Oncolytic viruses (OV) are a form of immunotherapy using viruses to infect and destroy tumors. The practice is based on evidence suggesting infections of certain viruses have led to the development of certain forms of cancer, and a possible reversal of this trend, paired with historical observations of certain viral infections leading to cancers moving into remission. Some viruses tend to infect and kill tumor cells, and these viruses have been modified in laboratories to reproduce the effects that attack tumor cells without harming healthy cells. The viruses are weak enough to allow the human immune system to deal with the virus once a tumor is destroyed.
These viruses are capable of attacking cancer cells, because the cancer cells often have impaired antiviral defenses, making them susceptible to infection. And when these viruses can be engineered to have advantageous properties, they can be used to deliver therapeutic payloads specifically to tumors and can produce immune-boosting molecules. After the infection, these oncolytic viruses can cause cancer cells to burst and release cancer antigens, which stimulate the body's immune response that seeks out any potential remaining tumor cells in the body to destroy them.
One of the challenges for researchers into oncolytic viruses is finding ways to enhance the immune response to a tumor. This can be done through a variety of strategies, including combining oncolytic therapy with immunotherapy, which has been demonstrated in two early-phase clinical trials. Patients with melanoma who have received approved oncolytic viral therapy with a type of immunotherapy known as checkpoint inhibitor have shown higher response rates than those who received a checkpoint inhibitor alone.
In one such trial into the effectiveness of an oncolytic virus paired with immunotherapy, nearly 200 patients received an oncolytic virus, T-VEC, with or without ipilimumab. The results suggested the combination therapy could induce an immune response. In the second trial, which included 21 patients, T-VEC was combined with pembrolizumab. The oncolytic virus induced the infiltration of immune cells known as T-cells into tumors, and suggested the viral therapy could change the local microenvironment to make an immunologically cold tumor, or a tumor lacking T-cells, into an inflamed tumor.
In a phase three clinical trial, which involved 600 patients with melanoma, the patients received T-VEC with or without pembrolizumab to assess the combination therapy in a large, randomized study. The same combination has been evaluated in clinical trials for patients with advanced melanoma that has progressed despite treatment with a checkpoint inhibitor.
At the Duke Cancer Institute, a research team began testing an engineered poliovirus, PVS-RIPO, in patients with glioblastoma. When the research began in the mid-1990s, oncolytic viruses were primarily viewed as agents for killing cancer cells. As PVS-RIPO was tested in patients, thinking changed with noted changes to immune responses in patients. Based on these results, the FDA granted "breakthrough status" to Duke's poliovirus therapy in 2016. The status allows officials at the FDA to accelerate the agency's review of the therapy for approval.
Despite the potential of oncolytic viruses, limitations to their study and use exist. These factors include viral tropism, delivery platforms, viral distribution, dosing strategies, antiviral immunity, and oncolysis. In solid tumors, there are a range of obstacles that oncolytic viruses need to circumvent to reach the tumor site. One of these includes physical barriers that can stop the delivery of an oncolytic virus as it must get past the endothelial layer to reach the target cells. In addition, an abnormal lymphatic network and vascular hyperpermeability inside tumors can result in interstitial hypertension, which can impair viral infiltration.
Oncolytic viruses can also induce strong immune responses from the interaction between viruses and tumors. This response is more likely to clear the oncolytic virus, especially when the virus has been weakened so as not to harm the patient. In the case of an oncolytic virus being cleared by the host immune system, it can be difficult to determine whether it has reached the tumor site and if it has reached the site in sufficient numbers.
There are different possible applications for oncolytic viruses, which include tumor diagnosis and tumor treatment, and some which have not necessarily been discovered.
There are various types of imaging technology for the diagnosis of tumors that play an irreplaceable role, especially in the case of CT and MRI, in the positioning and local invasion assessment of tumors. However, the early detection of primary tumors and small metastases cannot be effectively acquired, so higher sensitivity and accuracy of imaging technology is needed. Oncolytic viruses have been suggested for higher sensitivity imaging, with certain viral genes that can selectively infect tumor cells and replicate within them or express genes of interest that can be used to detect gene expression products to obtain non-invasive, real-time molecular imaging in vivo. When used with fluorescence imaging, obtained from invertebrate marine animals, this can be used to detect tumor behaviors—including amplification, invasion, and metastasis.
