallpox. Vaccinia has a short life cycle and rapid spread, strong lytic ability, inherent systemic tumour targeting, a large cloning capacity and well-defined molecular biology. In addition, the virus produces no known disease in humans, has been delivered safely to millions of people and has already demonstrated antitumoural efficacy in trials with vaccine strains. These qualities, along with strategies for further improving the safety and antitumour effectiveness of vaccinia, will be discussed in relation to the broad spectrum of clinical experience already achieved with this virus in cancer therapy.Expert opinion on biological therapy 09/2004; 4(8):1307-21. · 3.22 Impact Factor
Article: Oncolytic viruses.[show abstract] [hide abstract]
ABSTRACT: Although the cytotoxic effects of viruses are usually viewed in terms of pathogenicity, it is possible to harness this activity for therapeutic purposes. Viral genomes are highly versatile, and can be modified to direct their cytotoxicity towards cancer cells. These viruses are known as oncolytic viruses. How are viruses engineered to become tumour specific, and can they be used to safely treat cancer in humans?Nature reviews. Cancer 01/2003; 2(12):938-50. · 35.00 Impact Factor