15 jul;i 2012: onderaan referentielijst toegevoegd van studies met het reovirus.

17 oktober 2009: Reolysin is een vorm van vaccinatie met een virus als medicijn dat ook sterk lijkt op bv. het Newcastle Disease Virus en aanpak zoals bij dendritische celtherapie. Er zijn verschillende studies bij o.a. hersentumoren en prostaatkanker die wijzen op bijzonder goede effecten met Reolysin, al of niet in combinatie met chemo en/of bestraling. Hier de openstaande studies bij melanomen, niet-klein-cellige longkanker, hoofd- en halskanker en bot- en soft sarcoma's. Reovirus is een veilig medicijn nagenoeg zonder bijwerkingen en relatief goedkoop. Of u zich als Nederlandse of Belgische kankerpatient hiervoor op kunt geven weten we niet maar onderaan deze artikelen staan adressen waar u informatie kunt verkrijgen en aan kunt melden. De studie met hoofd- halskanker is recent nog met toestemming van de FDA opgewaardeerd naar een fase III studie. Nederlandse onderzoekers aan de Erasmus en LUMC Leiden beschreven recent nog uitvoerig hoe het Reovirus werkt..  Zie achtereenvolgens: studieoverzicht met het Reovirus, studieabstract van Nederlandse onderzoekers.en enkele abstracten van Reovirus bij verschillende kankersoorten.

Bron o.a.: http://www.oncolyticsbiotech.com/clinical.html

Modification of mammalian reoviruses for use as oncolytic agents

Diana JM Van Den Wollenberg‌¹, Sanne K Van Den Hengel‌^1,2, Iris JC Dautzenberg‌¹, Onno Kranenburg‌³ & Rob C Hoeben‌^†1

¹Leiden University Medical Center, Department of Molecular Cell Biology, Postal Zone S1-P, P.O. Box 9600, Leiden, 2300 RC, The Netherlands +31 (0) 71 526 9241; +31 (0) 71 526 8270; r.c.hoeben@lumc.nl

²Erasmus University Medical Center, Department of Neurology, 3015 CE Rotterdam, The Netherlands

³University Medical Center Utrecht, Department of Surgery, 3584 CX Utrecht, The Netherlands

† Author for correspondence

The Reoviridae are a family of viruses with a non-enveloped icosahedral capsid and a segmented double-stranded RNA genome. Prototypes of the mammalian Orthoreoviruses have been isolated from human respiratory and enteric tracts and are not associated with human disease. One of these, human reovirus type 3 Dearing (T3D), usually serves as a model for the family. In the last decade the mammalian Orthoreoviruses, especially T3D, have been evaluated as oncolytic agents in experimental cancer therapy. This is based on the observation that reoviruses induce cell death and apoptosis in tumor cells, but not in healthy non-transformed cells. Several clinical trials have been initiated in Canada, the USA, and the UK, to study the feasibility and safety of this approach. Due to the segmented structure of their double-stranded RNA genomes genetic modification of Reoviridae has been notoriously difficult. Several techniques have been described recently that facilitate the genetic modification of reovirus genomes. The basis for reverse genetics of reovirus is the discovery in 1990 that reovirus RNA is infectious. Subsequently, it took ten years before a foreign gene was introduced into the reovirus genome. Here we review the methods for reovirus modification and their use for generating new reovirus-derived oncolytic agents.

