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Kaufman H.L.,Rush University Medical Center | Kim D.W.,Rush University Medical Center | Deraffele G.,Mount Sinai School of Medicine | Mitcham J.,Mount Sinai School of Medicine | And 2 more authors.
Annals of Surgical Oncology

Background: An oncolytic herpes simplex virus engineered to replicate selectively in tumor cells and to express granulocyte-macrophage colony-stimulating factor (GM-CSF) was tested as a direct intralesional vaccination in melanoma patients. The work reported herein was performed to better characterize the effect of vaccination on local and distant antitumor immunity. Methods: Metastatic melanoma patients with accessible lesions were enrolled in a multicenter 50-patient phase II clinical trial of an oncolytic herpesvirus encoding GM-CSF (OncovexGM-CSF). An initial priming dose of 106 pfu vaccine was given by intratumoral injection, followed by 108 pfu every 2 weeks to 24 total doses. Peripheral blood and tumor tissue were collected for analysis of effector T cells, CD4 +FoxP3+ regulatory T cells (Treg), CD8 +FoxP3+ suppressor T cells (Ts), and myeloid-derived suppressive cells (MDSC). Results: Phenotypic analysis of T cells derived from tumor samples suggested distinct differences from peripheral blood T cells. There was an increase in melanoma-associated antigen recognized by T cells (MART-1)-specific T cells in tumors undergoing regression after vaccination compared with T cells derived from melanoma patients not treated with vaccine. There was also a significant decrease in Treg and Ts cells in injected lesions compared with noninjected lesions in the same and different melanoma patients. Similarly MDSC were increased in melanoma lesions but underwent a significant decrease only in vaccinated lesions. Conclusions: Melanoma patients present with elevated levels of Tregs, Ts, and MDSC within established tumors. Direct injection of OncovexGM-CSF induces local and systemic antigen-specific T cell responses and decreases Treg, Ts, and MDSC in patients exhibiting therapeutic responses. © 2009 Society of Surgical Oncology. Source

Coffin R.S.,Biovex Inc.
Current Opinion in Virology

Viruses have been suggested to be useful as anti-cancer agents since the early 20th century, although following the advent of chemotherapy and radiotherapy work largely stopped until the 1990s when a number of groups began to explore the use of engineered viruses. This overview summarizes the development of the field from the 1990s to the present day, an era when oncolytic viruses have now demonstrated clear clinical benefit to patients. The hurdles and challenges which needed to be overcome are discussed, and in particular the importance of the immune component in achieving a therapeutic effect is highlighted. Today, oncolytic therapy is generally thought of as an immunotherapy, the term 'oncolytic immunotherapy' having been widely adopted. With the advent of immuno-oncology drugs based on immune checkpoint blockade, a clear rationale for synergy between the two approaches, and initial pre-clinical and clinical data suggesting this to be the case, it might be expected that oncolytic immunotherapy combined with checkpoint blockade will provide a cornerstone of future cancer treatment. © 2015 Published by Elsevier B.V. Source

Anesti A.-M.,BioVex Ltd | Coffin R.S.,Biovex Inc.
Expert Opinion on Biological Therapy

Importance of the field: Pain is a hugely important area of research attracting considerable academic and commercial interest. However, the application of RNA interference (RNAi) to the study of nociceptive processes and the development of new analgesics has been limited by the specific challenges associated with the delivery of RNAi triggers to the cell bodies of sensory neurons in the dorsal root ganglia (DRG).Areas covered in this review: In the past five years, delivery of small-interfering RNA (siRNA) to the DRG and spinal cord has achieved effective and specific silencing of targeted genes in various animal models of pain. However, delivery of short-hairpin RNA (shRNA) or artificial microRNA (miRNA) to sensory neurons in vivo has not been feasible using most delivery systems currently available. What the reader will gain: Replication-defective vectors based on herpes simplex virus (HSV), which are particularly efficient at targeting DRG neurons, have been recently engineered to express shRNA and artificial miRNA. Whilst silencing induced by siRNA is transient and requires relatively high doses of silencing triggers, HSV-mediated expression of shRNA/miRNA in sensory neurons allows silencing of targeted genes for at least one week following a single injection.Take home message: The potential to use inducible or tissue-specific promoters and to simultaneously silence multiple gene targets, in addition to recent studies suggesting that artificial miRNAs may have improved safety profiles, hold clear advantages for the use of miRNA-based vectors for gene silencing in sensory neurons. Source

