Finding the Cause – Finding the Cure
The first viral immunotherapy was approved 10 years ago in China, a cold virus engineered to treat head and neck cancer. China became a mecca for those who couldn’t get the therapy in their home countries.
After years of U.S. research established the therapy was safe, the FDA became sold.
Late last month, it approved the first U.S. viral immunotherapy, a herpes-based biologic to treat melanoma. The benefits seem modest – in its last clinical trial, it shrank tumors in patients with advanced disease, though the survival figures stopped short of statistical significance – but researchers called it “a huge milestone.”
“This is going to float all boats,” said Dr. Stephen Russell, a professor of molecular medicine and viral immunotherapy researcher at the Mayo Clinic in Minnesota. “It’s a signal to pharmaceutical companies that such drugs can be approved.”
The treatment is known as oncolytic virotherapy, in which the virus infects and replicates inside cancer cells, causing them to burst. The eruption releases tumor proteins that prod the immune response.
Dr David Baskin’s work is a cousin of such therapy. Instead of killing the tumor, his genetically engineered virus acts as a Trojan horse.
Patient Story: Futer, a former mechanic who managed his family’s trust, first sought medical care on Christmas Eve 2006. He’d spent three days in bed, sure “something wasn’t right,” though all he really felt was a severe headache. By the time he got to a clinic near his Cypress home, he was vomiting profusely, a little blood mixed in. Staffers sent him to the emergency department of Methodist’s Willowbrook campus.
After immediate care and testing, Futer was filling out paperwork when a doctor told him it could wait.
“That’s it,” he remembers the doctor saying. “Half your brain is cancer.”
The left half harbored glioblastoma multiforme, the most common and most aggressive malignant primary brain tumor.
Half of people diagnosed with the tumor die within a year, 85 percent within three years. Even when a surgeon seems to have removed the entire tumor, cells remain seeded in the brain, inevitably giving birth to new tumors. Doctors compare the cancer to a weed that keeps sprouting tendrils.
Willowbrook doctors sent Futer to Methodist’s flagship hospital in the Texas Medical Center, where neurosurgeon, Dr David Baskin was on call. One look at Futer’s scans told Baskin all he needed to know.
Dr Baskin, 63, had always been fascinated by the mind. He aspired to be, first, a psychologist, then a psychiatrist and finally a neurologist, each time finding the newly chosen specialty an upgrade over the old one.
He had no interest in surgery – “too bloody, gory” – but figured since he’d be referring patients to neurosurgeons, he should learn what they do. At a rotation soon after, an eminent neurosurgeon enlisted his assistance for a nine-hour operation removing a tumor from a patient’s spinal cord.
“The next day, the patient walked,” Baskin said. “I knew that’s what I wanted to do.”
Glioblastomas promise no such happy ending. Baskin describes the horrific moment when a patient, unaware what’s ahead, looks at him and says, “What do you think, doctor?” and the answer, however delicately put, is that his disease is usually a death sentence.
The news overwhelmed Futer, who’d been happily living day to day. He was calm, stoic, but Baskin could see the fear in his eyes.
Viral immunotherapy represented a long shot, but Baskin was excited to have something to offer Futer besides standard therapy, so unlikely to make any meaningful difference. Futer was all for it, not just on the chance it might help him, but for the more likely benefit it might provide future patients.
Ten days later, Baskin performed the surgery and injected the viral drug, called AdV-Tk. When he closed up Futer’s skull, he had no idea what to expect.
Many of the first researchers working with oncolytic viruses weren’t counting on an immune response. They just saw a virus’s potential as a killing machine.
At M.D. Anderson, for instance, the husband-wife team of Juan Fueyo and Candelaria Gomez-Manzano 15 years ago engineered a cold virus that targets proteins that exist only in cancer. Injected into brain tumors through a hole in the skull, the virus enters malignant cells and begins making copies of itself until the cells explode, which propels viral particles forward in a wave-like motion that infects other cancer cells.
Those experiments were in mice lacking immune systems. Only in a recently completed early-stage clinical trial did Lang’s team confirm the therapy also generates a response from the immune system, which, tricked into thinking the patient is suffering from the common cold, mounts an attack on the virus. Cancer cells get caught in the crossfire.
Baskin’s work always aimed to enlist the immune system. It dates to laboratory work, initially focused on prostate cancer, conducted at Baylor College of Medicine in the late 1990s. Intrigued by presentations of the research, Baskin determined to apply it to brain cancer, where there had been little progress over the decades.
In Baskin’s research program, a non-replicating, gutted cold virus is used strategically – like the ancient Trojans with their wooden horse – to carry a piece of herpes DNA into tumor cells. The virus doesn’t attack by itself, but following the injections, patients are given Valtrex, the oral medication used to treat herpes. When the drug attacks the herpes DNA, it creates a new protein that blasts the cancer cells, making them self-destruct and release other proteins that initiate an immune response.
