Before scientists could safely engineer viruses for treatment, researchers in the 1940s and ’50s injected unaltered wild-type viruses into critically ill patients.

“It was like the Wild West,” said John Smestad, MD, PhD, third-year Hematology & Medical Oncology fellow. “Doctors would come back with a sample of a virus from a patient who got ill in Africa, then stick that in a patient with leukemia to see what would happen.”

While today’s experimental ethics and safety standards bear little resemblance to those of the era, those early experiments were attempts at what is now called oncolytic virotherapy (OV)—the therapeutic use of viruses to infect and destroy cancer cells. Unlike their mid-century predecessors, modern researchers are developing genetically engineered viral therapies that show real promise, particularly for patients with treatment-resistant melanoma. Smestad examined the historical roots, current clinical landscape, and future direction of OVs in a recent narrative review published in Cells titled “The Evolution, Current Landscape, and Future Prospects of Oncolytic Virotherapy in Melanoma.”

Building a treatment-friendly virus
Smestad credits a virus with shaping his interest and growing expertise in melanoma sarcoma: talimogene laherparepvec (T-VEC). T-VEC is the first and only OV currently FDA-approved for use in solid tumor treatments.

“T-VEC is a herpes simplex virus type 1-derived (HSV-1) oncolytic virus that was engineered to attenuate pathogenicity and enhance immune stimulation compared to a wild-type herpes virus,” Smestad said. “It is designed to activate the body’s immune processes—to be able to see the cancer and then fight it.”

To prepare a virus to target cancer, scientists attenuate some of its genes to weaken the virus in healthy cells while preserving its ability to infect and destroy tumor cells. For T-VEC, scientists insert a gene called GM-CSF, which the virus expresses once it infiltrates the tumor. GM-CSF attracts immune cells—especially dendritic cells—into the tumor microenvironment, training T cells to better recognize and attack melanoma.

The future of virotherapy: RP1
Smestad’s review highlights how the next generation of OVs are incorporating new sophisticated features to enhance antitumor effects. One of the most studied examples is vusolimogene oderparepvec (RP1).

“I think the most exciting agent that we’ve seen come through trials recently is a virus called RP1,” said Smestad. “The recent IGNYTE trial was a single-arm clinical trial investigating the use of RP1 in patients with advanced melanoma that had stopped responding to standard immune therapy. The results were very compelling. It showed that this virus confers enough benefit to make it to prime time, with effects potentially stronger than T-VEC.”

In his review, Smestad explains that RP1 retains T-VEC’s core safety and immune-priming features while incorporating additional engineering that increases its activity within tumors. One of these modifications increases the expression of the viral US11 gene, enabling RP1 to replicate more efficiently within cancer cells without harming healthy tissue. Another edit introduces a fusogenic protein that helps the virus spread from one tumor cell to the next, amplifying tumor destruction. Overall, scientists have engineered RP1’s biology to enable robust virus tumor killing and immune stimulation while reducing effects in other tissues.

As Smestad suggested, the impact of these upgrades is beginning to emerge in clinical trials. Mohammed Milhem, MBBS, director of the UI’s Holden Comprehensive Cancer Center’s Melanoma Program, led recruitment for the IGNYTE clinical trial, which tested RP1 in combination with Nivolumab, an immunotherapy, in patients with treatment-resistant melanoma. The results were promising, showing a 33% response among participants.

For Milhem, who served as a senior author on Smestad’s review, the project was an opportunity to combine their shared expertise and capture the future potential of injectable therapies.

“It is a whole new form of drug delivery for metastatic melanoma patients who don’t respond to normal therapy,” Milhem said. “The virus’s DNA takes over the tumor’s machinery, and then it starts making more of itself. Basically, you make the tumor make any drug you want it to—instead of doing it through an IV, you’re injecting it into the cancer, and forcing the cancer to make its own killer.”

Smestad and Milhem continue to meet weekly as they pursue new research in the virolytic realm. Milhem says he enjoys mentoring Smestad for his “industrious and curious spirit” and for “possessing the brain of a real scientist.” The review, he added, represents just one piece of their ongoing collaboration within oncology fellowship and faculty mentorship.