Work on viruses as antitumor agents began in the 1950s, but advances in molecular biology have provided new tools and new possibilities for engineering their potency, selectivity, and safety.
1This mutant version of HSV displayed attenuation of neurovirulence but was still able to operate in mouse glioblastoma cells.
Twenty years later, modifications to viruses include not only reduction of viral pathogenicity to better protect healthy cells and modification of viral genes to reduce infections of certain cell types, but also manipulation of the viral genome to add useful mammalian genes.One of the most intriguing new areas for engineering viruses is creation of properties to boost antitumor immune responses in the host/patient, thereby delivering a combination of tumor-killing virus and cancer signal to enlist the patient’s own immune system to aid in destroying the tumor. Another fertile area of development is the administration of conventional chemotherapy agents with oncolytic virus treatments for a combination therapy approach.
Several varieties of viruses, in addition to HSV, are being investigated for potential use as antitumor agents. Each virus has advantages and disadvantages, depending on the type of cancer and the specific approach employed. More than 100 clinical trials are being conducted worldwide on various oncolytic viral therapies.2One of the most promising candidates, which could be the first in line to be approved by the US Food and Drug Administration (FDA), is intended for treatment of late-stage melanoma. Talimogene laherparepvec (T-VEC) from Amgen is in a phase III trial that is scheduled for completion in September 2014. T-VEC is an attenuated HSV virus that is engineered to release granulocyte macrophage colony stimulating factor (GM-CSF) after infection of the melanoma, priming the host’s immune system to also attack the tumor.3
Howard Kaufman, MD
A randomized, open-label trial is comparing the safety and efficacy of T-VEC with a control of GM-CSF alone in more than 400 patients with unresected, stage IIIB, IIIC, or IV melanoma. T-VEC data were released by Amgen on November 18, 2013, at the 2013 Society for Melanoma Research Congress. Results on overall survival (OS) from a predefined interim analysis of the trial showed a median OS of 23.3 months in the T-VEC arm compared to 19.0 months in the GM-CSF arm (hazard ratio [HR] = 0.79; 95% confidence interval [CI] 0.61-1.02;P= .075).4
“A favorable trend in overall survival was observed in patients who received talimogene laherparepvec and the trend was pronounced in patients with stage III and IV M1a disease where an important clinical need exists for patients whose disease has not yet spread to distant organs,” said Howard Kaufman, MD, professor and director of the section of surgical oncology in the department of general surgery, Rush University Medical Center in Chicago.4
In an updated analysis, Amgen noted that the HR for OS and the median improvement in months for T-VEC versus GM-CSF was nearly the same as reported at the interim analysis. However, the updated P value from more mature data failed to reach statistical significance (P= .051).
T-VEC, like many other oncolytic viruses, is administered by intratumoral injection. However, this approach would not be practical for metastatic cancers, and intravenous delivery would be preferred for all oncolytic viral therapies. Ongoing research efforts may make systemic approaches more practical in the future.A key issue in delivering effective dosages is viral titer, with potential limitations related to manufacturing capacity.2 In a recent phase I clinical trial, an oncolytic virus delivered intravenously could only be recovered from tumor biopsies when doses above 109 infectious units were used.5The study indicated that systemically administered oncolytic viruses are able to extravasate from tumor vasculature to specifically target, infect, and replicate within tumors. However, success depends on sufficient viremic concentration above threshold. While oncolytic viral therapy has, to date, been characterized by clinical tolerability even at the highest feasible doses,6future work will likely use even higher amounts, so it may be too early to say whether or not effective oncolytic virotherapy will be free of serious side effects at clinically effective dosages.One oncolytic viral therapy that is being administered systemically is REOLYSIN® from Oncolytics Biotech of Calgary, Alberta, Canada. REOLYSIN® is a proprietary variant of the reovirus, an acronym for respiratory enteric orphan virus (type 3 Dearing [RT3D]), which is widely found in the environment. It is a common, nonpathogenic virus for which replication is typically blocked in healthy cells. However, cancer cells with an activated Ras pathway, which lack the activated form of protein kinase R (PKR), an interferon-inducible double-stranded RNA protein kinase, cannot defend against reovirus replication, leading to death of infected cancer cells and subsequent infection of nearby cells.7REOLYSIN® is involved in 30 clinical trials worldwide on a wide variety of cancers, but the most advanced of these (phase III) compares REOLYSIN® treatment combined with paclitaxel/carboplatin (PC) chemotherapy with chemotherapy alone for squamous cell tumors of the head and neck.8
