Oncolytic Virus Basis
The strategy implementation of immunotherapeutic for the treatment of cancer has gained prominence over the past decade in preclinical development and clinical practice. Traditional oncological treatments, including surgery, radiation, and chemotherapy, aim to directly remove or kill cancer cells, but receive high probability of recurrences or serious side effects. In contrast, immunotherapy seeks to enhance the host immune system's ability to eliminate cancer cells, contributing to tumor regression, antitumor immune memory formation, and ultimately durable responses.
There has long been interest in innovating an approach by which tumor cells can be selectively and specifically targeted and destroyed. Surprisingly, Oncolytic viruses (OVs) are viral strains that can infect and kill malignant cells without harming normal cells, while simultaneously stimulating the immune system and creating antitumor immunity.
Figure 1. The anti-tumor mechanism of oncolytic virus
Taking advantage of the OncoVirapy™ platform, Creative Biolabs provides a comprehensive overview on the basic biology that supports OVs as cancer therapeutic agents, including the history of oncolytic virus development, mechanisms of oncolytic virus targeting cancer cells, and mechanisms of action of virus destroying tumor cells, as well as the properties of inherent and engineered oncolytic viruses. Based on this basic knowledge review, we hope you can have a comprehensive understanding of OVs and quickly capture one of the frontiers of immunotherapy research.
Brief history of oncolytic virus
Although viruses have been utilized as therapeutic agents in the form of vaccines since the late 1700s, their potential application as a cancer therapy was not explored until a series of earliest clinical references reports were published dating back to the early 1900s, when several cancer patients were relieved after concurrent infection with naturally-acquired viral illnesses. The first documented case of viral infection-induced regression was in 1904 when a 42-year old woman with chronic myelogenous leukemia experienced a marked reduction in white blood cells during a flu-like illness. In another case, a four-year old boy with leukemia demonstrated a remarkable remission after acquiring chickenpox. Unfortunately, after a one-month remission, his leukemia relapsed and progressed rapidly to death. These observations led to the hypothesis that viruses, in particular genetically engineered viruses, were immunogenic and might be employed in the treatment of cancer.
Whereafter, a variety of different tumor types (including leukemia, cervical cancer, lymphomas, solid tumors, melanoma, and multiple myeloma) and viruses (including rabies virus, mumps virus, measles virus, adenovirus, parvovirus, and Newcastle disease virus) got involved in tentative oncolytic therapies (Figure 2). Although some patients experienced short-lived clinical remission of their cancers, a notable proportion either died from the side effects of the viral therapy or had the brief remissions that were reversed by a strong anamnestic response from the patient's immune system, leading to continued cancer progression and death from the primary disease. Several early landmark clinical trials highlighted both the potential of viral therapy as a cancer treatment, as well as its dreadful side effects. Following a series of disappointing clinical trials, interest in oncolytic viruses waned in the 1970-80s until the development of genetic engineering in the 1990s made it possible to alter viral genomes. This technological advancement allowed manipulations of the viral genome to improve selectivity and decrease toxicity.
Since then, the development of viral therapy from laboratory to bedside has finally been realized. ONYX-015 became the first virus to enter Phase I clinical trials in 1996 and the adenovirus mutant H101 became the world's first OV approved for cancer treatment in 2005 in China. Following a Phase III trial showing improved durable response rate for the intralesional treatment of melanoma, IMLYGIC™ (T-VEC/Talimogene Laherparepvec), a genetically engineered HSV, became the first oncolytic virus approved by the FDA in October 2015. Thus far, various OVs have been successfully tested for their oncolytic activities against almost all types of cancers, and are being evaluated in numerous international Phase I, II, and III clinical trials.
Figure 2. Brief history of oncolytic virus
How dose oncolytic virus work?
The potential of OVs to improve the therapeutic ratio is derived from their ability to preferentially infect and replicate in tumor cells while avoiding destruction of normal cells surrounding the tumor (tumor tropism). Two main mechanisms exist through which these viruses are reported to improve outcomes: direct lysis of tumor cells and indirect augmentation of host anti-tumor immunity.
Mechanisms of Tumor Tropism
Tumor tropism (selective viral replication in tumor cells but not in healthy tissue) is important for oncolytic viruses to function as a cancer immunotherapy. Interests in oncolytic viruses has been increasing based on a better understanding of viral biology, tumor immunology and molecular genetics. Many viruses have been reported to carry oncolytic property. As an experienced service provider, we have summarized the mechanism of oncolytic virus targeting tumor cells.
