Huang B.,University of Pittsburgh |
Sikorski R.,University of Pittsburgh |
Kirn D.H.,Jennerex Biotherapeutics |
Thorne S.H.,University of Pittsburgh
Gene Therapy | Year: 2011
Recent developments in the field of oncolytic or tumor-selective viruses have meant that the clinical applications of these agents are now being considered in more detail. Like most cancer therapies it is likely that they will be used primarily in combination with other therapeutics. Although several reports have shown that oncolytic viruses can synergize with chemotherapies within an infected cancer cell, it would be particularly important to determine whether factors released from infected cells could enhance the action of chemotherapies at a distance. Here, we demonstrate in vitro synergy between oncolytic vaccinia and taxanes. However, we also show, for the first time, that this synergy is at least partly due to the release of factors from the infected cells that are capable of sensitizing surrounding cells to chemotherapy. Several cellular factors were identified as being mediators of this bystander effect, including type I interferon released soon after infection and high-mobility group protein B1 (HMGB1) released after cell death. This represents the first description of these mechanisms for beneficial interactions between viral and traditional tumor therapies. These data may provide a direct basis for the design of clinical trials with agents currently in the clinic, as well as providing insight into the development of next generation viral vectors. © 2011 Macmillan Publishers Limited All rights reserved.
Moehler M.,Johannes Gutenberg University Mainz |
Goepfert K.,Johannes Gutenberg University Mainz |
Heinrich B.,Johannes Gutenberg University Mainz |
Breitbach C.J.,Jennerex Biotherapeutics |
And 3 more authors.
Frontiers in Oncology | Year: 2014
Human tumors develop multiple strategies to evade recognition and efficient suppression by the immune system. Therefore, a variety of immunotherapeutic strategies have been developed to reactivate and reorganize the human immune system. The recent development of new antibodies against immune check points may help to overcome the immune silencing induced by human tumors. Some of these antibodies have already been approved for treatment of various solid tumor entities. Interestingly, targeting antibodies may be combined with standard chemotherapy or radiation protocols. Furthermore, recent evidence indicates that intratumoral or intravenous injections of replicative oncolytic viruses such as herpes simplex-, pox-, parvo-, or adenoviruses may also reactivate the human immune system. By generating tumor cell lysates in situ, oncolytic viruses overcome cellular tumor resistance mechanisms and induce immunogenic tumor cell death resulting in the recognition of newly released tumor antigens. This is in particular the case of the oncolytic parvovirus H-1 (H-1PV), which is able to kill human tumor cells and stimulate an anti-tumor immune response through increased presentation of tumor-associated antigens, maturation of dendritic cells, and release of pro-inflammatory cytokines. Current research and clinical studies aim to assess the potential of oncolytic virotherapy and its combination with immunotherapeutic agents or conventional treatments to further induce effective antitumoral immune responses.
Russell S.J.,Mayo Medical School |
Peng K.-W.,Mayo Medical School |
Bell J.C.,Ottawa Hospital Research Institute |
Bell J.C.,Jennerex Biotherapeutics
Nature Biotechnology | Year: 2012
Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Recent advances include preclinical proof of feasibility for a single-shot virotherapy cure, identification of drugs that accelerate intratumoral virus propagation, strategies to maximize the immunotherapeutic action of oncolytic viruses and clinical confirmation of a critical viremic threshold for vascular delivery and intratumoral virus replication. The primary clinical milestone has been completion of accrual in a phase 3 trial of intratumoral herpes simplex virus therapy using talimogene laherparepvec for metastatic melanoma. Key challenges for the field are to select 'winners' from a burgeoning number of oncolytic platforms and engineered derivatives, to transiently suppress but then unleash the power of the immune system to maximize both virus spread and anticancer immunity, to develop more meaningful preclinical virotherapy models and to manufacture viruses with orders-of-magnitude higher yields than is currently possible. © 2012 Nature America, Inc. All rights reserved.
Jennerex Biotherapeutics | Date: 2011-01-05
The present invention concerns the use of an attenuated vaccinia virus comprising a mutation in a gene encoding an interferon-modulating polypeptide for use in the treatment of cancer. Specifically, the mutation renders the B8R or the B18R genes non-functional.
