Cancer-killing virus plus PD-1 and MEK inhibitors make for a 3-pronged attack on melanoma

melanoma
Combining an oncolytic virus with PD-1 and MEK inhibitors appears to boost the immune response to melanoma. (National Cancer Institute)

When Amgen’s cancer-killing virus Imlygic—also known as T-Vec—was approved by the FDA in late 2015, experts expected it would work best in combination strategies for melanoma. Now a team led by scientists at Massachusetts General Hospital (MGH) has early evidence showing that adding the virus to a combination of PD-1 and MEK inhibitors could improve the prognosis for patients.

The addition of Imlygic to Novartis’ MEK inhibitor Mekinist and an FDA-approved anti-PD-1 monoclonal antibody led to regression of tumors in nearly 100% of animals in a study with mouse models of melanoma, the team reported in the journal Science Translational Medicine.

“All three agents we used are already FDA approved, so our study provides justification for using them in combination. A clinical trial to examine this three-drug regimen should be a priority,” said Howard Kaufman, M.D., of MGH, senior author of the study, in a statement.

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Imlygic is a genetically engineered herpesvirus that treats advanced melanoma that has recurred after surgery, and it’s currently the only oncolytic virus to have received FDA approval. It works by infecting and killing cancer cells directly, in addition to eliciting an anti-tumor immune response.

Nearly half of all melanoma cases are driven by mutations in the BRAF gene, and targeting BRAF and its related MEK pathway has been a well-established strategy against the skin cancer. As is the case in many cancer types, scientists are exploring ways to combine targeted therapies in treating melanoma. For their study, Kaufman and colleagues first combined Roche’s BRAF inhibitor Zelboraf with T-Vec in human melanoma cell lines and mouse models. Surprisingly, they found that combining T-Vec with Novartis’ MEK inhibitor Mekinist—which was first used as a control—increased cell death in both BRAF-mutated and nonmutated melanoma cell lines.

After testing the combination in mice, the team found that its anti-tumor activity is dependent on competent CD8+ T cells and certain dendritic cells. What’s more important, the combination of T-Vec and the MEK inhibitor boosted the expression of PD-1 and PD-L1, "checkpoints" that prevent the immune system from recognizing and attacking cancer.

PD-1 inhibitors Keytruda and Opdivo were first approved to treat advanced melanoma. So Kaufman’s team reasoned that blocking PD-1 might boost the effectiveness of the virus-MEK combination.

Data in mice corroborated their assumption. While combining T-Vec and Mekinist completely eradicated tumors in about 30% to 40% of mice, the triple therapy increased the odds of survival, as six of the seven mice saw complete durable responses. The researchers reported similar results in a mouse model of colon cancer, where the triplet completely eradicated tumors in all treated animals.

Despite the limited market potential for Imlygic so far, the biopharma industry continues to explore multiple uses for oncolytic viruses. Early this year, Merck put down $394 million to acquire Australian biotech Viralytics. That company’s most advanced candidate, Cavatak, triggered objective responses in 61% of late-stage melanoma patients when combined with Keytruda in a small phase 1b trial. Johnson & Johnson snatched up oncolytic immunotherapy startup BeneVir Biopharma with $140 million upfront in May, and Boehringer Ingelheim followed suit in September by acquiring ViraTherapeutics.

Amgen and Merck are already collaborating on a phase 1b/3 clinical trial that tests Imlygic with Keytruda. In a study published in Cell last September, investigators reported that the phase 1b part of the trial saw the combination produced an overall response rate of 62% in a small group of 21 patients with advanced melanoma. The ongoing second phase of the trial enrolled 713 patients, with a primary completion date set for the end of this year.

Kaufman’s team says there are still some unanswered questions about the combination therapy, but further investigation is warranted. “While we still don't know the mechanisms behind effects such as the improved response against tumors that lack BRAF mutations, an interaction between T-Vec and [Mekinist] appears to be involved,” Kaufman said in a statement. “Now we need to develop appropriate clinical trials to see if this approach will benefit patients with melanoma and other types of cancer.”

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