Jennerex, Charging Ahead With Tumor-Killing Virus, Follows Biotech Road Less Traveled Sometimes the innovation community can be a tough insider’s club. If you’re a biotech startup, you’re only real when Merck/Pfizer/Novartis/Glaxo/Roche or some big VC like Kleiner Perkins bets cash that says you might be real. So sometimes a potentially groundbreaking idea has to find some other way to get critical support. That’s what San Francisco-based Jennerex is doing. This startup, founded in 2005, has raised $45 million from a group of wealthy individuals and struck three key partnerships with pharmaceutical companies that aren’t exactly household names in this country—South Korea-based Green Cross, China-based Lee’s Pharmaceuticals, and France-based Transgene. This cast of unusual suspects is setting out to do something that lots of scientists—including those at Emeryville, CA-based Onyx Pharmaceuticals and South San Francisco-based Cell Genesys—have failed to accomplish in the past. Jennerex, like those companies once did, is betting on the intriguing concept of oncolytic viruses. These are viruses that are genetically modified to replicate strictly inside tumors, killing tumor masses from the inside out, while also sparking the immune system to hunt down any residual cancer cells that have spread throughout the body. No one has yet secured an FDA approval for a cancer drug that works this way, despite lots of trying, so people have a right to be skeptical. But Jennerex has scored some new validation for a new variation on this theme, via a $116 million partnership announced this week with Transgene. That’s enabling Jennerex to lay the groundwork for the next serious step—the third of three stages of clinical trials needed to win FDA approval. If Jennerex’s team of 40 people have learned from the mistakes of the past, they could be sitting on a treatment that fights all sorts of solid tumors—starting with liver and colorectal cancer. And if that Phase III trial delivers proof that its treatment can extend lives, Jennerex will have done it without giving up massive ownership stakes and control to Big Pharma or VCs along the way. “Everybody acknowledges this has phenomenal potential,” says Jennerex CEO David Kirn. “Everybody is interested and wants to talk to us, but in terms of putting big money down, Big Pharma wants to see want randomized survival data with at least 80 to 100 patients. Once we have that, or have an FDA approval, it will break this field wide open.” “It’s really too novel for big companies to bite off just yet,” he adds. Kirn knows all the players quite well, having pursued this idea personally for a long time. He’s an oncologist, currently an adjunct professor for Oxford University, and a veteran from the early days of Onyx Pharmaceuticals. He pushed for the oncolytic virus approach there in the 1990s, just like he is pushing for it today at Jennerex. Of course, this isn’t just one committed guy at Jennerex up against a wall of resistance from Big Pharma. Woburn, MA-based BioVex raised $70 million in venture capital last year for its oncolytic virus treatment, which is currently being tested in the pivotal stage of clinical trials for patients with melanoma. Calgary, AB-based Oncolytics Biotech (NASDAQ: ONCY) is also in the hunt, as well as more than 100 academic groups around the world, Kirn says. BioVex and Jennerex appear to be the leaders in the field at the moment, he adds. So what’s new and different with this new crop of oncolytic viruses? Oncolytic viruses of the past tended to be safe and show some activity, but … Next Page »

Amgen’s R&D Chief, Roger Perlmutter, on Why BioVex’s Cancer-Fighting Virus Is Worth $1B Roger Perlmutter, the guy who runs R&D at the largest biotech company in the world, is an immunologist by training. So it shouldn’t be any surprise that he’s fascinated by recent advances in which scientists have shown they can harness the immune system to fight tumors. Now he’s acting on that emerging knowledge of cancer immunology in a big way, through Amgen’s potential $1 billion acquisition of Woburn, MA-based BioVex. Thousand Oaks, CA-based Amgen (NASDAQ: AMGN), which has significant R&D centers in South San Francisco, Seattle, and Cambridge, MA, made headlines yesterday with its big bet on a novel cancer treatment in development at BioVex. Perlmutter, the executive vice president of R&D at Amgen, has his fingerprints all over this deal, since he’s been working to transform Amgen into a more aggressive developer of anti-tumor drugs over the past decade. I’ve known Perlmutter for almost the entire time he’s been at Amgen, so I was eager to hear his thoughts the day after the big BioVex deal was struck. Scientists have been dreaming for decades about alternatives to traditional chemotherapy, radiation, or surgery—particularly those that can harness the body’s immune system to fight tumors as if they were a foreign invader like a virus. Most of these efforts went down in flames, until Seattle-based Dendreon (NASDAQ: DNDN) won FDA approval last year for the first treatment of this kind—which analysts say now has multi-billion dollar annual sales potential. One variation on this theme is through what BioVex and others have done, utilizing what are known as oncolytic viruses. These viruses are designed to specifically replicate inside tumors, causing them to burst, while also sending signals that alert the immune system to seek and destroy any residual cancer cells that might have been able to evade the virus. Neither BioVex, nor anybody else, has proven that it can fight tumors well enough to win FDA approval, but Amgen’s bet is that BioVex will validate the oncolytic virus approach much like Dendreon proved cancer immunotherapy a year ago. “I’ve looked at this field for a long time and found it to be rather discouraging,” Perlmutter said of oncolytic viruses. But over the last couple of years, after seeing what BioVex has done in clinical trials, Perlmutter says he was impressed by not just the company’s engineered virus, but the immune system effect it was able to trigger. “It seemed to me it was more and more likely they were seeing an effective immune response. It looked more and more promising.” BioVex has been pursuing this challenge for a long time, having been founded in 1999 by Robert Coffin, a virologist from University College London. A dozen years later, Amgen snapped it up as BioVex was pushing its lead program, OncoVex GM-CSF, through the third and final stage of clinical trials normally required for FDA approval. The company is enrolling patients with both melanoma, a deadly form of skin cancer, and head and neck cancer. The science is really interesting here, and Perlmutter was clearly happy to talk about what interested him (maybe he was bored with poring over spreadsheets on yesterday’s earnings call?). Here’s the basic idea. The BioVex team has … Next Page »

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