June 29,by James Doroshow, M. James Doroshow, M.
Oncolytic Virus Therapies
Although NCI operates the program, it runs very much like a small pharmaceutical or biotechnology company, working with external investigators and top scientific experts to advance promising or novel therapies from the earliest stages of research to human clinical trials.
Earlier this week, in fact, we were encouraged to see signs of promise from one NExT-developed therapy, when researchers from Duke University reported results from the first human trial of their cancer-killing, or oncolytic, virus therapy in patients with the brain cancer glioblastoma. The genetically-modified poliovirus therapy, called PVSRIPO, is a feat of remarkable engineering: an inactivated poliovirus that has been programmed to target cells harboring a protein called CD, which is overexpressed in many different cancer types, including glioblastoma.
The results from the phase 1 trial—presented on June 26 at the International Conference on Brain Tumor Research and Therapy and published simultaneously in the New England Journal of Medicine —are preliminary, but they also hint at a potentially important advance.
The trial enrolled patients with advanced glioblastoma whose cancer had progressed after numerous earlier treatments. Far more work needs to be done to determine whether the therapy is truly safe and effective. But the release of these results is an ideal example of what the NExT program was designed to do.
NExT focuses primarily on therapies that have the potential to provide an important advance or meet a critical need but are unlikely to initially attract private sector investment because they are too high risk or may only be of potential benefit to a small patient population.
For more than hypertune 2jz intake manifold decade, NCI worked with the Duke team to transform a virus with a propensity for killing cancer cells into a clinical-grade therapy. That painstaking work improved the virus's potency in eradicating tumor cells while ensuring that it would not mutate into a disease-causing infectious agent. This effort involved extensive laboratory testing and manufacturing work by many investigators, including the development of a next-generation sequencing test to ensure the engineered virus was genetically stable from batch to batch.
The development and production of this oncolytic virus required difficult, complicated science that relies on technology and expertise that is not available at most institutions, even large academic centers. And it involved a type of therapy that, at the time PVSRIPO was accepted into the program, the private sector considered to be high risk and was unwilling to pursue. Excitingly, this therapy will soon be tested in trials involving ijingle mac cancer types, including childhood brain cancers, breast cancer, and melanoma.
This oncolytic virus is just one example of NExT in action. There are others, and their rapid ascension through the NExT development pipeline reflects the evolution and maturation of this program. For example, although NExT has always relied on cutting-edge science and the expertise of leading researchers and clinicians, over the past decade NExT has approached developing drugs much like biotechnology or pharmaceutical companies do.
That includes doing things like forming multidisciplinary teams to address the critical factors needed to move a therapy forward. The members of these teams include scientists from outside NCI with the specific expertise needed to advance drugs through the development process, from optimizing the chemical structure of a small-molecule drug to how best to test certain types of therapies in cell lines and preclinical animal models.
It also means embracing a sense of urgency by establishing aggressive timelines so that the agents in the NExT pipeline can advance through this preclinical process as expeditiously as possible. For example, researchers at Vanderbilt University initially discovered a small-molecule drug that targets the protein MCL-1, one of the most commonly overexpressed proteins in human cancer. MCL-1 has also been linked in a number of studies to treatment resistance, making it a highly attractive target for a cancer therapy.
Stephen Fesik, Ph. After being accepted, the compound then went through numerous studies, including complex analyses to understand and optimize its structure so that it more effectively binds to its target on cancer cells, thus reducing the risk of side effects. Those efforts paid off earlier this spring, with the licensure of this agent to the pharmaceutical company Boehringer Ingelheim, where it is anticipated to be tested in human clinical trials.
Oncolytic virus immunotherapy: future prospects for oncology
Another compound that recently graduated from NExT is one that blocks the activity of mutant forms of the protein IDH1, which are thought to be important drivers in glioblastoma. Initially accepted into the NExT program inthis compound has been tested extensively in the lab to ensure that it potently blocks the activity of IDH1 in cancer cells, to validate its ability to shrink tumors with IDH1 mutations, and to identify any signs of potential side effects.Thank you for visiting nature.
OVs offer a multifaceted therapeutic platform because they preferentially replicate in tumour cells, can be engineered to express transgenes that augment their cytotoxic and immunostimulatory activities, and modulate the tumour microenvironment to optimize immune-mediated tumour eradication, both at locoregional and systemic sites of disease.
