I think [these novel therapies] and immunotherapy for brain tumors in general will result in a paradigm shift in treating brain tumors, probably within the next 10 years.
—Darell D. Bigner, MD, PhD
Although the idea of using viruses to target cancer cells dates back more than 100 years, technologic advances in the genetic engineering of viruses are now making it possible to safely test oncolytic virotherapy as a valid strategy against cancer cells. One type of genetically engineered virus that is getting attention is the PVS-RIPO poliovirus, which is being tested in a phase I clinical trial for recurrent glioblastoma multiforme at Duke University School of Medicine in Durham, North Carolina, and was recently featured on the television program 60 Minutes.1
The study was launched in 2012 by Darell D. Bigner, MD, PhD, Edwin L. Jones, Jr. and Lucille Finch Jones Cancer Research Professor and Director of the Preston Robert Tisch Brain Tumor Center, and his colleagues Allan H. Friedman, MD, The Guy L. Odom Professor of Neurological Surgery; Henry S. Friedman, MD, James B. Powell, Jr. Professor of Neuro-Oncology; Annick Desjardins, MD, FRCPC, Associate Professor of Neurology; and John H. Sampson, MD, PhD, Chief, Division of Neurosurgery and Dr. Robert H. Wilkins and Gloria Wilkins Professor of Neurosurgery, at Duke University Medical Center. To date, 24 patients have been treated with the vaccine, which is delivered via a catheter placed stereotactically directly into the tumor by a method known as convection-enhanced delivery.
Dr. Desjardins will be presenting an update of the results from a phase I trial of PVS-RIPO in recurrent glioblastoma at the 2015 ASCO Annual Meeting in Chicago.
The PVS-RIPO poliovirus was invented by Matthias Gromeier, MD, Associate Professor of Surgery, Associate Professor in Molecular Genetics and Microbiology, and Associate Professor of Medicine at Duke University School of Medicine, more than 2 decades ago, when he discovered that many cancer cells, including glioblastoma cells, produce the poliovirus receptor Necl-5/CD155. The vaccine works by killing tumor cells and initiating an antitumor secondary immune response. After years of preclinical safety studies to prove the vaccine would not infect patients with polio, the U.S. Food and Drug Administration (FDA) granted investigational new drug (IND) status for PVS-RIPO in 2011.
The ASCO Post talked with Dr. Bigner about the current results of the poliovirus study, the treatment’s use in other cancer types, and why he thinks PVS-RIPO may prove to be a turning point in the care of patients with glioblastoma.
What has been the result so far of your phase I study of the poliovirus in patients with recurrent glioblastoma?
There were 24 patients enrolled in the study, and 12 patients have died. There are three long-term survivors, meaning patients still alive 22, 34, and 35 months after treatment. Overall, 2 patients have no evidence of disease, 11 are doing well with no disease progression, and 1 had disease progression but is still alive.
Can you re-treat the patient whose disease has progressed on the poliovirus?
The current protocol is not written for retreatment with the therapy, although we did get a compassionate plea release from the FDA and re-treated one patient. We certainly could re-treat patients with the poliovirus, and that will be something we would probably want to consider in the future.
The patient who did have disease progression is being treated with one of the nitrosoureas, and that is proving effective.
Mechanism of Action
Why is the PVS-RIPO poliovirus effective against glioblastoma?
The vaccine is effective against any tumor that expresses the poliovirus receptor, and we found that all of the solid tumors we and others tested except for Burkitt’s lymphoma express large amounts of the poliovirus receptor. The genetic alteration of the poliovirus rendered it incapable of killing nerve cells but retained its ability to kill tumor cells.
From a mechanistic standpoint, the virus does two things: It kills tumor cells immediately after the injection and then sets up an inflammatory reaction, which sets up a very potent secondary immune response. We think the secondary immune response is the most important part of the antitumor killing mechanism.
Other Cancers and Patient Groups
Are you testing the poliovirus therapy in other cancer types?
We’ve only tested the vaccine in vitro against melanoma and pancreatic and prostate cancers, and we are in the process of doing animal studies in prostate and pancreatic cancers. Once we have completed those studies and have gotten further along in the glioblastoma clinical trial, we will undertake other clinical trials, starting with prostate and pancreatic cancers. But these studies are some time away because we have to do the animal studies first.
All of the patients in your glioblastoma trial are adults; do you have plans to initiate trials in children?
We have tested pediatric tumors, and they do express the poliovirus receptor. So after additional safety studies, yes, ultimately we will be treating children with brain tumors with this therapy.
