By Kendall Morgan
January 31, 2016
When Duke’s Matthias Gromeier, a seasoned polio virologist, first suggested that a modified poliovirus might be harnessed to fight a deadly form of brain cancer, many dismissed the idea as being downright crazy. Gromeier himself admits it was a long shot at best, a journey begun in the 1990s with laboratory experiments that were in some ways naive. Crazy or not, by 2001 Gromeier’s team had evidence that the treatment, known as PVSRIPO, might actually work to kill cancerous cells in lab dishes and in mice.
Now 25 years in, a group of patients with recurrent glioblastoma who received a single infusion of the experimental treatment within the last 3.5 years in an ongoing Phase I trial are doing spectacularly well. In a 60 Minutes interview aired last year, director of The Preston Robert Tisch Brain Tumor Center Henry Friedman called PVSRIPO “the most promising therapy I’ve seen in my career, period.”
As promising as the early results may be, there’s a long and treacherous road ahead. Gromeier, an associate professor in the departments of Neurosurgery, Medicine, and Molecular Genetics, as well as a member of the Duke Cancer Institute, must get his new treatment across the proverbial “valley of death”—the gulf between an experimental new agent available to a limited few and a successful, FDA-approved therapy out in the “real world.”
It’s not an easy road to travel. Most medical discoveries never make it, with nine of every 10 discoveries for possible new therapies perishing at some stage along the way.
But Gromeier isn’t facing the journey alone. He’s recently been given a DTRI Transformative Award – an investment of $500,000 and a team of experts dedicated to facilitating progress toward an FDA-approved therapy.
“The DTRI program provides a critical bridge toward the next level, which is commercial manufacture,” Gromeier said.
2016-2018 DTRI Transformative Pilot Program Offers Up to $350,000 – Application Deadline Feb 29, 2016
Commercial manufacture. The words trip off Gromeier’s tongue easily these days, but it wasn’t always so.
Gromeier, who considers himself a basic scientist, remembers well feeling very much out of his element when he and his colleagues in the Preston Robert Tisch Brain Tumor Center first reached out for help to Alan Herosian, director of Corporate and Venture Development within Duke’s Office of Licensing and Ventures (link is external). Gromeier wanted to determine what he might need to do to move the PVSRIPO therapy beyond a Phase I trial.
Herosian’s answer sounded simple: “We need to find a CMO,” he said.
CMO is short for commercial manufacturing organization and what Herosian meant was this: Before pivotal clinical studies to test PVSRIPO in more glioblastoma patients could proceed, more of the modified virus would need to be made. To do this, the technology associated with the manufacture of the virus would have to be transferred from the National Cancer Institute — Duke and Gromeier’s partner in the PVSRIPO project — to a commercial vendor qualified to handle this type of work.
Gromeier had no idea where to begin.
“I’m a basic scientist, and there are many issues I’m not familiar with,” he admits.
Rather than try to solve the problem on his own, he wrote a five-page application for a DTRI Transformative Pilot Program Award, with support from Herosian and the Office of Licensing and Ventures.
The DTRI award would offer financial support towards commercial manufacture. Just as important, it would provide a team of people with the expertise Gromeier needed. He hoped it would be the bridge he needed to get across that valley of death before him.
The application was received with excitement by the DTRI, but also with caution: In May, the DTRI told Gromeier they would offer him the Transformative Award, with one caveat. He and his team, which included Vonda Rodriguez, PhD, as the DTRI project manager, had six months to prove that the proposed plan for transferring the manufacturing – the key step to enable the therapy into the next stage of clinical trials — could actually be implemented.
The caution comes because the Transformative Award represents a major investment on a single project from the DTRI and the Duke CTSA.
“Since it is challenging to truly assess whether such a large award is a good investment without getting to really know the project well, we work closely with the faculty for a six month roll-in period to make sure that a major success is achievable before releasing the funding,” says Bruce Sullenger, PhD, the director of DTRI, and someone who has extensive experience with translating ideas into marketable ideas. “This diligence is very analogous to the approach used by the private sector and it helps prepare the research team to translate their invention into the real world.”
Making the Case
On December 11, 2015, Gromeier sat at a large round conference table with the DTRI oversight committee and the DTRI team with whom he had been working for six months. There was only one item on the agenda: to review the team’s progress and decide whether to move forward with the DTRI Transformative Award, or pull the plug.