Lysis of tumour cells releases tumour-specific antigens that trigger both the innate and adaptive immune systems. OVs also represent attractive combination partners with other systemically delivered agents by virtue of their highly favourable safety profiles.
Robert, C. Nivolumab in previously untreated melanoma without BRAF mutation. Motzer, R. Nivolumab versus everolimus in advanced renal-cell carcinoma.
Brahmer, J. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. Topalian, S. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. Kather, J. Genomics and emerging biomarkers for immunotherapy of colorectal cancer.
Cancer Biol. Khunger, M. JCO Precis. Rao, S.February 9,by NCI Staff. Researchers are developing tumor-targeting viruses, like this engineered poliovirus, as potential cancer treatments.
For more than a century, doctors have been interested in using viruses to treat cancer, and in recent years a small but growing number of patients have begun to benefit from this approach. Some viruses tend to infect and kill tumor cells. Known as oncolytic virusesthis group includes viruses found in nature as well as viruses modified in the laboratory to reproduce efficiently in cancer cells without harming healthy cells.
To date, only one oncolytic virus— a genetically modified form of a herpesvirus for treating melanoma —has been approved by the Food and Drug Administration FDAthough a number of viruses are being evaluated as potential treatments for cancer in clinical trials.
Oncolytic viruses have long been viewed as tools for directly killing cancer cells. But a growing body of research suggests that some oncolytic viruses may work—at least in part—by triggering an immune response in the body against the cancer.
When a virus infects a tumor cell, the virus makes copies of itself until the cell bursts. This can lead to an immune response against nearby tumor cells a local response or tumor cells in other parts of the body a systemic response. For this reason, some researchers consider oncolytic viruses to be a form of immunotherapy —a treatment that harnesses the immune system against cancer.
But many in the field would agree that more studies are needed to learn how different oncolytic viruses work against cancer. Since the late s, doctors have observed that some patients with cancer go into remission, if only temporarily, after a viral infection.
Today, several dozen viruses—and a few strains of bacteria—are being studied as potential cancer treatments, according to research presented at an NCI-sponsored conference on using microbes as cancer therapies in Although the notion of using viruses in cancer therapy is old, the science only began to move forward in the s with advances in genetic engineering technology, noted Matthias Gromeier, M.
Gromeier continued. The treatment, which is injected into tumors, was engineered to produce a protein that stimulates the production of immune cells in the body and to reduce the risk of causing herpes. In some patients receiving the therapy, tumors that could not be injected have shrunk, suggesting that T-VEC can generate a systemic immune response, noted Howard Kaufman, M.
Kaufman, who co-led the clinical trial that led to the approval of T-VEC. At the NCI meeting about using microbes as cancer therapies last year, more than investigators discussed many topics, including the need to better understand how infectious agents interact with tumors and with components of the immune system. Some viruses work primarily by killing tumor cells, whereas others work by directing local or systemic immune responses, he explained.
Kaufman noted that T-VEC, when given alone or in combination with other therapies, generally has been well tolerated by patients in clinical trials.
One of the challenges for researchers now is to try to enhance the immune response to the tumor through a variety of strategies, including by combining oncolytic virus therapy and immunotherapy. The promise of this approach has been demonstrated in two early-phase clinical trials. Patients with melanoma who received T-VEC plus a type of immunotherapy known as a checkpoint inhibitor had higher response rates than those who received a checkpoint inhibitor alone. The results suggested to the researchers that the combination therapy could induce an immune response.
Chesney, who co-led the clinical trial with Dr. The oncolytic virus induced the infiltration of immune cells known as T cells into tumors that had low levels of these cells prior to treatment, the researchers found. Haanen, Ph. The therapy was generally well tolerated, he noted, and the most common side effects were fatigue, fever, and chills. A phase 3 clinical trial involving patients with melanoma who will receive T-VEC with or without pembrolizumab is under way to assess the combination therapy in a large, randomized study.
This NCI-sponsored trial is testing the idea that injections of T-VEC into accessible melanoma tumors will increase the infiltration of immune cells into these and potentially other tumors, making them susceptible to treatment with pembrolizumab.Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer.
In addition, some oncolytic viruses can be engineered to express therapeutic genes or can functionally alter tumour-associated endothelial cells, further enhancing T cell recruitment into immune-excluded or immune-deserted tumour microenvironments. Oncolytic viruses can also utilize established tumours as an in situ source of neoantigen vaccination through cross-presentation, resulting in regression of distant, uninfected tumours.
