Engineering Viruses to Fight Cancer

With EMA approval in December 2015, and US FDA approval in October 2015 of an oncolytic herpesvirus for the treatment of nonresectable melanoma, we now have a novel class of anticancer agents to add to our ever-promising arsenal of cancer (immuno-) therapeutics. Talimogen laherparapvec (T-VEC) therapy involves direct, intratumoral injection of a herpes simplex type 1 (HSV-1) virus which has been genetically altered to decrease pathogenicity, and to stimulate the host's own immune response by both expressing the immunestimulatory cytokine GM-CSF as well as increasing the presentation of tumor antigens by the infected cell. In this sense, the approach is “twopronged” in that the virus is not only designed to infect and destroy cancer cells and leave healthy ones alone, but—in doing so—the virus infection and subsequent breakdown of the tumor cells help to stimulate the immune system to recognize and kill these infected cells, as well as other cells expressing the same patient-specific tumor antigens. A Phase 3 randomized clinical trial (OPTiM) published earlier in 2015 looked at T-VEC treatment in stage IIIB-IV melanoma patients. Results indicated that T-VEC was relatively well tolerated, and significantly improved the overall durable response rate (DRR) patients compared to GM-CSF treatment alone (16.3% versus 2.1%, respectively), meeting the primary endpoint of the study. DRR to T-VEC was even more pronounced in patients with less advanced melanoma (33%, compared to 0% in the GM-CSF treatment group). Although overall survival was not significantly extended (4.4 months, P= .051), the results arewidely heralded as amajor success as they provide proof of principle that oncolytic viruses are a viable class of anticancer treatments ready for application in the clinic. Indeed, several other clinical trials are underway to examine whether other cancers may be similarly treated with either modified HSV or other engineered viruses. Researchers at Duke University, for example, have shown encouraging results in a Phase 1 study treating recurrent glioblastoma patients with modified poliovirus, also by injecting the therapeutic virus directly into the patient's tumor. This particular poliovirus strain was altered in the laboratory (20 years ago) by replacing part of its RNA (the internal ribosomal entry site, or IRES) with the equivalent IRES sequence from human rhinovirus. The resultant chimeric virus is still able to bind to and enter glioblastoma cells, which happen to express high amounts of poliovirus receptor — but the genetic alteration reduces its neuropathogenic potential. Although results from the trial using this virus are still quite preliminary, they are indeed striking—with a number of patients apparently experiencing a complete disappearance of their tumors. Given that this type of cancer often has a very poor prognosis, this is an encouraging potential new option for the field.