Jennerex Biotherapeutics | Date: 2011-01-05
The present invention relates to an oncolytic vaccinia virus for use in combination with a chemotherapy for treating cancer. A preferred form of chemotherapy is with taxol. A preferred vaccinia virus is one in which either the B8R or the B18R gene is inactivated.
PubMed | Jennerex Biotherapeutics
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016
3573 Background: JX-594 is a first-in-class targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell cycle abnormalities and EGFR/ ras pathway activation. Direct oncolysis plus GM-CSF expression also stimulates tumor vascular shutdown and anti-tumoral immunity.A Phase I-II dose-escalation trial was carried out with JX-594 administered by intratumoral injection every three weeks in patients with end-stage refractory primary or metastatic tumors within the liver. Standard dose- escalation guidelines were used. Data was collected on safety, efficacy, pharmacokinetics and pharmacodynamics.Fourteen patients were enrolled in four dose cohorts, including hepatocellular (HCC), colorectal, melanoma and lung cancers. Patients were heavily pretreated and had large tumors (median 6 cm.). The mean number of JX-594 treatments was 3.5 (range 1-8). All patients experienced mild to moderate flu-like symptoms and transient dose-related thrombocytopenia. Grade III hyperbilirubinemia was dose-limiting at the highest dose level. JX-594 replication-dependent mechanism-of-action was demonstrated, including dissemination in blood and resultant infection of distant tumor sites, plus GM-CSF expression resulting in significant increases in neutrophil counts. Ten patients were radiographically evaluable. Objective responses of the JX-594-treated tumors were demonstrated by RECIST (30%) and by Choi (80%) criteria; only one patient had progressive disease. PET-CT and serum tumor marker responses were also demonstrated. Non-injected tumors were present in 7 patients, and 6 had responses or stable disease.Intratumoral JX-594 treatment resulted in high level replication, GM-CSF expression, systemic dissemination and reproducible efficacy against a spectrum of refractory carcinomas. [Table: see text].
News Article | August 31, 2011
Jennerex Shows that Unorthodox Cancer-Fighting Virus Can be Delivered the Usual Way Most patients who take cancer drugs today get them through an intravenous infusion. Scientists have never been quite been able to consistently get this delivery route to work for genetically engineered cancer-fighting viruses, but San Francisco-based Jennerex Biotherapeutics is reporting today that it has found a way, in a move that could help its oncolytic viruses break out of a narrow market niche. Instead of relying on a direct injection into a single bulky tumor, the usual way oncolytic viruses are delivered, Jennerex and its collaborators were able create an IV formulation that migrated from the bloodstream into tumors, according to research published this week in the journal Nature. The study looked at 23 patients with a variety of tumor types, and found that the drug made its way into tumors in greater amounts when given in an escalating series of doses. Side effects were mostly mild to moderate flu-like symptoms that lasted a few days, consistent with prior studies of the other formulation. “The idea has been around for decades, but nobody has been able to show you could deliver [an oncolytic virus] through an IV. If you can achieve IV delivery, it opens up the possibility of treating 10-fold more tumors,” says David Kirn, the CEO of Jennerex, and the lead author on the scientific publication. No one has yet come up with an FDA-approved therapy from this field of oncolytic viruses, although plenty have tried. Jennerex is one of a handful of companies, along with Calgary, AB-based Oncolytics Biotech (NASDAQ: ONCY) and Woburn, MA-based Biovex (recently acquired by Amgen), pursuing the method. The basic idea here is to genetically modify viruses to selectively infect tumors, replicate like crazy in there, and cause the cancer cells to burst. Most of the treatments, Jennerex’s included, are also designed to provoke an immune reaction to mop up residual cancer cells. Jennerex reported some encouraging, albeit preliminary, results last May from a clinical trial of its experimental oncolytic virus, when it was directly injected into the tumors of 30 patients with liver cancer. But the new intravenous study, which started about 18 months ago, gives Jennerex a potentially more attractive delivery route for liver cancer patients, and opens the door to treating other malignancies, beyond just helping people with inoperable liver tumors. Here’s how the study worked. Researchers gave just a single IV infusion of Jennerex’s JX-594, and then followed up one week later to take a biopsy from each patient, Kirn says. Scientists looked at those biopsies a couple of different ways, through traditional pathology staining, and through quantitative PCR measurement, to see if the drug infected the tumor, and if