One-Upping Mother Nature
A Cincinnati Children’s research team is turning viruses into cancer-fighting machines
The same viruses that have plagued us with diseases like influenza and chicken pox could potentially offer a cure for some of the most difficult-to-treat cancers in children, Cincinnati Children’s researchers believe.
Tim Cripe, MD, a clinician and researcher in the Division of Hematology / Oncology at Cincinnati Children’s, is working with a team to fight cancer by injecting a genetically modified herpes virus into tumors. The virus kills the cancer without harming healthy tissue. Their work was published early this year in Cancer Research.
Tim Cripe, MD (foreground), is working with a team to fight cancer by injecting a genetically modified herpes virus into tumors.
There are documented cases dating from the late 1800s of people whose cancers diminished or disappeared after they naturally contracted influenza or other viral illnesses. In an attempt to improve on what Dr. Cripe calls “nature’s experiment,” physicians in the ‘40s and ‘50s deliberately injected patients with viruses in the hope of curing their cancers. While this offered some improvement in the cancer, it also resulted in patients having to battle serious viral infections, often unsuccessfully.
Only in the last few decades have scientists learned how to manufacture and genetically manipulate viruses to attack the cancer cells without making the individual sick with the viral disease.
Cripe and his teamare taking this approach a giant step further.
Arming the Virus
“In addition to the virus just infecting and killing the tumor cell,” Dr. Cripe says, “we’ve been able to add something to the virus to make it better at killing tumors.”
That something is a gene called “tissue inhibitor of metalloproteinases 3” (TIMP3), which Dr. Cripe and his team, including then graduate student and lead author Yonatan Mahller, PhD, inserted into the herpes virus genome. What they’ve found is remarkable. “It not only stops the growth of some tumors, but in some cases makes them shrink and disappear,” Dr. Cripe says.
In their recently published study, they tested the herpes virus on particularly stubborn neuroblastoma and malignant peripheral nerve sheath tumors. When the virus was loaded with the TIMP3 gene, it killed much of the cancer in human tissue samples and prolonged the lives of cancer-ridden mice.
How It Works
Loading the virus with TIMP3 affects the tumor cell in a variety of ways.
“The virus goes into the cell and starts to make more of itself, but it also secretes the TIMP3, which can kill other tumor cells,” says Dr. Cripe. He adds that TIMP3 interferes with angiogenesis, a process in which the tumor grows new blood vessels from pre-existing ones. This interference cuts off the tumor’s primary means of feeding and spreading. TIMP3 also keeps enzymes called “matrix metalloproteinases” (MMPs) from degrading the protective barrier around the cancer cell, thereby preventing the cancer from migrating to other locations.
As if these effects aren’t promising enough, the team’s work with TIMP3 in neuroblastomas yielded an additional, unexpected benefit: it slowed vasculogenesis, a process in which the tumor recruits bone marrow cells to form new blood vessels where none previously existed.
“The TIMP3 expressing virus seemed to halt or diminish the recruitment of those bone marrow cells to the tumor,” Dr. Cripe says.
Bringing It to the Clinic
Because he also spends time in the clinic caring for children who are battling cancer, Dr.Cripe is all too aware of the need to translate laboratory findings into effective, safe treatments.
“Clinical practice stimulates me to want to come back to the lab and find new things,” he says, “and it keeps me in touch with what’s really important–what are the unmet medical needs that we need to be addressing in the lab?”
Meeting those needs can’t happen quickly, despite the promise that viral therapy offers. Obtaining appropriate study funding, meeting regulatory requirements and putting the therapy through stringent toxicology studies are crucial steps that take time, says Dr. Cripe.
And then there’s the team’s need to get it right.
“At what point do you pull the trigger and say, ‘I’m going to take this one into the clinic?’” he says. “My intention is to find even better versions, to improve on it even more, before we take that step.”
Many of the children Dr. Cripe and his teamtreat have aggressive tumors that have relapsed or spread, with no good treatment options. While the doctors don’t expect viral therapy to be a stand-alone treatment, they do believe it will play an important role in the arsenal of treatments used to fight these difficult cancers.
“Ultimately we hope it will help these kids either extend life, or gain cure,” Dr. Cripe says.