These features make oncolytic viruses attractive agents for combination strategies to optimize cancer immunotherapy. In the initially published version of this article online in advance of print, a reference Ajina, A. Prospects for combined use of oncolytic viruses and CAR T-cells. Gajewski, T. Innate and adaptive immune cells in the tumor microenvironment. Topalian, S.
Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27— Hodi, F. Improved survival with ipilimumab in patients with metastatic melanoma. This is a randomized clinical trial demonstrating a clinical benefit of ipilimumab, the first immune checkpoint inhibitor that was approved for the treatment of melanoma.
Grosso, J. CTLA-4 blockade in tumor models: an overview of preclinical and translational research. Cancer Immun.
Sehgal, A. Programmed death-1 checkpoint blockade in acute myeloid leukemia. Expert Opin. Larkin, J. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.
Michot, J. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Cancer 54— Andrews, A. Health Drug Benefits 89 Wolchok, J. Overall survival with combined nivolumab and ipilimumab in advanced melanoma.Viruseslike the flu virus, try to enter the cells in our body because they need a host to survive.
Viruses continue to spread to other cells throughout the body, breaking down and killing increasing numbers of healthy cells, until the immune system is able to regain control and destroy the virus particles. Scientists have figured out methods of using the destructive nature of viruses to kill tumor cells in cancer patients. Oncolytic virus therapy OVT uses a virus that infects and destroys cancer cells but not normal cells.
This promising treatment approach is a targeted therapy that is typically used in conjunction with chemotherapy and radiation therapy. The viruses used in OVT are genetically engineered to exclusively replicate inside cancer cells and kill them without harming healthy cells. Researchers have found that viruses can be controlled to selectively affect cancer cells. In many OVTs the virus also is altered to contain genes that will boost the immune response.
In these cases, as the virus is making copies of itself inside tumor cells, the role that the immune cells play becomes increasingly significant in destroying the tumor. REIC gene therapy uses OVT in a unique way, in which the virus is modified to create a protein called REIC, triggering the normally suppressed pathway that leads to programed cell death.
Due to the cancer-cell-selectivity of OVTs, side effects are generally minimal. Imlygic is the first approved OVT in the Western world, and trials are continuing for the application of this therapy in pancreatic cancer and for use with chemotherapy and radiation therapy in the treatment of head and neck cancer.
A number of additional OVTs are still being tested in clinical trials, including those mentioned above. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
How OVT works The viruses used in OVT are genetically engineered to exclusively replicate inside cancer cells and kill them without harming healthy cells. Current OVTs Imlygic is the first approved OVT in the Western world, and trials are continuing for the application of this therapy in pancreatic cancer and for use with chemotherapy and radiation therapy in the treatment of head and neck cancer.
Ok Read more.The MarketWatch News Department was not involved in the creation of the content. The Oncolytic Virus Therapy market report clarifies market overview with definitions and classification, product types, applications and industry chain structure.
Today, researchers can modify existing viruses to create new oncolytic viruses that are less susceptible to immune suppression while more specifically targeting particular classes of cancer cells. Additionally, these modified oncolytic viruses can be adapted to insert and express cancer-suppressing genes and diagnostic proteins. Oncolytic Virus Therapy Market report includes detailed profiles of key players with regional analysis and focus on opportunities and challenges faced by Oncolytic Virus Therapy industry.
This Oncolytic Virus Therapy report deals with major aspects including region-wise manufacture capacity, price, demand, supply chain, profit and loss, row material parameters and specifications, consumption, export and import details, growth rate from toand Oncolytic Virus Therapy market trends. Economic Calendar. Retirement Planner. Sign Up Log In. Mark Cuban is moving to cash ahead of what the billionaire sees as another rough stretch for the stock market. What's next for gold prices amid continuing market volatility.
Dow futures soar points as investors pin hope on Gilead coronavirus treatment and U. Advanced Search Submit entry for keyword results.
No results found.Although gene therapy has huge potential for modern medicine, our enthusiasm for its powerful potential must not cloud our judgment about the dangers of using increasingly diverse, yet relatively untested, replicating viruses. Gene therapy is currently being studied in both the laboratory and the clinic in relation to many conditions, including cancer, heart disease, and autoimmune diseases.