so, to what extent. Patients were given an escalating series of five doses. While the drug didn’t appear to have any effect at the lowest dose, it infected tumors in increasing concentrations as the doses got higher, Kirn says. “We were worried at the start that we were looking for a needle in haystack, that we could miss seeing a replicating virus if it was spotty in the tumor. What surprised us was the extent of replication in tumors,” Kirn says. This work is still at a very early stage, so all the usual caveats apply. Researchers will need to show the IV method can work with the repeated dosing required in real-world cancer treatment, and that the drug can help people live longer with acceptable side effects. Doctors will want to know which specific forms of cancer are most vulnerable to this treatment method (so far, it looks like liver and colon cancer, Kirn says). But the early findings are encouraging enough that Jennerex is incorporating the IV dose into the design of an ongoing a 120-patient Phase II liver cancer study, and plans to use it in a Phase III study to come later, Kirn says. Jennerex recently raised $8.5 million to finance the Phase II liver cancer study, which should be enough to run the company through the first quarter of 2013, when it expects to find out whether its drug offers longer survival times than today’s best supportive care, Kirn says.
News Article | February 25, 2011
Gilead Bets $600M on Cancer, Genentech Gets a Hearing, Jennerex Shows Early Survival Edge, & More Bay Area Life Sciences News This week we covered a lot of news about cancer, and some of it came from a surprising new source. —Gilead Sciences (NASDAQ: GILD), the Foster City, CA-based company that made its name with drugs that turn HIV into a chronic disease, has placed a big new bet for the future on cancer and inflammation. Gilead agreed to pay as much as $600 million to acquire Seattle-based Calistoga Pharmaceuticals to obtain its pipeline of oral pills that it hopes will turn certain cancers and inflammatory conditions into more manageable, chronic diseases like HIV. I got the skinny from Gilead’s chief scientist, Norbert Bischofberger, in this follow-up interview. —The controversy about whether to use Genentech‘s hit antibody, bevacizumab (Avastin) for treating breast cancer is far from over. The South San Francisco-based unit of Roche said this week that the FDA has agreed to let the company make its case on June 28 & 29 for why the drug should continue to be cleared for sale as a treatment for breast cancer, after the FDA said in December it planned to revoke the breast cancer clearance. If the FDA decision to yank breast cancer off the approved prescribing label, Genentech stands to lose hundreds of millions in future sales, analysts say. —Redwood City, CA-based Pearl Therapeutics, the developer of treatments for lung diseases, said this week it has hired a new CEO, Charles (Chuck) Bramlage, from healthcare giant Covidien. Pearl raised $69 million in venture capital last fall, and soon after, showed its drug beat a multi-billion dollar blockbuster for chronic obstructive pulmonary disease in a head-to-head study of 118 patients. —Here’s one angle you don’t see every day: A life sciences-focused VC firm moving away from the Bay Area. Thomas, McNerney & Partners, which has $600 million under management, said it plans to move its West Coast office from San Francisco to San Diego. —Speaking of moves to San Diego, we reported on another big one this week. UC Berkeley chemist Michael Marletta was formally introduced as the new president of The Scripps Research Institute in San Diego. Xconomy was the first to report, back on Jan. 31, that Marletta would soon be named the top guy at Scripps, a major center for biomedical research. —We also has the scoop last week about San Francisco-based Jennerex Biotherapeutics, which has produced some intriguing (albeit quite preliminary) data which suggests its cancer-fighting virus treatment is prolonging lives of patients with severe forms of liver cancer. Jennerex plans to present more detailed results later this year, with more time for follow-up, at the American Association for the Study of Liver Diseases. —BayBio CEO Gail Maderis offered up a guest editorial this week with her view of how the federal government, if it wants to spur more entrepreneurship, could do some specific things with the people on the ground making it happen in the Bay Area. —Unfortunately, I wasn’t able to personally make it into town this week for a cool event at UCSF Mission Bay which celebrated the 10th anniversary of QB3. Former Gov. Gray Davis, and Lt. Gov. Gavin Newsom were there, along with QB3’s founding director Regis Kelly. You can check Ron Leuty’s recap on this for the San Francisco Business Times. I’m working on some related themes for another big Xconomy event, with help from the folks at QB3 and BayBio, which will explore the 20-year outlook for the life sciences industry in the Bay Area. I hope to see you there at UCSF Mission Bay on March 16.
