[Rich66]

Harmless Virus Could Be an Answer to Cancer

By MELLY ALAZRAKI Posted 11:00 AM 02/06/10


LINK


"We're working on a product that is widely applicable to quite a few indications of cancer and is based on a naturally occurring virus that's commonly found in the environment and that happens to have a preference of growing in cancer cells as opposed to growing in normal tissue."

It's called a reovirus (short for Respiratory Enteric Orphan virus), and it's a type which most people pick up by age 12 through inhalation or contact that causes few or no health problems. But when the virus enters cancer cells, it kills them.

On-Off Switch

Viruses, naturally, prefer cells that can't fight them off. And these cancer cells all have a common characteristic: They have a certain growth pathway, called the Ras pathway, turned on. "If a cell doesn't have that pathway turned on, nothing happens, so it's like an on-off switch for the virus's growth," Thompson explained. In the human body, very few normal cells have that Ras pathway turned on, and those die in the same amount of time the virus takes to kill them, so the body is not affected. "And that's where the story would end if only these few cells had the Ras pathway turned on all the time," Thompson added. "But it happens to be the state in most cancers."

"When the Ras pathway is turned on, it turns off the virus defense mechanism in the cell so the virus can go in and replicate itself," Thompson continued. It keeps replicating until its host -- the cancer cell -- is overwhelmed and dies, which happens within three days.
"Anywhere between two-thirds to 75% of the primary carcinomas -- ovarian, prostate, non-small cell lung cancer and so on -- actually have that pathway turned on," Thompson said. "In metastatic disease, which spreads beyond the primary tumor, it's between 95% to 100% that have the Ras pathway. So you have a disease that has this pathway, and a virus that for other reasons requires that pathway to grow."

Infecting the Cancer

That's where Oncolytics and its drug, Reolysin, come in play. Reolysin is "a variant of the virus we found in nature," explained Thompson. The treatment "is rather straightforward," he said. It involves five days of intravenous injections, and the side effects are few: Most commonly, patients run a small fever and feel a little tired.

Once the virus has killed the cancer cells, "the body actually clears the virus pretty effectively," Thompson explained, because the body mounts a normal immune response to the infection. "Normally, the latest we ever find the virus in the body is a couple of weeks after the first injection, and then it's completely gone," he says.



Thompson lost his mother and an uncle to cancer, and himself got melanoma. "Right after that, while the surgery was still healing in my leg, I got a call from a colleague of mine in the Alberta government asking me whether I would talk to this group of researchers at the University of Calgary who were working on a virus. I had very heightened sensitivity to cancer at that time and had expertise in the area. So I got a close look at it, and that's how I got involved in it."

"That's how Oncolytics started," he added. "In less than a year, we went public, cross-listed and did six financings."

Phase 3 Clinical Trial

The company has completed about a dozen early-phase clinical trials so far, and has seven to eight ongoing for a broad range of cancers, including melanoma, lung and ovarian. But the real test will be the upcoming Phase 3 clinical trial for head and neck cancer.

The study is designed to combine Reolysin with the standard chemotherapy care for head and neck. In earlier studies, the response rate to the treatment was 42% when Reolysin was added to common therapy, much higher than the average 10% response rate for the disease.

If that response rate holds up, no doubt patients would be eager for the drug to reach the market. "We could be selling product by 2012, if everything lines up properly," said Thompson. "The sad part about head and neck patients is that you know very quickly whether your product works on them or not. The patients we're looking at have a median life expectancy of 4.5 months, so you don't have to wait much to know whether your product had benefit for the patients."

(more at link)



1: Mol Ther. 2009 Jun;17(6):972-9. Epub 2009 Mar 17. Links

Oncolytic reovirus effectively targets breast cancer stem cells.

Marcato P, Dean CA, Giacomantonio CA, Lee PW.
Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.