Cold and herpes viruses are the most common infections being used as immunotherapies against cancer, but researchers are experimenting with measles, mumps, polio, viruses that cause diarrhea and respiratory problems, viruses that afflict cattle and birds. A handful of researchers are working with bacteria, such as listeria and salmonella.
In all, more than 60 clinical oncolytic virotherapy trials are ongoing in the U.S., according to the Cancer Research Institute, a 62-year-old immunotherapy advocacy group. The trials involve cancers from breast and ovarian to prostate and pancreatic.
“It’s impossible to know what’s the best agent at this point, but I think the best perspective is the more options we have, the better,” said M.D. Anderson’s Lang. “Different tumors might respond best to different viral immunotherapies.”
Experts caution that the research is effective in at best a fraction of patients and much in need of randomized trials to provide hard evidence of real benefits. Russell estimated the field is at the equivalent of mile 5 in a marathon.
Big questions remain. Do the injections work better if given before surgery so there’s ample tumor tissue for the virus to grow in? Can the immune system be controlled so it doesn’t kill the virus before it can proliferate through cancer cells and have its desired effect?
One big hope involves combining viral efforts with checkpoint blockade therapy, an approach pioneered by Houston scientist Jim Allison.
Allison identified a natural brake that reins in the body’s defense, then developed a drug that removes the brake and unleashes the immune system to attack cancer. A network of such brakes was subsequently discovered, and scientists around the world are now investigating the best ones to target different cancers, often in combination with other therapies.
Researchers at Advantagene Inc., AdV-Tk’s manufacturer, have combined the two therapies in mice and found they worked better than the viral biologic alone. Merck recently announced plans to launch an intermediate-stage trial pairing a checkpoint blockade drug with M.D. Anderson’s oncolytic virotherapy.
The furthest along of the viral immunotherapies may belong to Baskin, who expects Advantagene to launch a late-stage, randomized trial of AdV-Tk in early 2016. At a major cancer conference in June, Baskin reported that 32 percent of patients who got AdV-Tk plus standard treatment in the trial that enrolled Futer survived at least three years after diagnosis, compared to 6 percent of patients who concurrently got identical treatment minus the AdV-Tk. Three of the trial’s 48 patients are still alive, all more than five years out.
From the beginning, Futer had an agreement with Baskin: that he always be honest with him. If his chances of living more than a year were just 20 percent, Baskin shouldn’t shade the truth. Baskin hadn’t – that was the prognosis he originally gave Futer.
Studying Futer’s scans before his three- and six-month follow-ups, Baskin fretted. Futer’s tumor appeared bigger than it had been before surgery.
“I don’t know about this,” Baskin told Futer at the second appointment. “This looks bad.”
Still, Baskin figured any patient with a tumor that big would be horribly impaired. Futer was doing fine – so fine he was able that summer to persuade Baskin to let him fly to England, where he was born and lived for eight years, so he could assist an old friend participating in a sheepdog trial. Baskin thought Futer’s lack of symptoms suggested things might not be as they seemed.
They weren’t. At one year, scans showed Futer’s tumor had shrunk by a third. At two years, it was down to half its original size, and at three, just 25 percent remained. In ensuing years, the tumor melted away, culminating last month, at Futer’s first appointment with Baskin in a year, when a last sliver seen on the 2014 scan was gone. Baskin had never before had a glioblastoma patient still alive nearly nine years after diagnosis.
What initially appeared to be tumor growth was actually inflammation caused by the immune system’s attack on Futer’s cancer, now a known hallmark of immunotherapy. The medical term is “pseudo-progression,” which often precedes a positive, prolonged response to therapy.
The cancer left Futer with short-term memory issues, and he is on disability. Since his initial diagnosis, he’s become extroverted and temperamental. Where he formerly had the disposition of a St. Bernard, according to his dad, he now occasionally brings to mind a German shepherd.
Futer’s recovery has been an “emotional boost for everyone,” Baskin said. “If I wasn’t a scientist,” he said, “I’d call this a miracle – and maybe it is.”
At last month’s appointment, Baskin and Futer looked at scans, from pre-surgery to now. Baskin floated the idea of having an immunologist analyze Futer’s blood in hopes of finding clues that might suggest why he responded so well. He told of tweets doctors sent after a lecture that highlighted Futer’s case.
“You’re helping more people than you know,” Baskin said.
“I’m having a hard time not crying,” said Futer, head lowered, voice breaking.
The battle is likely not over. This spring, Futer was diagnosed with kidney cancer, unrelated to his brain tumor.
A surgical team removed the mass, and for now, he is cancer-free.