Harnessing the power of viruses to fight brain cancer
New developments in brain cancer treatment bring hope to an otherwise bleak prognosis
Between the five brain surgeries, the shunt implanted in her head to drain excess cerebrospinal fluid, and the metal wedge patching up a hole doctors drilled into her skull, Kyle Donohue is a human embodiment of what modern medicine can do.
Donohue has glioblastoma multiforme (GBM), the most common and deadliest form of brain cancer in adults. Though symptoms might start with something as innocuous as a headache, a GBM tumor — which doubles in size approximately every seven weeks — rapidly steals space and nutrients from healthy cells, causing swift decline for the patient’s health.
GBM has no cure. Its cancerous cells are so diverse that there is no singular mechanism to target, and the body’s system of blocking foreign substances from entering the brain makes it difficult to design drugs that can even reach the tumor. GBM is so complex that its standard treatment — a combination of surgery, chemotherapy, and radiation — has barely changed in over 20 years.
On average, people diagnosed with GBM have 15 months left to live. That was what doctors told Kyle in early April 2021. An avid skier and mother of two, she was perfectly healthy until one morning, when she woke up barely able to walk or talk. A GBM tumor was blocking cerebrospinal fluid drainage in her head, and the buildup of pressure against her brain was impairing cognitive function and possibly damaging tissue.
The doctors at Beth Israel Plymouth put Kyle and her husband, Jim Donohue, on a life flight to Boston for emergency surgery. She needed an external ventricular drain to alleviate the pressure, which was later replaced by the shunt.
But she doesn’t remember any of this. To this day, Kyle has no recollection of what happened in the weeks after they got to the hospital. In the weeks that followed, she was so dazed that she told doctors the wrong ages for her children, and even the wrong number of children she had. She couldn’t even remember the food she’d just eaten.
The neurosurgeon that Jim talked to said that the tumor’s location meant that the harms of surgery would likely outweigh the benefits. Their neuro-oncologist, Dr. David Reordan of the Dana-Farber Cancer Institute, initially agreed with the sentiment. But Jim didn’t want to give up.
“I think I knew what Kyle wanted, which was to do everything [she] could do,” Jim said, from getting a second opinion to opting for surgery despite the risks. “But then, [I was] always asking, ‘Am I doing this for me, or am I doing it for her?’”
A few days after their appointment with Dr. Reordan, the Donohues got a call. “I hope you don’t mind, but I bumped into the director of our neurosurgery department, Dr. Chiocca,” Dr. Reordan told them. “He’s looked at the films, and he knows he can do the surgery.”
Cutting out the cancer
A practicing neurosurgeon, neuro-oncology researcher, and professor at Harvard Medical School, Dr. Ennio Antonio Chiocca is an expert on glioblastomas.
In the first week of April 2021, Dr. Chiocca opened Kyle’s skull and removed a golf ball-sized tumor from her brain. “He got virtually all of it,” Dr. Reordan, who works closely with Dr. Chiocca, told the Donohues.
Going into the surgery, they had no way of knowing if Kyle’s memory would ever recover, but “within a month, she was back to almost her normal memories,” Jim said.
That made her glioblastoma’s recurrence a few months later all the more devastating. Cells from the original tumor, which spread across the brain and infiltrated healthy tissue, had grown and divided. They were strong enough to have survived a summer of chemotherapy and radiation; now they formed clumps of cells big enough to show up in scans.
“Kyle’s never been a ‘why me?’ [person],” Jim said, but the day scans showed the tumor was back “was the day she really got emotional about it.”
“If I go within six months, I’ve got so much more I want to do,” Kyle remembered thinking.
For most glioblastoma patients, when all other treatments fail, their best bet is to join a clinical trial. And for Kyle, Dr. Chiocca was the person to ask.
Searching for a cure
In addition to being a neurosurgeon, Dr. Chiocca runs a lab that studies neuro-oncology, particularly focusing on immunotherapies. “My idea was always that I want to invent something in my lab that I can then personally take to humans,” he said.
Dr. Chiocca is particularly interested in oncolytic immunoactivation, which involves harnessing the power of viruses to fight cancer.
“Tumors escape the immune system,” Dr. Chiocca said. “Guess what? Viruses love things that escape the immune system because it lets them grow better.”
Over the past 25 years, Dr. Chiocca has been developing a new treatment for recurrent GBM. Named CAN-3110, this treatment is a re-engineered version of the herpes-simplex virus that gets injected into the tumor, where it replicates in cancerous cells and works with the body’s immune system to destroy them.
The idea of re-engineering viruses to activate the immune system against cancer isn’t new. But recent developments in fields like genomics have enabled Dr. Chiocca’s lab to design a virus that infects cancerous cells while sparing healthy ones.
Dr. Chiocca’s team began with a laboratory strain of the herpes simplex virus, which was already known to be safe in humans. To make it lethal only to tumor cells, the lab engineered the virus to choose hosts with mutations in the P-16 tumor suppressive pathway. The unmutated form typically prevents cells from dividing uncontrollably; nearly every tumor has to “inactivate that pathway” to facilitate unregulated cell growth, according to Dr. Chiocca.
Next, the team modified the virus’s DNA so it could replicate without being identified as a threat, while also causing enough inflammation to train T-cells — the disease-fighting forces of the immune system — to recognize and attack the tumor.
“We’ve done it very logically,” Dr. Chiocca said. However, the process for developing this drug wasn’t easy. Getting to this point took 25 years of work from scientists across a multitude of research groups; even the paper describing the clinical trial Kyle participated in had over 60 collaborators.
