Cancer cells have a unique vulnerability: the same mechanisms that shield them from the immune system also make them prone to viral infections. Scientists have long tried to exploit that vulnerability by developing viruses that will infect and replicate in cancer cells until the cells burst, releasing virally infected particles into the bloodstream. Ideally, those particles will then generate a systemic immune reaction against cancer cells.
Those efforts hit a milestone last fall when the US Food and Drug Administration approved Talimogene laherparepvec (T-Vec) for melanoma treatment. A modified form of the herpes simplex type 1 virus, T-Vec is the first oncolytic virus to reach the market. In a multicenter phase III study, 26% of 291 treated patients with stage IIIB–IV disease had an objective response to the virus. In more than half those cases, responses lasted at least six months. Complete responses were achieved in nearly 11% of treated patients, and treatment lengthened overall survival to a median of 23.3 months, compared with 18.0 months among control subjects who took the endogenous immune stimulator granulocyte–macrophage colony-stimulating factor.
T-Vec has received a favorable opinion in Europe, where regulatory approval is now pending. Unlike Food and Drug Administration approval, which applies to melanoma of all stages, European approval will probably be limited to stage 3 and 4M1a—tumors of the skin and lymph nodes.
James Gulley, MD, PhD, head of the immunotherapy section at the National Cancer Institute, said T-Vec has the potential to become a powerful therapeutic tool.
“We need new and better ways to turn T cells against cancer, and that’s what T-Vec appears to do,” he said.
But Gulley said that T-Vec’s greatest benefits will probably be achieved in combined treatment with immune checkpoint inhibitors, such as ipilumumab, a CTLA-4 inhibitor, and pembrolizumab, an anti–PD-1 agent.
T-Vec’s approval follows a long struggle in oncolytic virus development. According to Brian Lichty, PhD, immunologist and professor at McMaster University in Hamilton, Ontario, earlier viruses were so weakened for safety that they didn’t work well, and negative results tarnished the field. By contrast, scientists engineered T-Vec with just two gene deletions: the ICP47 gene, which shields the virus from the immune system, and ICP34.5, which might otherwise facilitate neurological infections in immunocompromised patients.
To maximize exposure, clinicians inject T-Vec directly into melanoma growths on the skin. Treatments start with a minimal dose intended to prime the immune system without unleashing a dangerous antiviral reaction. Then they advance to larger doses given every two weeks until the lesions disappear or until patients shows signs of clinical progression. As with all immunotherapies, the lesions can grow before they shrink, reflecting an influx of tumor-infiltrating lymphocytes. According to Yvonne Saenger, MD, director of melanoma immunotherapy at New York Presbyterian Hospital’s Columbia Campus, patients often feel minor flu symptoms after treatment, such as low-grade fever, chills, and muscle aches. The advantage, she said, is that T-Vec stimulates local immune reactions within the tumor itself, which otherwise tends to be immunosuppressive.
Delivering the treatments can be challenging, added Saenger, who was a principal investigator on the phase II and III clinical trials.
“T-Vec is a live virus, so there are issues and potential complications to consider,” she said. “Nurses can be reluctant to handle it, and should never do so if pregnant, and you need to keep it away from people who are very immune compromised, such as bone marrow transplant patients.”
But Howard Kaufman, MD, chief of the surgical oncology division at Rutgers Robert Wood Johnson Medical School in New Brunswick, NJ, said that with proper guidance, clinical staff can learn to manage injection sites and minimize infection risks.
“We haven’t heard of a single report of household transmission,” he said. “But it will take some focused education before the average practitioner in the oncology community feels comfortable using it.”
The best treatment candidates, said Kaufman, T-Vec’s global principal investigator, are those with advanced local disease rather than widespread visceral metastases. T-Vec does appear to have systemic benefits extending beyond treated lesions. During the phase III trial, 15% of visceral metastases shrank by more than half, even though they hadn’t been injected.
“That T-Vec induces regression in peripheral, noninjected lesions makes it superior to other injectable treatments for melanoma that only shrink the injected lesions,” Saenger said.
Citing evidence from retrospective data, Kaufman added that T-Vec treatment appears to delay the onset of metastases, in turn allowing patients to delay systemic therapy. Durable responses are more pronounced in treatment-naive patients, Kaufman said, than in patients receiving T-Vec as second-line therapy. According to Kaufman, other good candidates for T-Vec include elderly patients who don’t tolerate checkpoint inhibitors, in addition to patients with head-and-neck melanoma.
Meanwhile, preliminary results from combination trials with checkpoint inhibitors look promising. At last June’s American Society of Clinical Oncology annual meeting, investigators reported results from a phase Ib trial with 19 patients given T-Vec with ipilimumab. The objective response rate was 56%, with 44% of treated patients having durable responses. A phase II study has been launched and has reached its target of accruing 200 patients.
At last September’s European Cancer Congress, investigators reported preliminary safety findings from a phase Ib trial combining T-Vec with pembrolizumab. Georgina Long, PhD, associate professor at Australia’s University of Sydney and the trial’s principal investigator, said the treatment was well tolerated with no observations of dose-limiting toxic effects. Efficacy results for the combination have not yet been reported.
Saenger said that T-Vec’s future in melanoma probably hinges on efficacy results from combination trials.
“T-Vec’s strength is that it’s a pathogen that works by a completely different mechanism than checkpoint inhibition,” she said. “Yet its role in melanoma treatment has yet to be fully established. If it adds to anti–PD-1 treatment, which is currently the favored approach in melanoma immunotherapy then I anticipate it will be widely used. If not, I would expect to see it in well-defined clinical contexts, but perhaps not as the dominant therapy.”
Featured image credit: Metastatic Melanoma Cells by Julio C. Valencia. Image released by the National Cancer Institute. Public Domain via Wikimedia Commons.