Eradicating cancer without damaging healthy tissue is the Holy Grail of cancer researchers.
Wills Eye Hospital in Philadelphia is testing a novel, light-activated drug designed to do just that in the eye, raising hopes for the first ocular melanoma treatment that would preserve patients' vision. Sparing eyesight could encourage earlier detection and treatment, thus reducing the chance of metastases — the deadly spread that killed acclaimed author and neurologist Oliver Sacks in 2015.
"This could be a game-changer if it works," said Carol Shields, an ocular oncologist at Wills Eye and Thomas Jefferson University.
That's still a big if. Shields treated the first patient, a 46-year-old man from Hazleton, Pa., in March. A dozen patients in all will be treated at Wills and five other centers over the next two years – and that's just the first of three clinical trials needed to win approval from the U.S. Food and Drug Administration.
But if Aura Biosciences' experimental therapy vanquishes the rare eye malignancy, it could pave the way for a new class of exquisitely precise cancer therapies. In lab experiments, the drug's artificial viral nanoparticles — derived from groundbreaking technology pioneered at the National Cancer Institute — have been shown to zero in on and bind to many types of malignant cells without harming normal cells.
"We decided to first focus on a cancer with medical need and no other drug option," Aura's founding CEO, Elisabet de los Pinos, said of ocular melanoma. "But we think that our technology can be applied to other cancers," including bladder and head and neck.
Many people have a harmless freckle, or nevus, in their eyes, formed by the same pigment-carrying melanocytes that produce freckles in the skin.
Just as in the skin, the eye spots can turn malignant. Sun exposure is not clearly linked to ocular melanoma, but fair skin and light eye color are risk factors.
While the disease is rare, with about 3,100 new diagnoses and 330 deaths in the United States each year, it often goes undiagnosed until it affects vision. Sacks — known for books including Awakenings and The Mind's Eye, in which he tells the story of his own cancer — said his symptoms hit suddenly, wiping out a triangular chunk of the vision in his right eye.
Sacks decided to have a chip of radioactive iodine embedded in his eye to treat the tumor. It caused severe pain, hallucinations, and vision loss in the center of that eye. The radiation and, later, lasering, ultimately left that eye blind.
Other ocular melanoma treatments, including proton beams, gamma knife, and surgery to cut out the tumor, also have damaging side effects. If these fail to control the cancer, the eye must be removed.
The first patient, Ed Tuggle, a maintenance supervisor for a food company, never had symptoms. In 2010, his ophthalmologist spotted a tiny freckle during a routine eye exam. Last year, the same doctor saw that the lesion had grown. Although it was still small — about one-tenth of an inch — he sent Tuggle to Wills, where Shields did a battery of tests and concluded that it was malignant.
Patients with small tumors such as Tuggle's often choose monitoring rather than immediate vision-damaging treatment. But holding off can be anxiety-provoking, given that studies indicate up to 40 percent of ocular melanomas metastasize.
When Shields proposed another option — Aura's clinical trial — Tuggle and his wife, Daneen, a nurse, were eager.
The actual procedure in early March was a breeze, Tuggle recalled. Shields numbed his eye, injected the drug, and six hours later, used a laser to activate the light-sensitive dye that is part of the therapy.
His dose was purposely low, intended more to test safety than effectiveness. Patients in the next trial will get multiple, higher doses. Still, a month after Tuggle's injection, Shields was pleased to find that the tumor had begun to atrophy. Based on animal studies, it takes three or four months to gauge the response.
"I've got a lot of faith," said Tuggle, who said he has had no side effects. "In my mind, it's already worked."
De los Pinos, a molecular biologist who previously worked in Eli Lilly & Co.'s oncology division, founded Cambridge, Mass.-based Aura in 2009 with the goal of developing a highly targeted approach to cancer treatment.
The first product candidate is built on decades of advances involving, of all things, the human wart virus — human papillomavirus, or HPV.
In the 1980s, certain virulent strains of HPV were shown to cause cervical cancer. In the 1990s, scientists figured out how to make harmless, empty HPV shells — called virus-like particles — to prime the immune system to ward off the real germ. Virus-like particles became the basis of Merck's groundbreaking cervical cancer prevention vaccine, Gardasil, approved in 2006.
More recently, a team at the National Cancer Institute led by John T. Schiller and Douglas R. Lowy deciphered how HPV infects certain cervical cells in the first place. Physically "disrupted" cells overproduce a carbohydrate molecule that normally helps with wound healing. The virus binds to that molecule, called heparan sulfate proteoglycans. Healthy intact cells, meanwhile, resist being bound.
Using animal models, the NCI researchers showed that virus-like particles behaved like the actual virus, using the carbohydrate to attach to tumors. And not just in the cervix. In 2015, Schiller, Lowy, Aura's de los Pinos, and others published a study that showed virus-like particles "can infect a broad range of cancer cell types," including ovarian and lung, by binding to the carbohydrate.
Since virus-like particles are harmless on their own, Aura's are coupled with a light-sensitive dye. When activated by laser light, the dye becomes toxic to the tumor cells' membranes and — if all goes as expected — selectively kills the cancer.
Although ocular melanoma is rare, Shields has long urged people to get annual eye checks because finding it early is critical.
Now, she foresees a way to make early detection less dreadful.