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An engineered version of the poliovirus has been in development for more than 20 years as a treatment for one of the most difficult-to-treat cancers, a brain tumor called glioblastoma multiforme, abbreviated GBM. A human safety trial of the virus, called a Phase I study, is ongoing at Duke University’s Brain Tumor Center in Durham, North Carolina. The patients who’ve been enrolled have the toughest form of this disease: GBM that has returned after previous surgery and treatment.
Last night, the CBS News program60 Minutesdevoted two segments of the broadcast to correspondent Scott Pelley’s 10-month-long glimpse into this clinical trial. (Disclosure: I have held an unpaid adjunct faculty appointment in Duke University’s Department of Medicine since 2002, was a paid faculty member there in 2001, and did a year-long research sabbatical there in 2000 while I was a pharmacy professor at the University of Colorado.)
The segment, called“Killing Cancer,”was produced by Michael Radutzky and Denise Schrier Cetta and did a responsible job of illustrating the potential power of this new treatment with the sober realities of the challenges presented by a cancer whose prognosis is measured in months. The program, the entire transcript, and supplementary materials are available at the60 Minuteswebsite.
Using the virus that causes the childhood paralytic disease called poliomyelitis to treat cancer seems outrageous. We’ve been trying to eradicate the virus from the planet since the 1950s, when two types of vaccines were developed by Drs. Jonas Salk and Albert Sabin. The Americas were declared polio-free in 1994 and the disease only remains in three countries: Nigeria, Pakistan, and Afghanistan.
But the way that the polio virus infects cells and what it does afterwards are the precise actions that Matthias Gromeier, MD, thought could be harnessed to treat cancer. Gromeier has been at Duke for the last 15 years painstakingly shepherding his studies from lab to clinic. But the German-trained molecular biologist began this work in earnest 25 years ago when he came to the States to work with the renowned virologist,Eckard Wimmer, at the State University of New York at Stony Brook.
Some technical background
Detailed inthis seminal 1996 paperin theProceedings of the National Academy of Sciences, Gromeier and colleagues in Wimmer’s lab replaced a segment of the poliovirus’s RNA genome with a corresponding piece from a human rhinovirus, a type that causes the common cold. (The virus is still known in the literature and on Duke’s webpage by the cumbersome name, PVS-RIPO.)
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They found that this recombinant (or chimeric) virus could still infect cells that had the poliovirus receptor, but that the virus didn’t replicate. Many cancer cells, including glioblastoma, overproduce the poliovirus receptor (known as CD155 or Necl-5). So, by using the right amount of this designer virus, the researchers could selectively kill glioblastoma cells in culture without affecting normal neuronal cells. For this reason, this virus is called an oncolytic virotherapy, meaning that it causes lysis or bursting open of cancer cells.
But that’s not all. The way that cancer cells make proteins is different from that of normal cells. So even when the virus gets into some normal cells that have the receptor, it’s not as damaging. This two-part difference between cancer cells and normal cells is the basis for trying to treat human glioblastomas by directly infusing very small amounts into the tumor through a one millimeter diameter catheter that’s inserted into the tumor through the skull, guided by 3-D imaging. That part of the work is done by Duke neurosurgeon, John Sampson, MD.
But once in the brain, the virus triggers the body’s immune response against the tumor cells. In fact, the patient’s own immune response is probably more important than the initial bursting of the cancer cells.
As Gromeier explained on60 Minutes, “So cancers, all human cancers, they develop a shield or shroud of protective measures that make them invisible to the immune system. And this is precisely what we try to reverse with our virus. So by infecting the tumor, we are actually removing this protective shield. And telling the– enabling the immune system to come in and attack.”
But the immune response must be carefully manipulated because too much virus can cause a massive swelling of the brain. So that’s why the goal of this first Duke trial isn’t to determine the virus’s effectiveness. The purpose is to get to the right dose, as explained by the Brain Tumor Center’s deputy director, Henry Friedman, MD.
A personal aside
While I was on sabbatical at Duke in 2000, Gromeier had joined the faculty in microbiology and immunology in the same building where my mentor, Ken Kreuzer was located. I remember when Gromeier’s first independent grant was funded through the National Cancer Institute’s RAID program, a mechanism that allowed unique cancer treatments discovered in academia to be cultivated for clinical trials using the preclinical toxicology, medicinal chemistry, and biologics expertise of the NCI Developmental Therapeutics Program to produce the clinical trial-quality viral study agent.
When I ran into Gromeier again a few years into the process, he said that the level of detail required to get the product even made was tortuous. When they were using cholesterol in the mix to originally help the virus into the cells, he said that NCI and FDA were concerned about the source of the cholesterol being cattle and that they had to be sure that the preparation didn’t have any miniscule amount of the virus that causes mad cow disease. Every step of the process had to overcome this degree of scrutiny. And even when the clinically-qualified batches of virus were made, the FDA required seven more years of safety testing, up to and including administration to three dozen monkeys, before the first human subject was permitted in 2011.
My near-teenage daughter just walked past the computer as I’m writing this and I was struck by the fact that Gromeier has been working on this at Duke a couple of years longer than she has been alive. The rigor with which the safety of this approach is being evaluated is remarkable.
I encourage you to watchboth parts of the60 Minutesstory. Knowing some of the folks involved but also putting on my critical hat as a scientist and writer, I have a few thoughts on how the story was presented.
