Using modified poliovirus to jumpstart the immune system and fight cancer—a therapy developed by research at Duke—showed promise in numerous studies and even garnered appearances on CBS's 60 Minutes. 

Now, the first results with human patients are in.

Out of 61 patients with recurrent glioblastoma—the most prevalent and deadly brain cancer—21 percent survived until two years after the treatment. All patients alive after two years were still living at the end of the study. In a control group of glioblastoma patients who sought treatment before the poliovirus therapy was developed, the percentage of survivors steadily decreased from 14 percent after two years to only 4 percent after three years.

However, the median survival time of the two groups differed by only around a month, with an average of 12.5 months for the poliovirus group and 11.3 months for the control group.

“In general, in evaluating cancer treatment effects, the [Food and Drug Administration] wants to see differences in median survival. But what they’re beginning to understand and recognize now is that median survival in the immunotherapy era is not going to be able to be used as the measurement endpoint,” said Darell Bigner, director emeritus of the Preston Robert Tisch Brain Tumor Center. “Overall survival is going to be a much more important efficacy measurement than median survival.”

Bigner, who is also co-senior author of the paper, explained that a greater percentage of patients surviving in the long term is a more valuable metric to evaluate the quality-of-life improvement that a therapy brings.

“Put yourself in a patient’s shoes. If you were told that if you get treatment X, it’s going to increase your chances of survival for two months, but a small proportion of you are going to get a chance to live for a very long period of time, which would you choose?” he asked.

John de Groot, professor and chairman ad interim of the department of neuro-oncology at MD Anderson Cancer Center, cautioned against too much optimism after any Phase 1 trial. 

Because these trials are designed to address safety first and efficacy second, he said, there have been “many clinical trials where Phase 1 looks very promising” but that the treatment was not successful in future trials.

De Groot also questioned the Duke researchers’ choice of a control group—the group to which the patients who receive the treatment are compared. The Duke study used a historical control group of glioblastoma patients treated in the past who would have qualified for the poliovirus treatment, which could have introduced an element of bias because researchers were handpicking the group, he said.

Using a traditional randomized trial—where the study’s patients are randomly assigned to either a group that receives the treatment or a group that does not receive that treatment—would be the ideal “unbiased method,” he said.

‘Big safety hurdle’: Evaluating the treatment’s side effects

Although evaluating the effectiveness of the modified poliovirus was important, Bigner explained, the primary goal of Phase 1 clinical trials is establishing the safety of the treatment. 

Because the injection contains a modified version of the virus that killed and crippled thousands of people in the United States before the polio vaccine’s development in the 1950s, researchers had to be sure that the modified poliovirus would not carry the same malignancy.

Matthias Gromeier, the creator of the modified poliovirus and co-lead author of the clinical trial study, had to first establish the treatment’s safety in non-human primates before moving to humans, Bigner said.

There was no indication of poliomyelitis—the disease typically caused by the poliovirus—in primates, clearing the way for a Phase 1 clinical trial. Bigner added that these findings were also replicated in humans.

“There was absolutely no evidence of any infection of nerve cells or any ability to cause poliomyelitis, so that was the big safety hurdle,” he said.

However, another concern that arose in the clinical trial was related to the dose level of the treatment. The first portion of the trial featured nine patients and five different dose levels to determine the optimal dosage for the modified poliovirus infusion, according to the paper.

The patients receiving higher dosages had a number of side effects, as the three participants receiving the highest dose all suffered seizures. One patient at the highest dose level also suffered bleeding inside the skull after the catheter used to deliver the treatment was removed, according to the paper. This patient was still alive nearly five years after the infusion but suffered from weakness in the right side of the body and a language impairment.

Moving into the next portion of the trial, the researchers started using one of the lower doses but were forced to continually lower the dosage due to safety issues, Gromeier noted.

“From day one, we really had to be open-minded, learn from it, respond to what we saw from the patients and adjust the clinical trial when it needed to be changed,” he said.

Bigner explained one of the most common side effects from the procedure is cerebral edema—or swelling of the brain—because the poliovirus must be injected into the tumor itself. 

Typically, this inflammation would be treated with drugs known as corticosteroids, but because corticosteroids would dampen the immune response—which is a key component of the treatment’s efficacy—the researchers were forced to find another way of quelling the inflammation. They chose a medication called Avastin, Bigner said, which is commonly given after radiation therapy to reduce swelling.

He added that developing strategies for combatting the most prevalent side effects was essential for making the modified poliovirus treatment a viable option going forward.

Gromeier explained that optimizing the modified poliovirus is a two-pronged approach involving both clinical and laboratory work. Researchers can take what they’ve learned from patient trials to investigate certain aspects more closely in the lab, which facilitates a “constant exchange” of ideas.

“We have learned a tremendous amount of information,” he said.

How the treatment works

The modified poliovirus—created by Gromeier in 1994 when he exchanged a piece of normal poliovirus' DNA with genetic information of the common cold—packs two punches, Bigner explained.

The virus is able to recognize a protein expressed on the surface of tumor cells called CD155. This allows the invader to gain access to the tumor cell, where the virus continually replicates, eventually killing the cell.

The second prong of the attack is a result of cellular debris from the dead tumor cells, which alerts the immune system and elicits a series of responses from different types of immune cells. Bigner noted that some of these cells—including a type called cytotoxic T cells—are capable of chewing away at the tumor even further.

Knowing the mechanism of the treatment is vital, he explained, for troubleshooting any errors and designing additional interventions that can boost the poliovirus’ effectiveness.

“If you know what the mechanism is, you can add things to the mechanism’s approach that will allow you to improve success,” Bigner said.

Expanding the trials

A Phase 2 trial has been underway since June 2017, this time including the chemotherapy drug lomustine. The 62 participants are split into two groups to evaluate whether the coupling of poliovirus and lomustine is more effective than the virus on its own, Gromeier explained.

An additional trial—which began in December 2017—is examining the effectiveness of modified poliovirus to attack pediatric brain tumors in patients aged from 12 to 18 years old.

Bigner said he was optimistic that future studies and trials could raise the long-term survival rate to as much as 50 percent.

But the trials won’t stop at recurrent glioblastoma—the CD155 protein that the virus hijacks to gain entry to the tumor cell is present in nearly every solid tumor. Bigner listed pancreatic, lung, prostate, colon and stomach cancer as potential targets for future Phase 1 trials.

Gromeier wrote in an email that Phase 1 trials for melanoma and breast cancer are scheduled to begin in the fall but that paperwork and bureaucracy could delay them.

Treating other cancers might also provide easier delivery and more opportunities for analysis, Gromeier added. Because the treatment must be injected directly into the tumor, treating breast tumors and skin cancer provides a much simpler injection procedure without the catheters and neurosurgery required for treating gliobastoma.

He added that the melanoma and breast cancer trials may also allow researchers to take tissue samples and monitor the treatment, with the possibility of carrying out subsequent poliovirus injections if necessary.

These additional trials have caught the attention of 60 Minutes, Bigner noted, and the treatment is due to appear on the show yet again this fall or the following spring, once these trials have begun and others have progressed further.

With a number of trials ongoing or slated for the future, Gromeier said he foresees learning more about the poliovirus and how to optimize its ability to attack cancer.

“We’re very optimistic about this enhanced chance of success,” he said.