News Article | May 19, 2011
Jennerex Shows Survival Edge for Liver Cancer Patients in Small Study of Anti-Tumor Virus San Francisco-based Jennerex Biotherapeutics isn’t ready to show results from its tumor-fighting virus at the meeting that attracts all the big boys and girls in the cancer drug business, but today it is unveiling some provocative results that suggest it may help liver cancer patients live longer. Jennerex’s data is still preliminary, and comes from a small study of just 30 patients that began in early 2009. More follow-up is required before any firm conclusions can be drawn, but it’s intriguing nonetheless. Patients with advanced liver cancer who got a low dose of Jennerex’s engineered anti-tumor virus, JX-594, lived for a median time of about 6.5 months, which was in line with expectations. What’s interesting is that statisticians haven’t yet been able to calculate the median survival time for the high dose because not enough have died yet after a median of one year of follow-up, according to Jennerex CEO David Kirn. Eight patients on the high dose are still alive for at least a year, and some are still being followed up for two years, he says. For comparison, patients with this same prognosis are generally expected to live a median time of about 10.5 months when taking sorafenib (Nexavar) from Bayer and Onyx Pharmaceuticals. The findings from this study, called HEP007, are being presented today at the American Society of Gene and Cell Therapy in Seattle. It’s a small meeting compared to the big kahuna of the cancer drug development world—the American Society of Clinical Oncology, which is holding its annual meeting in Chicago in a couple weeks. Jennerex’s data wasn’t ready in time for ASCO’s data submission deadline in January, so it had to skip ASCO, Kirn says. But he adds that final results from this small trial, including the survival readout for patients in the high dose, will be ready for one of the big medical meetings in the fall, Kirn says. “We will need to further confirm it, but this is the first time in medical history that a viral or gene therapy has shown a survival advantage in a randomized, controlled study,” Kirn says. “It’s quite a stunning survival benefit.” I wrote about the Jennerex drug back in February, shortly after Kirn offered an earlier peek at how this trial was unfolding. The program is sure to attract interest on scientific grounds, since it’s one of a handful of treatments in the works that uses viruses that are genetically modified to replicate strictly inside tumors. These injectable viruses are designed to burrow into tumors, where they replicate very fast, causing the cancer cells to burst. The Jennerex treatment is also made to target the blood vessels that feed the tumor, and send signals that alert the immune system to track down any residual cancer cells that might have been able to evade the virus. Many companies-Onyx Pharmaceuticals and Cell Genesys-have tried similar approaches and no one has yet won an FDA approval. But Amgen stirred some renewed interest in the field earlier this year when it agreed to pay as much as $1 billion to acquire Woburn, MA-based BioVex. There’s plenty of room to doubt the data that Jennerex is presenting today. The primary goal of the study was to see if the high dose of the treatment is any better than the low dose at slowing down the spread of tumors, Kirn says. Survival time was a secondary goal. And, on the primary goal, Kirn says the data was “hard to assess” because the treatment caused swelling and an immune reaction around the tumors that became a confounding factor for radiologists. And, of course, the FDA and physicians won’t judge a drug’s ability to extend lives on a small study of just 30 patients. So far, the side effect profile is clean—Kirn says patients are experiencing flu-like symptoms that last a couple days. But Jennerex is hopeful that this study is tantalizing enough to help provide a lift as it heads into a more rigorous trial, known as Traverse, which will seek to enroll 120 patients, starting before the end of September, Kirn says. That study will be designed so that the primary goal is overall survival, the gold standard in cancer drug development, and to randomly assign patients to either get a high dose of the Jennerex drug or a placebo. If the Traverse study can come close to matching what was seen in this smaller study, then you can bet it will be time to take the stage at ASCO. “At the end of day for this drug, it’s all about survival,” Kirn says. “That’s all that matters.”