A few thousand patients have received genes in more than a thousand different clinical trials—overwhelmingly patients with cancer two thirds of the trialswith most receiving non-replicative retroviruses or adenovirus as the vectors for the delivery of the new genes.
The use of viral vectors has now expanded from relatively safe, non-replicating viruses to the use of viruses that replicate more selectively in cancer cells than in normal cells oncolytic viruses. Cancer cells are ideal hosts for many viruses because they have the antiviral interferon pathway inactivated or have mutated tumour suppressor genes 23 that enable viral replication to proceed unhindered. Adenovirus 34 and herpes simplex virus, 5 specifically mutated to replicate faster in cancer cells, are the main replicating human pathogenic viruses used in the clinic.
Before the Helsinki protocols were approved, only a handful of studies had used live viruses injected into solid tumours. Currently, laboratory and some clinical studies are using many different viruses such as Newcastle disease virus, reovirus, poliovirus, vesicular stomatitis virus, measles, 6 and vaccinia 7selected for their ability to actively replicate in cancer cells. Newcastle disease virus, for example, causes fatal disease in chickens.
An argument for the use of these viruses is that some have shown long term safety as immunogens in humans. However, the dosage used for immunisation and that being used for gene therapy by intravenous or intratumoral injection is quite different. Measles vaccine Priorix, GSKfor example, is used as an immunogen in humans at a dose of about 10 3 pfu in the measles, mumps, and rubella vaccine MMR vaccinew2 and in mice experiments a dose of 10 6 7 pfu is used, which is at least a fold increase.
Oncolytic virus use, or virotherapy. Is it safe?
Newcastle disease virus is already in phase I clinical trials, 11 with about patients having been treated. Such application has to be supported by toxicity data from animal studies to justify the route, dose, and schedule of administration in humans.
The researchers also have to demonstrate that the material is free of other harmful contaminants. This is very important as the genome of RNA viruses mutates rapidly.
The use of oncolytic viruses has a key limitation in that they are highly immunogenic. The host immune response limits their effectiveness to local sites of injection and possibly to a single or a few administrations. Kaufman and colleagues have suggested that, for longer lasting effects, viruses should be further engineered to induce T cell memory in the host to cancer antigens 13 or with genes to express therapeutic molecules such as cytokines, pro-drug activating enzymes, and anti-angiogenic factors.
Melanoma gene therapy with vaccinia virus has led to vitiligo in some patients due to the expression of identical antigens in melanoma cancer cells and normal melanocytes. Regardless of whether a replicative virus is armed, its safety and genetic variability and capability for recombination should be properly assessed.
Recently the FDA has called for a workshop to discuss this, and hopefully new guidelines will became available. Whether replicating armed viruses 8 will be able to modify the immune response of the host and become highly pathogenic is not known and may not be answerable in currently used animal models.
Such an approach, although expensive, would ensure at least proper assessment of changes in immune parameters, which cannot be done in the currently used models. These interactions will either synergize to increase, or conflict to decrease patient benefit. The arming of replicating viruses, particularly with immunomodulatory genes, can pose unforeseen consequences—one example being IL-4 producing, replication-competent ectromelia viruses mousepox in mice.
Despite these original studies being halted, the armed virus is now being used as a biological warfare model to develop more potent antiviral drugs. Different viruses have developed different mechanisms for immune evasion, including the expression of cytokine and cytokine receptor homologue genes. The use of a variety of oncolytic viruses has recently been reviewed. In view of the expected pandemic arising from avian influenza virus w7 and the knowledge that species adaptation can occur relatively quickly, is it safe to consider the use of viruses from other species, breaking all natural and tropism barriers by intravenous or intratumoral administration in humans?Combination of viroimmunotherapy with checkpoint inhibitors
The use of replicating viruses poses new and unpredictable risks not only to the individual treated but also to the population as a whole as these viruses may spread in the environment and also potentially recombine with other wild-type viruses. Specific guidelines are urgently needed to cover the clinical application of such replicating oncolytic viruses both at local and international levels. Furthermore, because of the biological limitations of the animal models described earlier, we need to have more discussion about how preclinical testing for safety should be carried out.
Cancer is indeed a terrible disease demanding aggressive, ingenious, and imaginative approaches. However, the balance of risk and benefit must always be of prime consideration, not only for the patients but now also for the rest of the population.