Gromeier began by flipping through slides showing the before-and-after brain scans of patients in the Phase I study. “By six months, there were signs of response,” Gromeier said, pointing to a series of images representing the very first patient ever to receive PVSRIPO. “By 11 months, it had almost disappeared. At 42 months, the tumor is gone.”
It’s particularly impressive when compared to the median overall survival for patients with newly diagnosed glioblastoma who receive standard treatment: about nine months. Recurrent glioblastoma patients have no satisfactory treatment and their survival prognosis is even worse.
That incredible potential visible in those brain scan images has been a big motivator for the DTRI project leader Vonda Rodriguez and the rest of the team. Before coming to Duke, Rodriguez worked for more than 25 years in drug development. Still, PVSRIPO isn’t your average drug and she had a lot to learn about the virus and its manufacture at the NCI in the early days of the project.
PVSRIPO is an engineered form of the live polio vaccine, tamed with a critical component borrowed from a rhinovirus that causes the common cold. When injected directly into a brain tumor, the modified poliovirus can attach to and infect malignant glioma cells. By destroying some of the cancerous cells, the virus elicits a broad series of inflammatory and immunogenic responses that lead to other tumor cells being recognized, flagged, and destroyed by the body’s immune system. The new treatment is therefore both an oncolytic (meaning cancer-killing) virus and a promising new form of immunotherapy, a class of treatments designed to fight cancer by enlisting the immune system.
“This is one of these projects that the more you learn about it, the more passionate you get,” Rodriguez said. “It really drives you because you see how transformative this therapy can be for people. You want to do everything you can—to ask any question and get as much done as possible.”
Following Dr. Gromeier’s presentation of the status of patients currently in the Phase I trial, Rodriguez described for the oversight committee her team’s search for a partner that could produce the PVSRIPO virus with the quality control, scale, and cost that would allow the project to move forward.
Rodriguez, along with the DTRI’s Patrick Killela. PhD, have quite literally scoured the globe in search of a commercial manufacturing organization with the right capabilities for the job. To aid their work, they hired Colin Love, a U.K.-based consultant. Love is an expert in the issues of manufacturing virus-based products rather than other biologics, such as the difficulty of ensuring that the viral product is stable and consistent from batch to batch. He was involved for more than a decade with the development and commercialization of Imlygic (talimogene laherparepvec), the first and so far only FDA-approved oncolytic virus therapy.
The team began with a list of 15 potential vendors from around the world, then narrowed the list to six that went through additional screening. Rodriguez described for the DTRI oversight committee some of the details they had to sort out along the way. What are the regulatory issues involved in handling poliovirus? How and where could the study’s virus and biospecimens be stored safely and securely? What exactly needed to be in a proposed budget of what it would cost to move the therapy all the way through clinical trials?
Yes or No?
After the presentations by Gromeier and the project team, there was a short moment of silence around the conference table. Then Gromeier and the DTRI team got the news they’d been hoping to hear. The DTRI Transformative Award is a go, with permission to start to transition manufacturing to a California-based company as soon as is practical.
If all goes well and the prospective investors in a new Duke start-up company, ISTARI Oncology, Inc., continue to be excited, the pivotal, multi-institutional trial to test the safety and efficacy of PVSRIPO could begin enrolling patients this year . While recurrent glioblastoma is the first planned indication and the primary focus for now, research is ongoing at Duke to explore the potential of the modified poliovirus for other solid tumor cancers, including advanced prostate and pancreatic cancer.
After the meeting, Gromeier shook hands all around and expressed his gratitude for the investment Duke is making in his research, and for the team that is backing him.
“It is these two contributions that are so crucial,” he said. “The financial support toward commercial manufacture and the expertise. They are both necessary.”
While the DTRI financial support will be exhausted after about 12 months, the DTRI project team has committed to working with Gromeier for the full 18 months of the award cycle. This will allow a smooth transition toward a marketable therapy as outside investors are found to propel ISTARI Oncology, Inc. forward.
Herosian is confident that this team support offers an incredibly powerful boost to move this once unbelievable idea of using the poliovirus as a therapy across the valley of death and on towards the healthcare market. He notes that the longstanding commitment and partnership of Duke with the NCI and the Tisch Brain Tumor Center resources have provided a solid foundation on which to build.
“You very rarely find a promising technology this advanced into the clinic in an academic medical center,” Herosian said. “Right now, everything is looking very good. All of the pieces are in place and there is a good plan forward being implemented. The most important thing is that patients with recurrent glioblastoma in our current trial here at Duke are doing well. As long as they continue to do so, our story is one that continues to provide hope.”