That was three years ago. The pets were considered too sick to derive much benefit, but their reactions would show whether the therapy, called TALL-104, had toxic side effects. If it was safe, the next step would be proving it worked.
To the Philadelphia researchers’ astonishment, six of the 19 dogs temporarily went into remission — and one was completely cured. There were no serious side effects. And the therapy not only attacked cancerous cells, but stimulated some of the dogs’ immune systems to take over the attack.
“We really did not expect much, so having seven responses was a remarkable thing,” said Wistar immunologist Daniela Santoli, leader of the research team.
TALL-104 has proven to be so effective in treating cancer in dogs and cats that Santoli and her colleague plan to seek federal marketing approval of the therapy for veterinary use. It also has begun human testing. A trial at Children’s Hospital of Philadelphia is enrolling children with advanced leukemia, lymphoma and bone, brain or kidney cancer; another trial at the Hospital of the University of Pennsylvania is enrolling women with advanced, spreading breast cancer.
“This is just the beginning of an adventure. It could take years,” said oncologist Edward Stadtmauer, who is leading the Penn breast cancer trial. “What’s exciting is this is a novel approach.”
The approach relies on T-cells, human immune system cells that are programmed by the body to destroy foreign invaders and cancerous cells.
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Ten years ago, Santoli was studying T-cells taken from a child with acute lymphoblastic leukemia, a blood cancer in which immature T-cells multiply uncontrollably. Under the microscope, Santoli saw that the child’s T-cells were filled with toxic proteins.
“I could tell. . . they were `killer’ cells,” recalled the 50-year-old immunologist, who came to Wistar from Italy in 1972.
She wondered whether these malignant immune cells could be harnessed to kill other malignant cells. The idea was innovative, but not far-fetched: some existing therapies, notably bone-marrow transplantation, involved giving healthy immune-system cells to cancer patients to stimulate their disease-fighting ability.
Santoli and her assistants, Sophie Visonneau and Alessandra Cesano, began growing batches of the child’s cells, dubbed TALL for T-cell acute lymphoblastic leukemia, and treating mice. Batch 104 became their focus.
The researchers faced several major obstacles in developing an anti-cancer treatment. The first — preventing TALL cells from causing leukemia in the mice — was accomplished by bombarding the TALL cells with radiation.
“After irradiation, the cells stop dividing, so they can’t give leukemia, but they can still kill efficiently,” Santoli explained.
Another obstacle involved the problem of rejection. If cells from a donor do not match those of the recipient, the recipient’s immune system will attack, or reject, the donated cells (or the donated cells will attack the recipient).
Surprisingly, TALL-104 cells did not trigger significant rejection, even when the testing moved from mice to dogs and cats — animals with immune systems similar to those of humans. The animals did not even need cyclosporin, a drug that suppresses the immune system and prevents rejection of transplanted tissue.
“If you could find a T-cell that is universal, you wouldn’t need a match” to use it therapeutically, said Stadtmauer. “The one Santoli found seems to be it.”
TALL-104 has turned out to have no serious side effects in animals. While conventional cancer chemotherapies work by attacking any fast-growing cells — including healthy hair and intestinal cells — TALL-104 apparently attacks only cancer cells. Equally important, TALL-104 somehow alerts the patient’s immune system to attack lingering cancer cells, thus preventing the cancer from recurring.
A stunning example was Pooh Bear, the dog who was cured in the early toxicity testing of TALL-104. The Scottish terrier had malignant histocytosis, a cancer common in dogs but rare in humans, that had spread to many lymph nodes.
After six TALL-104 injections, his cancer dramatically regressed. After eight injections, it disappeared. Two weeks after therapy ended, new signs of cancer appeared — but went away without treatment within days. Blood tests showed that the dog’s immune system was highly active. When he died 14 months later of unrelated causes, an autopsy found no sign of cancer.
“That shocked all of us,” recalled Ann Jeglum, a veterinary oncologist in West Chester who has collaborated in the testing of TALL-104.
The case of Buckley the golden retriever is equally dramatic.
Buckley, who inherited susceptibility to cancer from his parents, was a puppy when he developed skin cancer. After more than two years of chemotherapy failed to wipe out the cancer, TALL-104 did so in a few months. When TALL-104 was discontinued, however, another type of cancer grew.
With surgery and chemotherapy, he might have survived several more months, said his owner, Lauren West, a veterinarian in Manheim, Lancaster County.
Instead, today — more than a year later — Buckley is a frisky, healthy 6-year-old dog receiving monthly doses of TALL-104.
“I’m really amazed,” said West. “This therapy is the only thing that’s keeping him alive.”
TALL-104 is currently being tested on 45 dogs and 16 cats with less advanced cancers, including breast cancer, bone cancer, lymphoma and malignant histocytosis. All are now in remission, and many are beyond the point when they would be expected to suffer a recurrence of cancer, Santoli said.
Jeglum, who recently won marketing approval for a veterinary medicine she developed, predicted it will take at least another year to obtain federal approval for TALL-104, and to find a biotechnology company to mass produce the cells. Santoli said her lab spends about $80 to produce a single dose.