Three oncolytic viral drugs have been approved for some clinical cancer treatments, which include RIGVIR, Oncorine, and T-VEC, which have all achieved goo therapeutic effects.
The Riga virus is an picornavirus approved for the treatment of melanoma in Latvia, Georgia, and Armenia. It also became the first oncolytic virus that obtained regulatory approval globally in 2004. But, despite its regulatory approval, there has been a limited description of its biological characteristics and efficacy when used in the treatment of malignant tumors. Research has found that early-stage melanoma patients who received surgical resection and Rigvir survived longer than those who received resection alone. Though all patients were pronounced disease-free following surgery, Rigvir was administered post-surgery only after the surgical wounds had healed. Low-grade melanomas after surgical resection seemed in these conditions to be more sensitive to the treatment of Rigvir. However, the potential of Rigvir to treat melanoma patients remains somewhat unknown.
Oncorine was the first approved oncolytic virus for clinical use in China and was one of the first recombinant oncolytic viruses. It was used in treatment of patients with head and neck cancer since being approved by the Chinese State FDA (SFDA) in 2005. Oncorine is an attenuated serotype five adenoviral vector with a deletion in viral E1B-55k and four deletions in viral E3. The operation method used in clinical trials was for patients to receive combination cisplatin and 5-fluorouracil with or without Oncorine for five consecutive days in between two and forty-three week cycles. The response rates of patients with Oncorine plus chemotherapy were 78.8 percent, while the response rate of patients receiving chemotherapy alone was 39.6 percent. High seroprevalence against several adenovirus serotypes limits the ability to deliver Oncorine, and delivery methods have used modified knob proteins to transport Oncorine. Some of the adenovirus introduction vectors are in clinical trials to test their safety and efficacy for intravenous delivery.
Talimogene laherparepvec has been approved for use in the treatment of non-resectable metastatic melanoma by the United States FDA in 2015 and has also been approved for locally advanced or metastatic cutaneous melanoma in Europe. The treatment involves a herpes virus engineered to be less infectious to healthy cells while infecting cancer cells to produce the immune-stimulating GM-CSF protein. The side effects of this treatment can be influenced by the location and type of cancer and the patient's overall health. Due to the potential for oncolytic viruses to stimulate overall immune activity, it can cause the immune system to attack healthy cells. Other common side effects include chills, fatigue, flu-like symptoms, injection site pain, nausea, and fever.
T-VEC was approved for the treatment of cutaneous high-grade melanoma lesions through intratumoral injection and has shown single-agent efficacy. This has also been tested in patients with liver, pancreatic, and advanced nervous system solid tumors, as well as the safety and usefulness of T-VEC alone or in combination with checkpoint inhibitors, chemotherapy, or radiation therapy in melanoma. According to an article published in 2017, late-stage melanoma patients treated with T-VEC and PD-1 inhibitor pembrolizumab was able to achieve a satisfactory result in treatment with fewer side effects.
Besides the oncolytic viruses in use for treatment, there are various oncolytic viruses in preclinical trials. Among these, the herpes virus, adenovirus, and vaccinia virus have so far presented good experimental results. Other viruses being studied for use as oncolytic viruses include the Maraba virus, measles virus, Newcastle disease virus, picornavirus, reovirus, and vesicular stomatitis virus.
Ongoing oncolytic viruses in clinical trials
Therapeutic conventional surgery
The measles virus is a negative strand RNA paramyxovirus that can induce extensive cytopathic effects. Overall, no drug-related dose limiting toxicities have been observed in clinical trials with the measles virus, and in one study, MV-NIS induced complete remission of disseminated multiple myeloma after one systemic administration of the infectious virus. An immunological analysis of peripheral T-cells in ovarian cancer receiving the MV-NIS measles virus has shown an induction of tumor antigen specific T-cells after therapy. Other engineering strategies have included retargeting the H attachment glycoprotein to obtain viruses that will target tumors. These viruses have also been engineered to encode the wild type P accessory protein, which can enhance the viral spread to increase the chance for antagonizing the patients' antiviral immunity.