Reovirus-based therapy for cancer

Kevin Kelly‌¹, Steffan Nawrocki‌¹, Alain Mita‌¹, Matthew Coffey‌², Francis J Giles‌¹ & Monica Mita‌^†1

¹University of Texas Health Science Center, Institute for Drug Development, Cancer Therapy and Research Center, 7979 Wurzbach Road, San Antonio, Texas 78229, USA +1 210 450 1797; +1 210 692 7502; mitam@uthscsa.edu

²Oncolytics Biotech Inc, 210, 1167 Kensington Cres NW, Calgary, Alberta, Canada

†Author for correspondence

Reovirus is an oncolytic virus that is not associated with significant disease in humans, but is selectively able to replicate in cancer cells through exploitation of abnormal Ras signaling. Pre-clinical studies have demonstrated that treatment with reovirus is associated with significant anticancer activity across a range of tumor types. Reolysin is a proprietary formulation of the human reovirus developed by Oncolytics Biotech. Clinical evaluation of reovirus therapy has shown that it is well tolerated when administered locally or systemically. Encouraging anticancer efficacy has been observed with single-agent treatment and in combination with chemotherapy and radiotherapy. Phase II studies are currently evaluating reovirus alone and in combination with standard therapy in an array of tumor types. While immune sensitization hinders the anticancer efficacy of reovirus, it is important in preventing systemic toxicity. Immunosuppressive strategies are being developed that reduce immune neutralization of the virus to allow for improved tumor penetration, but retain sufficient antibody levels to protect normal tissues. The lack of toxicity and promising efficacy of reovirus has raised hopes that it will become an established anticancer agent.

 

10/2/2009 8:06:05 AM ET	News Release Index
Oncolytics Biotech® Inc. Reaches Special Protocol Assessment Agreement with the FDA on Design of Phase 3 Trial for REOLYSIN® in Head and Neck Cancers --Company to Host Conference Call--
CALGARY, AB, --- October 2, 2009 - Oncolytics Biotech Inc. (“Oncolytics”) (TSX:ONC, NASDAQ:ONCY) today announced that it has reached an agreement with the U.S. Food and Drug Administration (FDA) under the Special Protocol Assessment (SPA) process for the design of a Phase 3 trial examining REOLYSIN in combination with paclitaxel and carboplatin in patients with platinum-refractory head and neck cancers. The SPA is an agreement between Oncolytics and the FDA that the design and planned analyses of the Phase 3 study is adequately designed to provide the necessary data, that depending upon outcome, could support a license application submission for REOLYSIN. “Oncolytics is the first company to reach an agreement with the FDA on a Phase 3 trial design for an intravenously-administered oncolytic virus under the SPA process,” said Dr. Brad Thompson, President and CEO of Oncolytics. “This is an exciting step forward for our clinical program for REOLYSIN, which has become a first-in-class agent. A Phase 3 trial in patients with platinum-refractory head and neck cancers is a logical choice for our first pivotal trial with REOLYSIN. In Phase 1/2 trials, the treatment combination has increased the response rate by several-fold compared to historical outcomes.” As specified in the SPA, the randomized, two-arm, double-blind, multicentre, two-stage, adaptive Phase 3 trial will assess the intravenous administration of REOLYSIN with the chemotherapy combination of paclitaxel and carboplatin versus the chemotherapy alone in patients with metastatic or recurrent squamous cell carcinoma of the head and neck, or squamous cell cancer of the nasopharynx, who have progressed on or after prior platinum-based chemotherapy. All patients will receive treatment every three weeks (21 day cycles) with paclitaxel and carboplatin and will also receive, on a blinded basis, either intravenous placebo or intravenous REOLYSIN. All dosing takes place in the first five days of each cycle with all patients receiving standard intravenous doses of paclitaxel and carboplatin on day one only, and on days one through five, either intravenous placebo or intravenous REOLYSIN at a dose of 3x1010 TCID50. Patients may continue to receive the trial combination therapy for up to eight, 21-day cycles and, thereafter, blinded placebo or blinded REOLYSIN until the patient has progressive disease or meets other criteria for removal from the trial. The primary endpoint for the trial is overall survival (OS); secondary endpoints include progression free survival (PFS), objective response rate (complete response (CR) + partial response (PR)) and duration of response, and safety and tolerability of REOLYSIN when administered in combination with paclitaxel and carboplatin. The first stage of the trial is non-adaptive, and is designed to enroll 80 patients. The second stage is adaptive, and is designed to enroll between 100 and 400 patients with the most probable statistical enrolment being 195 patients in this stage. This adaptive trial design allows frequent data evaluation to determine if the probability of reaching a statistically significant endpoint has been achieved. The decision to pursue a Phase 3 trial in head and neck cancers was predicated on positive results seen in the Company’s U.K. Phase 1 and Phase 2 combination REOLYSIN and paclitaxel/carboplatin clinical trials, as well as significant preclinical work demonstrating synergy in combination with taxane or platinum-based drugs. Interim results of the U.K. Phase 1/2 trial reported in March 2009 demonstrated an overall response rate (PR and CR) of 42% and a total clinical benefit rate (PR + CR + stable disease) of 75%. Enrolment in the Phase 2 portion of the trial was concluded in July 2009, and updated results are expected to be presented in the fourth quarter of 2009.

