Trabectedin modifies immune microenvironment, enhancing virotherapy and increasing survival in mouse models
A combination of the drug trabectedin with a virus that can kill cancer cells significantly improved survival of mouse models with human Ewing sarcoma tumors, research at Nationwide Children’s Hospital shows.
“Each treatment alone doesn’t do much,” says Timothy Cripe, MD, PhD, division chief of Hematology and Oncology at Nationwide Children’s and leader of the investigation. “You expect you may get a sum of their effects. But in this case, there’s real synergy when they’re combined.”
The researchers found that together, the drug and the oncolytic herpes simplex virus rRp450, reduced immune cells that the tumor hijacks to promote its own survival and growth. And, the effect of the combined treatment lasted, preventing increases in the cells after therapy had been stopped.
Their study is published in Molecular Therapy Oncolytics.
Ewing sarcoma is found mostly in adolescents and young adults and is the second-most common bone cancer among that group. Traditional treatments are effective if the cancer is in one bone, but if it has spread, five-year survival rates plummet to 30 percent.
That’s unacceptable, the researchers say, and ample reason to consider new approaches.
“We used to talk of cancer as just cells growing and growing and growing but now we realize cancer cells are master manipulators of their environment,” says Dr. Cripe, who is also a professor of pediatrics at The Ohio State University College of Medicine. “They commandeer immune cells, non-cancer cells, to do their bidding.
“It’s no longer sufficient to target just cancer cells,” he says. “Another approach is to target the microenvironment of the cells cancer recruited.”
Trabectedin, derived from sea urchins, is FDA-approved for use in some adult soft tissue cancers. The researchers used the drug to target immune cells called macrophages and myeloid-derived suppressor cells, or MDSCs, which are important cells in the Ewing sarcoma microenvironment. There, macrophages, which come from bone marrow, are turned on as if they’re healing wounds in the tumor, which helps the tumor grow. Tumors manipulate MDSCs to suppress the body’s natural antitumor immune responses, helping the tumor survive and grow.
In a Ewing sarcoma tumor strain that appears to be reliant on commandeered macrophages, the addition of trabectedin leveraged the ability of the virus infection to do two things: kill cancer cells and stimulate the microenvironment to activate immunity against the tumor, Dr. Cripe says.
“Because we use a human tumor in a mouse model, we could look at the effects on the two different sets of cells,” he added. “I was surprised at how much the combination therapy affected the behavior of non-cancer cells in the microenvironment.”
The researchers believe the findings may be applicable to other cancer types.
Dr. Cripe’s team has submitted grants to test the approach in models of osteosarcoma, rhabdomyosarcoma, neuroblastoma and more solid tumors. They’ve also submitted grants to investigate further how the combined therapies work.
“We think that the therapy combination used in people would not have many side effects, unlike chemotherapy. But we need more data before we’d subject patients to the treatment,” Dr. Cripe says. “Trabectedin and a virus related to the strain used here are already FDA-approved so if upcoming studies confirm the approach works, a clinical study could be just two or three years off.”
Citation: Denton NL, Chen CY, Hutzen B, Currier MA, Scott T, Nartker B, Leddon JL, Wang PY, Srinivas R, Cassady KA, Goins WF, Cripe TP. Myelolytic treatments enhance oncolytic herpes virotherapy in models of Ewing sarcoma by modulating the immune microenvironment. Molecular Therapy Oncolytics. 2018 Oct 18; 11:62-74.