What I liked:
1. The program was careful to note that the effectiveness of the virus in three of the study volunteers interviewed was offset by an equal number of patients who are no longer alive. Eleven of the 22 volunteers have succumbed to their disease.
2. The program gave time for Henry Friedman to say that a clinical effect of the study agent is not the goal of a Phase I study.
3. Annick Desjardins, MD, the neurooncologist who followed the patients and evaluated their post-surgical functioning, showed the true level of compassion and teamwork that forms the nucleus of the Brain Tumor Center’s reputation.
4. Even when Scott Pelley pushed Friedman and center director, Darell Bigner, MD, PhD, to use the word “cure” or “miracle,” both were very measured and guarded but still conveyed a sense of optimism. In Friedman’s 34 years at Duke and Bigner’s 49 years, they’ve seen a lot of death. But they’ve also made significant contributions globally in the treatment of brain cancers. So for them to both say that the recombinant poliovirus approach was the most promising agent they’ve seen for glioblastoma in their careers, it’s hard not to be excited.
5. Both the program and Duke made it very easy for prospective patients to have their questions answered about potential eligibility for the trials: Editor’s Note: For more information on the Duke University polio trial or other brain cancer trials, click here or call 919-684-5301.TheDuke pageis very easy for interested subjects to navigate forreferralsand information onthisandother clinical trialsat the Brain Tumor Center. The site was clobbered last night and was unreachable for the first two hours after the program aired, but it has been available every time I’ve clicked this morning.
What I liked less:
1. At the outset, Pelley made it sound like very few advances have been made in cancer treatment over the last 100 years: “The long war on cancer has left us well short of victory. Radiation flashed on in the 19th century, chemotherapy began to drip in the 20th but, for so many, 100 years of research adds up to just a few more months of life.” That’s partly true, but partly nonsense. Tremendous strides have been made within many cancers, from childhood leukemia cures to cancer survivors who are counting decades since their treatment. The program needn’t have denigrated how far we’ve come to show the promise of the viral therapy. It’s impressive enough on its own.
2. Pelley: “Duke went to the FDA for approval of this new Frankenstein virus.” Frankenstein? No, no, no, no. Moreover, the virus wasn’t approved. It was granted Investigational New Drug status to begin clinical trials.
3. The emotional power of the two people who are in remission, particularly the first recipient, Stephanie Lipscomb, was so positively overwhelming that I don’t think the risks were fully balanced by the story of another patient who did not do well and withdrew from the study. The positive anecdotes were very compelling and a viewer hoping to get into subsequent trials might be overly optimistic. While I mentioned above that I liked the fact the the 11 of 22 response statistics were a valuable inclusion, the amount of time given to that point led to its underrepresentation.
4. ForForbesreaders, there was a paucity of information on the intellectual property considerations of the polio virus therapy and detail on how the drug will ultimately be commercialized. The program mentioned briefly that the investigators have a financial stake in the drug’s success, as with many clinical trials. But there was no discussion of the fact that the first patents on the therapy were granted to Gromier with Wimmer and the Research Foundation of SUNY-Stony Brook. Issued in 2003 and 2006, we don’t know if any hurdles exist for Duke’s commercialization of the technology (I have no inside information on this; I’m just raising it as a viewer who expected the issue to be addressed.).
5. While interviewing Gromeier, Pelley led him to speak about the use of the virus against other cancers. I don’t think the program made clear that the work in prostate, breast, and pancreatic cancer, among others, was still in the experimental phase.
6. The program only briefly touched on other therapies that exploit the immune system for cancer but didn’t mention that viral approaches are being taken by quite a few other research teams and companies.Forbescontributor, Arlene Weintraub, hasa more comprehensive discussionthis morning.
7. Without knowing Henry Friedman, one might think that CBS was being disrespectful to him because he chooses not to dress as a typical physician: He was wearing a Duke hoodie and jeans and Pelley said that’s how Friedman’s brain thinks about fashion. Indeed, his dress is most often casual but I know that it breaks down barriers with his patients, most who are coming from far away and freaked out about their disease. Friedman is a fierce advocate of every facet of Duke and has contributed immensely to the brain cancer treatment internationally. Moreover, I admire him most for his establishment of a program (with neurosurgery colleague, Allan Friedman, MD – not related) for Duke’s women athletes who wish to pursue medical school and his strong support of Duke women’s basketball. Perhaps that’s just me.
Why the absence of the Tisch name?
And my final observation was one that just struck me as odd. The Duke Brain Tumor Center, originally established in 1937, was renamed the Preston Robert Tisch Brain Tumor Center after the Tisch family donated $10 million for research at the Brain Tumor Center and the Duke Comprehensive Cancer Center. Yet the 60 Minutes program made no mention of this name.
The late Bob Tisch was treated at Duke for his brain cancer, living for 14 more months after he was given a two-month prognosis in New York. Bob Tisch was the brother of the late Larry Tisch, CEO of the CBS network from 1986 to 1995. During his tenure, Larry Tisch slashed jobs in the news division and one can’t help but think that the remaining old-timers at 60 Minutes might hold some grudge. Alternatively, they might not have wanted to cloud the story with this two-steps-removed association with the Duke Brain Tumor Center.
In any case and for whatever reason, the omission was glaring. CBS has not responded to a request for information.