NDV is an avian paramyxovirus and has been tested as an oncolytic or oncolysate cancer vaccine. Strains of NDV have been used and tested clinically for a while in immunotherapy. In the United States, PV701 has been given intravenously to patients with advanced cancers in three Phase 1 trials. In a trial of seventy-nine patients, a complete remission was observed for one patient and partial remission was observed in another patient. Meanwhile, the same study showed that higher doses of the PV701 strain have been better tolerated with less infusion reactions if patients received a five to ten fold lower dose for desensitization first. Further clinical studies have used a mesogenic strain of NDV as an oncolytic agent for cancer therapy has been hampered by its pathogenicity in avian species.
Rhabdoviruses are negative sense RNA viruses with rapid lytic replication cycles. The best studied oncolytic rhabdovirus Vesicular Stomatitis Virus (VSV) uses the low-density lipoprotein (LDL) receptor for cell entry, which allows VSV to infect nearly all cell types and cause lytic infection in a variety of permissive cells. Major modifications have been made in oncolytic rhabdoviruses to ensure and improve tumor selectivity. And an alternative modification was used to exploit VSVs to allow for better infection of cancer cells and for better virus replication in those cells to better combat tumors and engage the patients immune system.
Adenoviruses are non-enveloped icosahedral double-stranded DNA viruses with long fiber knobs protruding from each capsid vertex. At least seventy serotypes of human adenovirus exist, with a few serotypes including serotype 5 being the most commonly used. Attenuation strategies for oncolytic adenoviral vectors have revolved around two central mechanisms: targeting Rb-deficient tumors and targeting p53 deficient tumors. There have also been unique adenoviruses designed through directed evolution to replicate and kill colorectal cancer cells more efficiently than epithelial cells but without no attenuating mutations.
The vaccinia virus is related to the cowpox virus, and is a large, enveloped, double-stranded DNA virus with a linear genome that is approximately 190 kb in length. The vaccinia virus is the namesake virus for vaccination following its widespread use in the eradication of smallpox. Three oncolytic vaccinia viruses have been studied clinically, derived from Wyeth, Western Reserve, and Lister. The vaccinia virus has been modified with deletion and insertional mutations in order to be used in a clinical setting and to reduce the possible harm to a patient. As well, strategies to enhance oncolytic efficacy of vaccinia vectors tend to focus on transgene incorporation. Through transgenes, the vaccinia virus can be improved to attack tumors. Using these transgenes, a 1993 study showed the combination of dead or dying tumor cells could enhance anti-tumor immunity in tumor-bearing mice.
The herpes virus is a large double stranded DNA virus approximately 152 kb in length and was the first virus backbone to be engineered to combat cancer. Further development led to the generation, preclinical and clinical testing of the herpes virus lacking both neurovirulence and the ability to inhibit the antiviral response. Different variations of the herpes virus have been undergoing clinical trials and evaluated in patients with breast, head and neck, and pancreatic cancers. However, a high prevalence of herpes neutralizing antibodies in the United States population remains a barrier to systemic delivery of oncolytic herpes virus vectors. In that case, these oncolytic viruses are generally delivered locoregionally or intratumorally to avoid intravenous administration. There have been attempts to also boost the anti-cancer effects of the herpes virus, which have involved the inclusion of therapeutic transgenes to simultaneously boost anti-cancer and anti-viral immunity, with the goal of developing an adaptive anti-tumor response in treated patients.
The coxsackievirus is a single-stranded positive RNA picornavirus of approximately 7.4 kb, enclosed in an icosahedral capsid. Oncolytic strains of the coxsackievirus have been derived from the Kuykendall strain and has used the ICAM-1 as the primary receptor for cell entry. This strain has been tested in intratumoral or intravenous administration, with a checkpoint blockade, in a number of Phase I and Phase II clinical trials in patients with breast cancer, prostrate cancer, bladder cancer, multiple myeloma, melanoma, and non-small cell lung cancer.