Are there side effects from the therapy?
We have had two adverse events. There was one intracranial hemorrhage on removal of the catheter that was used to administer the virus, which is a known complication of stereotactic biopsies in the brain and implantation and removal of these catheters.
The purpose of this phase I study is to determine the optimal dose of the virus. Because the virus causes an inflammatory reaction, which is a necessary part of its effect, too much virus can cause massive swelling in the brain, and the higher doses did cause cerebral edema that had to be treated.
We have now lowered the dose significantly and have reduced the amount of inflammation and cerebral edema. We have to be careful because if you reduce the dose too much and don’t get any inflammatory response, you reduce the therapy’s effect. If patients get too much of an inflammatory reaction, we treat the cerebral edema with bevacizumab (Avastin) in the reduced dose and schedule that we use for treating radiation necrosis of the brain.
Do you have any theories as to why the therapy appears effective in some patients and not in others?
At this point, we really don’t, but we are investigating it. We think that there may be a significant variation in the immune response among the individual patients, which may account for the different responses, and we are investigating that in depth, but at present we don’t have a definitive answer.
Some of the early patients we enrolled in the study did not have a restriction on the amount of steroids they had received prior to participation in the study, and some of those patients had severe steroid myopathies. Also, when patients have been heavily pretreated with steroids, they don’t have any functional T lymphocytes left, so we are now significantly limiting the amount of steroids that patients can receive both prior to study enrollment and during treatment.
In the future, we will be adding checkpoint inhibitors to the treatment regimen, and we believe that they will enhance the immunotherapeutic effect of the poliovirus.
What is the next step in this research; are you planning on launching phase II trials?
The FDA has suggested that rather than go into a phase II trial we expand the phase I study, and we have just gotten permission to treat a total of 26 additional patients in the phase I study at what we think is the optimal dose of virus. As we get further along, we will request Breakthrough Therapy designation and if it is granted, we may be able to have as few as 200 patients in a multi-institutional setting with a constant virus dose and a constant standard treatment with bevacizumab at the radiation necrosis dose and schedule. That might be a single-arm study with historical controls from each
After the 60 Minutes program aired, you received requests from thousands of patients who wanted to enroll in the study. Do you have all the participants you need to expand the study?
Even though we received more than 3,000 referrals since the program was broadcast, most do not meet the trial eligibility requirements, so we definitely need all the referrals we can get. The FDA placed quite rigid requirements on eligibility, including tumor size between 1 and 5.5 cm in diameter. Right now, only about 15% of recurrent glioblastoma patients are eligible because of the tumor size restriction. Also, patients cannot have received more than 4 mg of dexamethasone and must have been previously vaccinated against polio. We vaccinate them again once they enter the study.
Turning Point in Glioblastoma?
How would you evaluate the effectiveness of this therapy thus far?
There are several ways to look at these therapies. The standard way is to look at the median overall survival. In the trial right now, the median is 16 months compared to 10 months in matched historical controls of equivalent eligibility, so this is better than any of the other agents that have been approved for recurrent glioblastoma.
Admittedly, the trial is still small. But I’ve never seen a recurrent glioblastoma trial with these types of results, both in terms of median survival and in these three very long-term survivors, although I have been doing malignant brain tumor research for 45 years.
Do you think this treatment is a turning point in care for patients with glioblastoma?
Yes, I really do. A lot of improvement is still needed, and my biggest hope is that the addition of checkpoint inhibitors with this poliovirus is going to be a big turning point.
We have a number of other vaccines in trials that we think will be complementary with the poliovirus treatment for glioblastoma. There is also an immunotoxin we will be testing in clinical trials soon, which should be complementary with this poliovirus.
I think this therapy and immunotherapy for brain tumors in general are going to result in a paradigm shift in treating brain tumors, probably within the next 10 years. I’ve spent my whole career getting to this point, and there was no belief in immunotherapy in the treatment of glioblastoma for most of that time. ■
Disclosure: Dr. Bigner reported no potential conflicts of interest.
1. Killing Cancer, Part 1. 60 Minutes, aired March 29, 2015. Available at www.cbsnews.com/videos/killing-cancer-part-one. Accessed May 1, 2015.
For more information on the PVS-RIPO poliovirus clinical trial and to refer patients, contact the Preston Robert Tisch Brain Tumor Center at Duke University Medical Center at 919-684-5301, or visit www.cancer.duke.edu/btc/modules/ClinicalTrials4/index.php?id=111.