“I feel like I’m the football coach,” Dr. Chiocca joked, referencing the “smart postdocs, smart undergraduate students, [and] smart students” working for him. “I’m not playing football. They’re the players, they’re the quarterback, they’re the offensive line, and I’m just there coaching.”
Beginning in 2005, Dr. Chiocca’s team spent over ten years working on an Investigational New Drug (IND) application, in which they demonstrated that the virus was effective and used mice to show that it was safe enough to begin testing in humans. After cycling between in-lab virus modification, mouse injections, and human testing, the scientists began conducting clinical trials for their current version of CAN-3110 in September 2017.
A star patient
Using the visual guidance of an MRI machine, Dr. Chiocca’s team inserted a catheter into Kyle’s brain, allowing them to inject virus-filled fluid into the tumor.
“They described it as first going in like a Pac-Man and eating the cancer cells, and then training [my] immune system to do the same,” Kyle said. “And it must have worked for me.”
When she returned to the hospital for her first MRI post-injection, the results were overwhelmingly positive. “They were like, oh my God, this is working,” Kyle recalled. “And every time I went in, it was a positive reaction.”
“She’s like a rock star walking into Dana Farber or Brigham,” Jim joked. Dr. Reordan “light[s] up when he sees Kyle.” The tone of the discussion is dramatically different, compared to those with most of his patients.
It’s been four and a half years since her diagnosis, and Kyle’s more than back on her feet. But she wouldn’t say that she’s in remission. “No one has ever used that word with me, so I’m still very hesitant to use it, though I feel great,” she said.
Kyle’s recovery isn’t the norm. Over the last eight years, almost 60 patients have been treated with CAN-3110. Of the 41 in the original clinical trial, the median survival time was just shy of a year, but it was higher for people who already carried immunity to the herpes virus. By contrast, most people diagnosed with recurrent glioblastomas die in less than ten months.
“I don’t want to tell you that we’ve cured patients, because it’s a difficult cancer to even think about,” Dr. Chiocca said. “We give people the gift of life, trying to buy them more time.”
For Jessica Morris, who joined the clinical trial in late 2019, that time was an opportunity to make a difference in the lives of thousands of people affected by GBM. After her diagnosis in 2016, she became the founder and chair of OurBrainBank, an organization that supports glioblastoma patients in everything from telling their stories to helping them find treatments to creating a Glioblastoma Bill of Rights. She also wrote to raise awareness for the disease; her memoir, All in My Head: A memoir of life, love, and patient power, was released after the disease took her life in 2021.
“This virus gives me a shot at longevity,” Morris wrote on her blog after her initial round of treatment. “A real shot. When you sing, the choir director will talk to you about breathing in your chest, or your belly, and the way this causes your voice to differ. I’m quite a smiley person. But now I feel I have a smile in my belly and in my heart as well as on my face. Because I have been given a real shot.”
Out into the world
CAN-3110 has now been bought and licensed by the drug company Candel Therapeutics. “As I’m finishing the academic piece of this, they’re going to start thinking about the next step of what to do and how to do this,” Dr. Chiocca said.
At the same time, what Dr. Chiocca dubbed as “Phase Zero” clinical trials are underway across Massachusetts hospitals through an MIT consortium called Breakthrough Cancer. The trials aim to capture a long-term picture of the treatment’s effects. Over the course of four months, 12 patients will receive six serial injections of the drug, regularly receiving biopsies to help scientists monitor how the cancer cells are changing.
“It’s exciting,” Dr. Chiocca said. “That’s never been done like that in glioblastoma. We now have the ability to really decipher, for the first time, the longitudinal evolution of the tumor at the level of deep molecular, cellular signaling and immunologic parameters.”
These experiments will be the last time Dr. Chiocca works on CAN-3110. Trials to determine its effectiveness are impractical for academicians to conduct, due to the large number of patients, regulations, quality control, and potential financial incentive for the drug to win federal approval.
“Unfortunately, that’s almost like your child leaving your home,” Dr. Chiocca admitted. “ I got them to 18, and now [I] just let them go free, and hopefully something will happen.”
Looking forward
Though glioblastoma claimed Morris’s life in 2021, her legacy lives on at OurBrainBank, where Dr. Chiocca is one of the medical advisors. Morris’s videos, spunky personality, and sense of humor continue to uplift and comfort glioblastoma patients.
“If GBM is my life challenge, then OurBrainBank is a determined effort to turn challenge into opportunity. From negative to positive. From death to life. To persuade all of you, and all of me, that we can turn this monster disease around,” Morris wrote.
Nowadays, Kyle wears a scarf over her head to hide the protrusion from the shunt. Every few months, she has an appointment to make sure that it’s still working properly. But she’s back home with her family five years after her initial glioblastoma diagnosis, which is something that less than 5% of patients achieve.
When she first got sick, the Donohues weren’t even sure she’d live long enough to see her older son’s high school graduation that June. Since then, not only has she gotten to see both of her sons graduate high school, but she also attended her older son’s college graduation.
“I really think [Dr. Chiocca and Dr. Reordan] saved my life,” Kyle said.
Last August, Jim and their two sons biked across Massachusetts as part of the Pan-Mass Challenge, which raises money for the Dana-Farber Cancer Institute. To Jim, the success of CAN-3110 shows just how important donations to cancer research can be. Kyle, Jim said, is “exhibit A of what a clinical trial can do.”