 

1: Brain Nerve. 2009 Jul;61(7):815-22. Links

[Oncolytic virus therapy for malignant brain tumors]

[Article in Japanese]

 

Ino Y, Todo T.

Department of Neurosurgery and Translational Research Center, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyoku, Tokyo 113 8655, Japan.

Oncolytic viruses are genetically engineered, recombinant viruses or naturally occurring, attenuated viruses that infect, replicate selectively within, and destroy tumor cells. These viruses are nontoxic to normal tissues, and progeny viruses released from destroyed tumor cells can spread and infect surrounding tumor cells. In addition, most oncolytic viruses can elicit specific antitumor immunity in the course of tumor cell destruction. Currently, the main route of virus administration is direct intratumoral injection that enables maximum virus delivery to tumor cells and minimum systemic adverse events. Several types of oncolytic viruses have been tested in clinical trials for recurrent malignant glioma, among which genetically engineered herpes simplex viruses type 1 seems to be the most promising because of its high tumor selectivity (indicating safety) and potency (indicating efficacy). Oncolytic virus therapy has been developed for various types of cancers other than glioma, including malignant melanoma and prostate, breast, head & neck and colon cancers. Thus far, oncolytic viruses that are inoculated intratumorally, are shown to be safe; adverse events typically observed are usually transient and include local inflammation and flu-like symptoms. Oncolytic viruses can be used in combination with chemotherapy or other conventional therapies, which, in some cases, can lead to synergistic effects. This review summarizes the recent advances in clinical and preclinical research on oncolytic virus therapy for malignant brain tumors.

PMID: 19618859 [PubMed - in process]

 

1: Gene Ther. 2008 Sep;15(18):1257-70. Epub 2008 Apr 10. Links

Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma.

Errington F, White CL, Twigger KR, Rose A, Scott K, Steele L, Ilett LJ, Prestwich R, Pandha HS, Coffey M, Selby P, Vile R, Harrington KJ, Melcher AA.

Cancer Research UK Clinical Centre, St James's University Hospital, University of Leeds, Leeds, UK.

Reovirus is a promising unmodified double-stranded RNA (dsRNA) anti-cancer oncolytic virus, which is thought to specifically target cells with activated Ras. Although reovirus has been tested in a wide range of preclinical models and has entered early clinical trials, it has not previously been tested for the treatment of human melanoma. Here, we show that reovirus effectively kills and replicates in both human melanoma cell lines and freshly resected tumour; intratumoural injection also causes regression of melanoma in a xenograft in vivo model. Reovirus-induced melanoma death is blocked by caspase inhibition and is dependent on constituents of the Ras/RalGEF/p38 pathway. Reovirus melanoma killing is more potent than, and distinct from, chemotherapy or radiotherapy-induced cell death; a range of inflammatory cytokines and chemokines are released by infected tumour cells, while IL-10 secretion is abrogated. Furthermore, the inflammatory response generated by reovirus-infected tumour cells causes bystander toxicity against reovirus-resistant tumour cells and activates human myeloid dendritic cells (DC) in vitro. Hence, reovirus is suitable for clinical testing in melanoma, and may provide a useful danger signal to reverse the immunologically suppressive environment characteristic of this tumour.

