The Food and Drug Administration on Friday approved a new cancer therapy that could one day transform the way a majority of aggressive and advanced tumors are treated.
The treatment, called Amtagvi, from Iovance Biotherapeutics, is for metastatic melanoma patients who have already tried and failed other drugs. It’s known as TIL therapy and involves boosting the number of immune cells inside tumors, harnessing their power to fight the cancer.
It’s the first time a cellular therapy has been approved to treat solid tumors. The drug was given a fast-track approval based on the results of a phase 2 clinical trial. The company is conducting a larger phase 3 trial to confirm the treatment’s benefits. The therapy’s list price — the price before insurance and other potential discounts — is $515,000 per patient.
“This is going to be huge,” said Dr. Elizabeth Buchbinder, a senior physician at Dana-Farber Cancer Institute in Boston. Melanoma is “not one of those cancers where there’s like 20 different” possible treatments, she said. “You start running out of options fast.”
Friday’s approval is only for melanoma, the deadliest form of skin cancer, but experts say it holds promise for treating other solid tumors, which account for 90% of all cancers.
“It is our hope that future iterations of TIL therapy will be important for lung cancer, colon cancer, head and neck cancer, bladder cancer and many other cancer types,” said Dr. Patrick Hwu, chief executive of the Moffitt Cancer Center in Tampa, Florida. Moffitt has been involved with Iovance’s clinical trials of TIL therapy.
TIL stands for tumor-infiltrating lymphocytes, which are immune cells that exist within tumors. But there are nowhere nearly enough of those cells to effectively fight off cancer cells. TIL therapy involves, in part, extracting some of those immune cells from the patient’s tumor and replicating them billions of times in a lab, then reinfusing them back into the patient.
It’s similar to CAR-T cell therapy, where healthy cells are taken out of a person’s body and then modified in a lab to fight cancers. That’s usually used for hard-to-treat blood cancers such as leukemia and lymphoma. With TIL therapy, the cells used are already programmed to recognize cancer — no lab modifications needed — they just need a boost in numbers to fight it.
Like CAR-T, TIL therapy is a one-time treatment, though the entire process can take up to eight weeks. The TIL cells are first harvested from the tumor through a minimally invasive procedure and then grown and multiplied in the lab, a process that takes 22 days, according to Iovance.
While that’s happening, patients are given chemotherapy to clear out their immune cells to make room for the billions of new melanoma-fighting TIL cells. Once the TIL cells are reinfused back into the body, patients get a drug called interleukin-2 to further stimulate those cells.
Hwu said that most side effects in patients undergoing TIL therapy are not from the reinfusion of cells, but from the chemotherapy and the interleukin-2. These can include nausea and extreme fatigue, and patients are also vulnerable to other illnesses because the body is depleted of disease-fighting white blood cells.
Putting billions of cells back into the body is not entirely risk-free, however, said Dr. William Dahut, chief scientific officer of the American Cancer Society. It’s possible that the body’s immune system could overreact in what’s known as a cytokine storm, which can cause flu-like symptoms, low blood pressure and organ damage. “There are risks for immune-related side effects, which could be serious,” he said.
Common side effects associated with Amtagvi can include abnormally fast heart rate, fluid buildup, rash, hair loss and feeling short of breath, the FDA said.
Those side effects can be managed, said Dr. Steven Rosenberg, chief of the surgery branch at the National Cancer Institute. “They’re a small price to pay for a growing cancer that would otherwise be lethal.”
Overall, Dahut said the approval of TIL therapy is “meaningful.”
“What’s nice about this is that patients will receive a wide variety of tumor fighting lymphocytes that will be able to have the capacity to overcome resistance and actually be a living therapy over time, too, to target additional cancer cells should they develop,” Dahut said.
In addition to melanoma, Dahut said that TIL therapy is most likely to be useful in cancers that respond to drugs that “take the brakes off the immune system,” called checkpoint inhibitors.
“Those would be things like non-small cell lung cancer, kidney cancer, maybe bladder cancer, that we know are responsive to immune-based therapies to begin with,” he said. “Many of those patients relapse, so another immune-based therapy that works in a different way, seems to me, the most likely way for this to be effective.”
Much more research is needed, and it may be years before TIL therapy is approved for other types of cancer.
One of Iovance’s clinical trials investigating TIL therapy for non-small cell lung cancer was forced to pause when a participant died. While the death is under investigation, the company said it may have been the result of either chemotherapy or interleukin 2 — therapies meant to knock down each patients’ immune system before they can get the reinfusion of their TIL cells.
The therapy is not expected to work for every metastatic melanoma patient. Clinical trial data that Iovance submitted to the FDA showed that tumors shrank in about a third of patients who received TIL therapy.
Of those patients, about half saw their tumors shrink for at least one year, Dr. Friedrich Graf Finckenstein, chief medical officer of Iovance Biotherapeutics. “Some of these patients even had their tumor completely disappear,” he said.
Another study, conducted in the Netherlands, did a head-to-head analysis of TIL therapy and another form of immunotherapy, called ipilimumab. Twenty percent of the patients who received TIL had complete remissions, compared with 7% of patients who got ipilimumab. Iovance was not involved with the Dutch trial.
The goal of the therapy, Hwu said, “is to get rid of the cancer and have it stay away. These immune cells stay in the body and live in the body for decades.”
The technology has been in development and studied for nearly 40 years. It was Rosenberg who pioneered TIL therapy — first describing how it could shrink melanoma tumors in the New England Journal of Medicine in 1988.
“I’ve been waiting for a very long time to see this given to patients, because I know that it can cure some patients that have metastatic melanoma that cannot be affected by any other treatment,” Rosenberg said.
It’s worked so far for Dan Bennett, 59, of Clermont, Florida. Bennett was diagnosed with melanoma in 2011 after his daughter noticed a suspicious mole on his neck that had changed color.
Despite surgery, chemotherapy and radiation, his cancer kept returning. In 2014, his doctors at Moffitt recommended he try TIL therapy.
“At first, we were pretty leery about it because it was unproven,” Bennett said. Ten years later, Bennett is convinced the TIL therapy is the reason he has survived so long with stage 4 melanoma, which usually has a five-year survival rate of 22.5%.
“I would recommend any experimental drug if it’s your last opportunity,” he said. “You owe it to yourself and your family to do whatever you can to stay alive and to be a productive member of society.”
Buchbinder, the Dana-Faber doctor, was not involved with Iovance’s TIL therapy trial for melanoma, but she is scheduled to begin similar trials with other drugmakers.
“We literally have patients right now waiting for approval because they are hoping they’ll be able to go on it,” Buchbinder said. “It is definitely a practice-changing therapy.”