Recent evidence suggests that cancer stem cells (CSCs) play an important role in cancer, as these cells possess enhanced tumor-forming capabilities and are resistant to current anticancer therapies. Hence, novel cancer therapies will need to be tested for both tumor regression and CSC targeting. Herein we show that oncolytic reovirus that induces regression of human breast cancer primary tumor samples xenografted in immunocompromised mice also effectively targets and kills CSCs in these tumors. CSCs were identified based on CD24(-)CD44(+) cell surface expression and overexpression of aldehyde dehydrogenase. Upon reovirus treatment, the CSC population was reduced at the same rate as non-CSCs within the tumor. Immunofluorescence of breast tumor tissue samples from the reovirus- and mock-treated mice confirmed that both CSCs and non-CSCs were infectible by reovirus, and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assay showed that both populations died by apoptosis. Ras, which has been shown to mediate reovirus oncolysis, was found to be present at similar levels in all cell types, and this is consistent with their comparable sensitivity to reovirus. These experiments indicate that oncolytic reovirus has the potential to induce tumor regression in breast cancer patients. More important, the CSC population was equally reduced and was as susceptible to reovirus treatment as the non-CSC population.
PMID: 19293772 [PubMed - indexed for MEDLINE]

Synergistic antitumor activity of oncolytic reovirus and chemotherapeutic agents in non-small cell lung cancer cells

Reovirus type 3 Dearing strain (ReoT3D) has an inherent propensity to preferentially infect and destroy cancer cells. The oncolytic activity of ReoT3D as a single agent has been demonstrated in vitro and in vivo against various cancers, including colon, pancreatic, ovarian and breast cancers.

Its human safety and potential efficacy are currently investigated in early clinical trials. In this study, we investigated the in vitro combination effects of ReoT3D and chemotherapeutic agents against human non-small cell lung cancer (NSCLC).

Results: ReoT3D alone exerted significant cytolytic activity in 7 of 9 NSCLC cell lines examined, with 50% effective dose, defined as the initial virus dose to achieve 50% cell killing after 48 hours of infection, ranging from 1.46 +/- 0.12 ~ 2.68 +/- 0.25 (mean +/- SD) log10 pfu/cell.

Chou-Talalay analysis of the combination of ReoT3D with cisplatin, gemcitabine, or vinblastine demonstrated strong synergistic effects on cell killing, but only in cell lines that were sensitive to these compounds. In contrast, the combination of ReoT3D and paclitaxel was invariably synergistic in all cell lines tested, regardless of their levels of sensitivity to either agent.

Treatment of NSCLC cell lines with the ReoT3D-paclitaxel combination resulted in increased poly (ADP-ribose) polymerase cleavage and caspase activity compared to single therapy, indicating enhanced apoptosis induction in dually treated NSCLC cells. NSCLC cells treated with the ReoT3D-paclitaxel combination showed increased proportions of mitotic and apoptoticcells, and a more pronounced level of caspase-3 activation was demonstrated in mitotically arrested cells.

Conclusions: These data suggest that the oncolytic activity of ReoT3D can be potentiated by taxanes and other chemotherapeutic agents, and that the ReoT3D-taxane combination most effectively achieves synergy through accelerated apoptosis triggered by prolonged mitotic arrest.

Author: Shizuko SeiJodie MussioQuan-en YangKunio NagashimaRalph ParchmentMatthew CoffeyRobert ShoemakerJoseph Tomaszewski
Credits/Source: Molecular Cancer 2009, 8:47



Oncolytics shares soar on cancer treatment trial news

Financial Post Published: Friday, October 02, 2009

OTTAWA - Shares of Calgary-based Oncolytics Biotech Inc. shot up Friday after the company announced it had reached an agreement with the U.S. Food and Drug Administration for the design of a Phase 3 trial involving its Reolysin cancer treatment.
"Oncolytics (ONC/TSX) 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 (special protocol assessment) process," Brad Thompson, chief executive of Oncolytics, said in a statement.
"This is an exciting step forward for our clinical program."
Shares of the Calgary-based firm rose as high as $4.10 in early morning trading in Toronto stock exchange, settling back to $3.70 by mid-afternoon.
The company said it will work with the FDA to develop trials to examine the effectiveness of its Reolysin treatment in combination with paclitaxel and carboplatin in patients with head and neck cancers, versus chemotherapy alone.
The main goal of the trial is to establish overall patient survival while secondary endpoints include response rates and safety and tolerability of Reolysin when used in combination.
The company said in a statement the study could eventually support a licence application submission for Reolysin, a virus that targets mostly solid-tumour cancers that have a tendency to spread, or metastasize, such as in head and neck tumours.
In previous tests, "the treatment combination has increased the response rate several fold compared to historical outcomes," the company said.