PMID: 18401435 [PubMed - indexed for MEDLINE

11 december 2005: Bron: Oncolytics

Een kleine preklinische studie geeft veelbelovende resultaten voor het gebruik van een virusinjectie intraveneus (Reolysin) bij kankerpatiënten met solide tumoren. We weten dat Reolysin al goede resultaten laat zien in lopende studies bij o.a. hersentumoren en prostaatkanker. Hier een kort artikel over deze nieuwe studieresultaten. Let wel dit zijn hele kleine studies en bekijk ze kritisch, desalniettemin wel hoopgevend want injecteren met een virus lijkt toch een hoopvolle benadering. Zie ook Newcastlevirus informatie

PRNewswire: Reovirus Destroys Cancer (M/Calgary)

Reovirus Seeks Out and Destroys Cancer Cells, Preliminary Study Results Show

CALGARY, Alberta, Dec. 5 /PRNewswire/ -- For the first time, researchers ave demonstrated that the reovirus, a naturally occurring virus found in the environment, can seek out and destroy cancer cells in a variety of tumor types and locations when delivered intravenously to patients.

Preliminary results from an ongoing patient study in the United Kingdom have demonstrated that Reolysin was well-tolerated by patients and there was vidence of virus replication within several types of tumors in patients who had failed all previous treatments. Of 12 patients who received doses of Reolysin on five consecutive days, at least four patients had stabilization of the measured tumor. Patients who experienced tumor activity included those with colorectal, prostate, non-small-cell lung and bladder cancers.

These early results, presented by Dr. Johann S. de Bono of the Royal Marsden Hospital in London at the most recent AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Philadelphia, showed that the reovirus, when delivered intravenously, enters cancer cells, replicates within them and ultimately kills them. It works by replicating within cancer cells that have an activated Ras pathway, a common mutation that is shared by approximately two thirds of all human cancers.

We believe that these early results are the most encouraging data we have seen to date in our work with Reolysin; says Dr. Brad Thompson, President and CEO of Oncolytics Biotech Inc., the company sponsoring the study. Oncolytics has also started patient enrolment in a similar intravenous trial in the United States at the Montefiore Medical Center in New York City. This clinical trial is an open-label, dose- escalation Phase I study in which a single dose of Reolysin is administered intravenously to patients with advanced and/or metastatic solid tumors.

FOR FURTHER INFORMATION PLEASE CONTACT:

For Canada:
Oncolytics Biotech Inc.
Brad Thompson
210, 1167 Kensington Cr NW
Calgary, Alberta T2N 1X7
Tel: 403.670.7377
Fax: 403.283.0858
info@oncolyticsbiotech.com

For Canada:
The Equicom Group Inc.
Joanna Longo
20 Toronto Street
Toronto, Ontario M5C 2B8
Tel: 416.815.0700 ext. 233
Fax: 416.815.0080
jlongo@equicomgroup.com

For United States:
The Investor Relations Group
Gino De Jesus or Dian Griesel, Ph.D.
50 Pine Street, 6th Floor
New York, NY 10005
Tel: 212.825.3210
Fax: 212.825.3229
theproteam@aol.com

Referentielijst van studies met Reovirus in combinatie met verschillende andere medicijnen

References

virusinjecties, reolysin

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• Virusinjectie (REOLYSIN) geeft in fase I studie veelbelovende resultaten bij kankerpatiënten met solide tumoren Artikel geplaatst december 2005

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• REOLYSIN: Virusinjectie geeft in verschillende studies veelbelovende resultaten bij kankerpatiënten. O.a. bij hoofd- halstumoren - melanomen - longkanker en sarcoma's.

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• REOLYSIN virus ingezet als vaccin, bereikt goede resultaten bij soft sarcoma's. Aldus een kleinschalige fase II trial.

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• Reolysin, een overzicht van recente ontwikkelingen en belangrijke studies met dit virus medicijn