In terms of oncolytic virus targeting cancer cells, both natural and engineered viruses take advantage of many differences of genetic characteristics and physiological features between tumor cells and normal cells, such as activation of proto-oncogene, the inactivation of tumor suppressor genes, cellular defense mechanism defect, abnormal growth signals, which result in some differentially or specific expression of surface receptors, and also exception of signal pathway. Due to the rapid proliferation of tumor cells, a hypoxic environment formed is another worthy channel. Those characteristics can make the oncolytic viruses find tumor cells in the complex human system (Figure 3).
Figure 3. Virus targeting tumor cells in various ways
- Cancer cells have been shown to overexpress selected surface receptors, a core mechanism by which viruses may selectively bind to and infect cancer cells. Measles virus has been shown to utilize the surface receptor CD46 for cellular entry, which is overexpressed in a variety of human cancers, including hepatocellular carcinoma, colorectal cancer, ovarian cancer, and breast cancer.
- Some viruses naturally exploit the aberrant signaling pathways that maintain sustained cancer growth in order to selectively infect and replicate within cancer cells as opposed to normal cells. For instance, constitutively active AKT pathway signaling serves as a sustained growth and survival signal in many different types of cancer.
- In addition, OVs can also capitalize on the hypoxic environment resulting from the rapid proliferation of tumor cells. The vesicular stomatitis virus (VSV), an oncolytic RNA virus, is capable of replication under hypoxic conditions. In cells undergoing hypoxic stress, VSV infection produced larger amounts of mRNA than under normoxic conditions.
Mechanisms of Action of Viruses Destroying Cancer Cells
Oncolytic immunotherapy employs viruses to directly lyse cancer cells (oncolysis). These viruses infect tumor cells, where they undergo a series of replication cycles and are subsequently released through cell lysis to infect adjacent cancer cells. This cycle can repeat hundreds of times, attacking and decreasing the tumor cell mass. Moreover, beside this primary effect, OVs can also stimulate the immune system. Tumor is an immuno-suppressive environment in which the immune system is silenced in order to avoid the immune response against cancer cells. The delivery of OVs into the tumor wakes up the immune system so that it can facilitate a strong and durable response against the tumor itself. (Figure 4)
Here, Creative Biolabs also provides a detailed mechanism of oncolytic viruses action destroying tumor cells.
- Tumor cell lysis
- Anti-tumor immune response
Figure 4. Mechanisms of actin of oncolytic viruses destroying tumor cells (Omid Hamid, 2017)
Inherent and engineered oncolytic viruses
Some viruses demonstrate to be inherently oncotropic to target tumor cells selectively and more efficiently than normal cells, and trigger the antitumor immune system, resulting in tumor degeneration and health improvement, such as Newcastle disease virus (NDV), vesicular stomatitis virus (VSV), parvoviruses, coxsackievirus and reovirus, which have been directly designed as natural elements in the treatment of cancer as virotherapy.
Although some viruses exhibit an innate tropism for tumors, other viruses must be molecularly engineered to selectively infect tumor cells. It is noteworthy that the wide types of such viruses may carry harmful pathogenic genes, which have to be modified for deleting. Moreover, the immune response to oncolytic viruses appears to be an important component of the anti-tumor effect, but it can be a double-edged sword. On the one hand, viruses can help to promote an immune response against the tumor cells by allowing tumor antigen presentation in the context of an active viral infection. On the other hand, neutralizing antiviral responses may block virus replication and ongoing infection of tumor cells. Therefore, it is also necessary to reduce the antiviral immune response for unstinted replicating and function.
Advances in molecular biology have afforded the OV field an opportunity to alter the DNA sequences of viruses and thus engineering viruses that are more specific for cancer cells than their normal counterparts. In general, viruses are chosen or modified to selectively target tumor cells, decrease pathogenicity to normal cells, decrease the antiviral immune response (to prevent viral clearance), and increase the antitumor immune response. At present, engineering of viruses including adenoviruses (Ad), Vaccinia viruses, influenza viruses, polioviruses, measles virus (MV) and HSV has enabled researchers to fight against a variety of cancers.
Based on years of research and timely tracking of information, Creative Biolabs offers a detailed description about both natural and modified oncolytic viruses, providing you with a convenient learning platform.
Figure 5. Inherent and engineered oncolytic viruses
Prospection
Oncolytic viral therapy has made great strides in recent years. By embracing immune manipulation as a route to enhanced viral efficacy, oncolytic virotherapy is bound to rapidly expand in the near future.
As the world's top technology consulting and services platform, Creative Biolabs can provide comprehensive oncolytic virus therapy development services, including oncolytic virus construction, oncolytic virus engineering, oncolytic virus validation, disease-specific oncolytic virotherapy development, which will help you get satisfactory result in a short time. Creative Biolabs also provides full range of products to facilitate your researches in the field of virotherapy and gene therapy. Our service can be designed to meet your special needs if you have any requirements. If you are interested in our service, please contact us by e-mail and our team will get back to you as soon as possible.