Read more: http://www.financialpost.com/news-se...#ixzz0SuA27LOe



Cancer trials cause excitement
Posted By CATHY DOBSON, THE OBSERVER
http://www.theobserver.ca/ArticleDisplay.aspx?e=2168478

11/10/09
Excitement is growing among Canadian scientists that certain viruses might be used to shrink or even destroy cancer cells, a leading authority in cancer research told a Sarnia audience Monday.
"We're seeing dramatic results. This is one of those times to stay tuned, folks. We're really, really excited," said Michael Wosnick, vice-president of research with the Canadian Cancer Society and scientific director of the newly-established Canadian Cancer Society Research Institute.
Dalhousie Medical School researcher Patrick Lee earlier this year used a common virus to kill breast cancer stem cells.
Previous trials using mice showed astonishing results, with a benign virus causing lung tumours to disappear in weeks.
This year, clinical trials started on people and the results so far have been dramatic, Wosnick said.
"This is a place where Canada has been a world leader," he said. "Canada excels at clinical trials and a number of researchers across the country are now involved in oncolytic
viruses that literally burst open cancer cells."
Numerous strains of viruses are being tested on various tumours, he said.
But it's too early to know if the viruses provide longterm cures or if there are significant side effects, he added.
Speaking at a volunteer and donor appreciation event for the Canadian Cancer Society's Lambton County Unit, Wosnick showed before-and-after slides of mouse tumours and a human tumour taken during the trials.
In both cases, the cancers disappeared in a few weeks and did not attack healthy cells.

......

Phase I/II trial of oncolytic reovirus (Reolysin) in combination with carboplatin/paclitaxel in patients (pts) with advanced solid cancers.

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Sub-category:
Other Novel Agents
Category:
Developmental Therapeutics: Molecular Therapeutics
Meeting:
2009 ASCO Annual Meeting
Abstract No:
e14519
Citation:
J Clin Oncol 27, 2009 (suppl; abstr e14519)
Author(s):

E. Karapanagiotou, H. S. Pandha, G. Hall, J. Chester, A. Melcher, M. Coffey, J. de Bono, M. E. Gore, C. M. Nutting, K. J. Harrington; The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom; University of Surrey, Guildford, United Kingdom; Leeds Institute of Molecular Medicine, Leeds, United Kingdom; Oncolytics Biotech Inc., Calgary, AB, Canada Abstract:
Background: Reolysin, a wild type reovirus (Dearing strain), replicates preferentially in Ras-activated cancer cells. Preclinical data have demonstrated synergistic tumor kill when reolysin is combined with standard chemotherapies including platinum agents and taxanes, justifying the clinical evaluation of this drug combination. Methods: Pts were initially treated in an open-label, dose-escalating, phase I trial and received iv reolysin, d1-5, iv carboplatin (AUC5), d1, and paclitaxel (175mg/m²), d1, qw3. Reolysin was administered at a starting dose of 3x10⁹ TCID₅₀ and then increased to 1x10¹⁰ and 3x10¹⁰ TCID₅₀ in cohorts of 3 pts. Primary endpoints for the dose escalation trial were to determine the maximum tolerated dose, dose limiting toxicity (DLT) and to recommend a dose for phase II studies. Secondary endpoints were to evaluate pharmacokinetics, immune response and anti-tumour activity. The primary endpoint for the phase II expansion cohort in head and neck (H&N) pts is to characterize response rate. Results:17 heavily pre-treated pts (11 M, median age 55 yrs) with advanced cancer: H&N (10), melanoma (4), peritoneal/endometrial cancer (2), and sarcoma (1) have received 82 cycles of treatment to date; 4 pts are still on study. There were no DLTs in the dose escalation. Toxicities were mainly grade 1 and 2 and included: nausea, fatigue, vomiting, myalgia, fever, neutropenia, lymphopenia, thrombocytopenia and hypotension. This combination resulted in a blunting of antiviral immune response as compared to monotherapy virus. Response rates in 15 evaluable patients were partial response (PR) (4 pts), stable disease (SD) (6 pts) and progressive disease (5 pts). Of note, all PRs and 4/5 SDs were in H&N disease. Conclusions: The combination of reolysin and carboplatin/paclitaxel was well tolerated and resulted in disease control in the majority of pts. Significant responses in refractory H&N pts recommended this combination for phase II evaluation. Enrollment is ongoing and randomized studies are planned.