The reovirus is a double-stranded RNA virus, non-enveloped, and has an icosahedral capsid composed of an outer and inner protein shell. This virus naturally infects the gastrointestinal tract without causing serious disease, and some estimate that up to 100 percent of the healthy adult population has pre-existing antibodies to reovirus. However, cells with an activated Ras path, such as cancer cells, have been shown to be susceptible to reovirus infection. Reovirus as a monotherapy has been suggested and investigated in several Phase I trials to understand the possible effects based on different administration pathways. These, and other Phase I and Phase II trials have seen a single patient out of twenty-six see complete remission, and a further six patients in partial remission.
The concept of immunotherapy has been used and acknowledged for centuries, as the relationship between microbial infection and spontaneous tumor regressions has been reported several times in medical literature. Some of the earliest known evidences come in the Ebers papyrus dated from around 1550 BC. This document, one of the oldest medical documents of ancient Egypt, which details the physicians of Egyptian pharaoh Imhotep (2600 BC) using poultice, followed by incisions, for the treatment of tumors. This created infections that helped to regress the tumors.
In the 17th and 18th centuries, various forms of immunotherapy became widely used. In the 18th and 19th centuries, septic dressing enclosing ulcerative tumors were sometimes used for cancer treatments. Sometimes surgical wounds could be deliberately left open to develop an infection as it was believed purulent infects were helpful. In one detailed case series, reported by surgeon William B. Coley, he treated cancer patients with a bacterial lysate.
Further, throughout the 1880s, doctors began to observe some patients with cancer enter remission, if only temporarily, after a viral infection. More recently, several viruses and strains have been studied for cancer treatments. Further, more reports of therapeutic effects of viruses in cancer appeared more in the beginning of the 20th century. Some of these early reports were leukemia patients becoming disease-free after viral infections, and the medical communities interest grew. By the 1950s and 1960s, multiple wild type viruses were used to treat different cancers in hundreds of case series. The results were variable, and often they were poorly documented, and during the period it became clear that wild type viruses lacked the necessary efficacy or safety.
For example, in 1956, thirty women with advanced epidermoid carcinoma of the cervix were treated with adenovirus. Intra-arterial, intravenous, and intratumoral administration were used, and within ten days, two-thirds of the patients showed necrosis in their tumors and the effects appeared to be restricted to the cancerous tissues.
The use of viruses for therapy received little attention, despite some of these results. And, in the 1970s and 1980s, the regulatory aspects of clinical trials with living pathogens grew stricter while chemotherapies, radiation therapy, hormonal therapy, targeted, and antiangiogenic therapies all became mainstream. It took three decades for oncolytic viruses to re-emerge, and were used to infect and break down cancer cells but not normal cells.
The interest in oncolytic viruses re-emerged at a time when increases in molecular biotechnology and related techniques meant new strategies to harness the immune system for cancer therapy. A number of approaches, including adoptive cell therapies, monoclonal antibodies, checkpoint inhibitors, and oncolytic viruses offer some of the more prominent advancements in cancer treatment.
With an increased interest in the innovation in oncolytic viruses, the growing amount of research, and FDA approval of the T-VEC strain for therapeutic use, interest from biotechnology companies has also grown. The therapeutic cancer market was evaluated at USD $158 billion market in 2020 and has been expected to continue to grow from there. Of this, the oncolytic virus market is expected to grow with it and is considered by some to be a possible breakthrough portion of the overall therapeutic cancer market.
Furthermore, starting in 2018, larger biotechnology and pharmaceutical companies began acquiring early-stage biotechnology companies working on oncolytic virus therapies. As well, in similar timeline, there was increased interest in companies developing oncolytic virus therapies from venture capital firms.
Companies developing oncolytic viruses
An engineered oncolytic virus expressing PD-L1 inhibitors activates tumor neoantigen-specific T cell responses - Nature Communications
March 13, 2020
Clinical landscape of oncolytic virus research in 2020
Oncolytic Virus Therapy
Oncolytic Viruses and Their Application to Cancer Immunotherapy
Oncolytic viruses for cancer immunotherapy
Otto Hemminki, João Manuel dos Santos, Akseli Hemminki
June 29, 2020