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Oncolytic Virus-Mediated Immunotherapy: A Combinatorial Approach for Cancer Treatment.

In recent years, there has been a resurgence of interest in cancer immunotherapy strategies because of encouraging preclinical and early clinical trial results. In parallel, many scientists have been engineering tumor-cell lysing oncolytic viruses (OVs) and evaluating their clinical potential. In addition to their obvious lytic effects on tumor cells, OVs may also improve long-term antitumor immunity by directing immune responses to the tumor, and they can be enhanced by incorporating immune stimulatory transgenes into the OV genome. This combination of OVs and immunotherapy— oncolytic virus–mediated immunotherapy— has now emerged as a promising approach in human patients. Amgen’s experimental melanoma treatment, talimogene laherparepvec (widely known as T-VEC) has shown significant benefits in a phase III trial for advanced melanoma (see the accompanying article by Andtbacka et al), and in April 2015, an independent advisory panel to the US Food and Drug Administration (FDA) voted 22 to 1 in favor of approval for this agent. T-VEC is a herpes simplex virus type 1 (HSV-1) – derived OV that selectively replicates in tumor cells causing cell lysis; it has also been engineered to provoke anticancer immunity via expression of granulocytemacrophage colony-stimulating factor (GM-CSF). The FDA Advisory Panel’s favorable vote was based on the outcome of a phase III clinical trial in patients with advanced melanoma (unresectable stage IIIB to IV). This open-label, randomized trial tested the effect of intralesional T-VEC versus subcutaneous GM-CSF in 436 patients by using durable response rate (objective response lasting continuously for at least 6 months or more) as the primary end point. Overall survival and overall response rate were secondary end points. The authors reported that the durable response rate was significantly higher with T-VEC, whereas median overall survival and overall response rate displayed a strong trend toward significance. The effects were most pronounced in patients with stage IIIB, IIIC, or IVM1a disease and in treatment-naive disease. If approved by the FDA, T-VEC will represent the first example of a novel class of anticancer agents. The concept of using viruses to treat cancer is not entirely new. In fact, several case reports or small trials using different strains of viruses were reported throughout the twentieth century. Although these reports used wild-type and often crudely prepared clinical or laboratory viral isolates, it was not until the beginning of the 1990s that the first genetically engineered OV was reported to possess anticancer selectivity in a preclinical model. Since then, a large variety of genetically engineered OVs have been tested preclinically and in clinical trials for a variety of cancers. OVs are based not only on HSV-1 but also on adenoviruses, reoviruses, measles viruses, vaccinia viruses, retroviruses, and many other types of viruses. Tumor selectivity can be imparted by modifying the viral entry functions so that they will target tumor-specific receptors and/or by deleting viral genes required for viral replication but whose function can be complemented by factors present in tumors but not in normal cells. In addition, OVs can also be engineered to express anticancer transgenes such as cytokines to stimulate antitumor immunity. As mentioned earlier, T-VEC is based on HSV-1. The wild-type virus is widespread in the human population, in which it usually resides in a latent form in trigeminal ganglia neurons and on reactivation causes the common oral cold sore. HSV-1 has a 158-kb genome with approximately 80 genes whose products are responsible for viral infectivity and/or replication, subversion of host antiviral mechanisms, and assembly of the structure of progeny virions. Most HSV-1 OVs are derived from laboratory virus strains and are engineered in various ways. T-VEC was modified by disrupting the ICP34.5 neurovirulence gene to improve safety and also to allow for tumor-specific replication and the ICP47 gene that provides immuno-evasion functions. Removing ICP47 thus would increase the immunogenicity of infected tumor cells. T-VEC was further modified by the addition of a transgene coding for human GM-CSF, thus further increasing immune recognition. Interestingly, T-VEC was not derived from a laboratory strain of HSV-1 but rather from a clinical isolate. Indeed, T-VEC’s original intellectual property designation was based on the rationale that a clinical isolate strain may be better adapted to replication in humans than similar oncolytic HSV-1 derived from laboratory strains adapted to replication in tissue culture. T-VEC is administered by intratumoral injection. Although some clinical trials of OVs have used intravenous administration, intralesional injection ensures high-dose delivery to the target, minimizes systemic reactions, and limits complement and antibody inactivation of the OV. In the T-VEC trial, an initial priming dose of virus was used to seroconvert all patients, and this was followed by a high dose (10 pfu/mL) every 2 weeks. An outline of intratumoral events in OV-mediated immunotherapy is shown in Figure 1. Several factors can influence tumor responses following virus injection into the tumor. After the OV enters tumor cells, a coordinated viral transcriptional program leads to OV replication, JOURNAL OF CLINICAL ONCOLOGY U N D E R S T A N D I N G T H E P A T H W A Y VOLUME 33 NUMBER 25 SEPTEMBER 1 2015