In December 2012, Oncolytics Biotech released data on initial percentage changes between pretreatment and post-treatment scans of the 105 patients with metastatic tumors who were enrolled. In the test arm, 86% (n = 50) showed tumor stabilization or shrinkage, compared with 67% of patients (n = 55) in the control arm (P= .025). REOLYSIN® in combination with PC surpassed PC alone in stabilizing or shrinking tumors (P= .03).9
In November 2013, Oncolytics Biotech delivered progression-free survival (PFS) data for 118 patients in the study with loco-regional head and neck cancer, with or without metastases. Median PFS for patients in the test arm was 94 days (n = 62) and 50 days in the control arm (n = 56). Loco-regional patients who received no additional therapy after discontinuation of treatment had a median overall survival (OS) of 150 days in the test arm (n = 50), versus 115 days in the control arm (n = 38).10
Brad Thompson, PhD, the CEO of Oncolytics, said of the results: ”We are excited to move forward with our head and neck program, and intend to discuss the design and execution of a follow-on registration study with regulators in the near future.”10Other issues in systemic administration of treatments such as REOLYSIN® involve successful delivery of the virus to the tumor site while evading the body’s defense mechanisms. “One of the greatest challenges we have faced is working out how to inject these viruses into patients so they are able to reach the tumors and kill them efficiently, before being inactivated by the immune system,” said Professor Kevin Harrington of the University of London’s Institute for Cancer Research.11For example, the mononuclear phagocytic system (MPS) seeks to sequester viruses to the liver and spleen. Recent strategies to minimize sequestration have involved chemical modification of the viral coat with polymers such as polyethylene glycol (PEG),12while serum factors that detect and destroy virus particles in the blood stream can be evaded by hiding the viruses within carrier cells. Mesenchymal stem cells (MSCs) preferentially find and bind solid tumor cells and have been used to efficiently carry measles virus particles to intraperitoneal ovarian tumors.13
Once the oncolytic virus has been delivered to the site of the tumor, different strategies are available for enhancing infection. Interferons (IFN) and their receptors play a major role in cellular defense against viruses, and even carcinogenic cells may still retain some of this capability. However, chemicals such as histone deacetylase (HDAC) inhibitors can be used to suppress residual antiviral activity in tumors by neutralizing IFN responses, thus increasing potency.14While the tropism of oncolytic viruses for particular cell or tissue is a handy and inherent protection against toxicity to healthy, nontumor cells, the preference is not absolute, particularly in immunosuppressed hosts. One exciting new twist to dialing in viral selectivity is exploiting the tightly regulated differential expression of microRNAs. Recent approaches have seen the engineering of tissue-specific microRNA binding sites onto the 3’ untranslated region (UTR) of viral genes. For example, in a recent study using adenovirus, researchers modified the 3’ UTR of theE1Agene to include liver-specific microRNA binding sites, thereby eliminating hepatotoxicity.15
In an even more sophisticated case of fine-tuning viral specificity, scientists drove adenovirus replication using a tumor-specific promoter, telomerase reverse transcriptase, not active in any adult somatic cell, while also using microRNA sites in the E1A UTR to block infection in nontumor cells.16Researchers are creating new oncolytic viral therapies faster than they can be tested in clinical trials. The many advantages of oncolytic viruses are potentiated by the almost endless possibilities afforded by genetic engineering of attenuated virulence, expression of mammalian proteins to boost antitumor immunity, and exquisite selectivity. The anticipated first-in-class US approval this year of an oncolytic viral therapy for late-stage melanoma will likely spur yet more research activity into this increasingly promising area.