An experimental treatment for advanced melanoma is poised to be the next major advance in cancer treatment, experts say.
The results of a phase 3 clinical trial published Wednesday in the New England Journal of Medicine showed that the treatment, which uses a superconcentrated boost of the person's own immune cells, was more effective than the leading existing treatment at putting patients into remission.
The trial, conducted by researchers in the Netherlands, caps off a stunning decade of progress in the treatment of metastatic melanoma, a disease that a little more than a decade ago had a 5-year survival rate of just 5%.
The new approach, called TIL therapy, uses immune cells harvested from the tumor itself to fight the cancer. The cells are called tumor-infiltrating lymphocytes — the "TIL" in TIL therapy.
“These are immune cells that are found in the tumor, trying to kill the tumor, but obviously not doing a good enough job because the tumor is growing,” said Dr. Patrick Hwu, the president and CEO of the Moffitt Cancer Center in Tampa, Florida.
To supercharge the cells, they’re taken to a lab where they’re multiplied until they number in the billions — an army now formidable enough to take on the tumor.
How TIL held up
The new clinical trial included 168 patients with advanced melanoma, nearly all of whom had already tried and did not respond to a first-line treatment called anti-PD-1-therapy. (Before Wednesday’s publication, the results were presented in September at the European cancer meeting ESMO Congress 2022 in Paris.)
In the trial, half of the patients got TIL therapy and the other half got an immunotherapy drug called ipilimumab. Following treatment, patients were tracked for a median time of 33 months.
Those who got TIL therapy had a 50% reduction in disease progression and death, compared to those who were treated with ipilimumab, the study found.
The therapy didn't work in all of the participants.
Just under half, 49%, of the TIL patients experienced at least partial remission — meaning a decrease of least 30% in their metastatic tumors — compared with 21% of patients who got ipilimumab.
More surprising was that 20% of the TIL patients had complete remissions — all their tumors disappeared — a result that was “better than we had expected,” trial leader Dr. John Haanen, a medical oncologist at the Netherlands Cancer Institute, said in an email.
In the ipilimumab group, 7% experienced complete remission.
“Patients with a complete remission have an excellent prognosis,” he said. “We estimate that more than 80% of these may be cured.“
Hwu was not involved in the Dutch trial, but conducts his own research on TIL therapy and has seen similarly impressive results.
"I have patients that we treated with TIL therapy a decade ago and they’re not getting any treatment right now, just living a normal life," he said.
A last-ditch effort
Bruce Hawley, 64, of Ocala, Florida, had already been through several rounds of immunotherapy for his advanced melanoma when he agreed to try TIL therapy as a last-ditch effort. By that point, the cancer, which had started on the bottom of his foot, had spread throughout his body.
He enrolled in a clinical trial studying TIL therapy at Moffitt.
There, doctors harvested TILs from Hawley's tumor and multiplied them into billions.
But before the concentrated infusion of cancer-fighting cells could be reinfused back into Hawley's bloodstream, he needed chemotherapy to clear out space for the billions of incoming cells.
"The chemotherapy knocks down the immune cells to make space for the TIL cells going in," Hwu said.
In addition to the infusion of the billions of TILs, patients are also given interleukin-2, which is a growth factor that supports the new cells and helps them proliferate, he said.
Hwu added that while the infusion of the TILs doesn't cause many side effects in patients, the chemotherapy and interleukin-2 do.
TIL therapy isn't commercially available yet, although the Moffitt Cancer Center is one of several research institutions that have been working with Iovance Biotherapeutics, a California-based biotech company that’s on track to apply for Food and Drug Administration approval for its TIL therapy product.
Jen Saunders, Iovance’s director of investor relations and public relations, said that the company is in the process of submitting its results to the FDA, and approval could possibly come in the second half of next year.
Improvements in melanoma treatments
Melanoma is the most dangerous form of skin cancer, and for decades, metastatic melanoma — which means cancer that has has spread to other parts of the body — was considered a death sentence.
"I used to call the melanoma clinic 'the sad clinic,'" said Dr. Hussein Tawbi, a melanoma oncologist at the MD Anderson Cancer Center in Houston, who was not involved in the new research. "It’s not that anymore. There’s so much hope, there’s so much promise. We can do so much for those patients.”
That change has come in the past 10 years, researchers reported Tuesday in the journal JAMA Network Open. From 2013 to 2017, death rates for metastatic melanoma decreased for the first time in 40 years.
The improvement in survival can be tied to the FDA’s approval of several new treatments for the disease, including ipilimumab, beginning in 2011, the study authors wrote. These novel treatments have increased a person’s odds of survival five years after a metastatic melanoma diagnosis from 5% to more than 50%.
Cell therapy for other types of cancer
One of the most striking results from the new clinical trial was the complete remission in one-fifth of the patients who got TIL therapy. In other words, their tumors completely disappeared.
“If you have a complete regression due to TIL therapy, it appears in my view to be curative,” said Dr. Steven Rosenberg, the chief of the surgery branch at the National Cancer Institute in Bethesda, Maryland.
He wasn't involved in the latest trial, but his view holds sway in the cancer community: he was the first to use TIL therapy in patients. In a paper published in 1988 in the New England Journal of Medicine, he and his colleagues described how TIL therapy could cause a patient’s metastatic melanoma tumors to shrink.
Some of those patients from 1988, Rosenberg said, are still alive. Other patients that he has treated with TIL therapy have been cancer-free for 20 years, according to him.
The difference between his TIL therapy research and the new clinical trial, he said, is that the clinical trial directly compared TIL to another treatment — and found that it worked better.
I think that it’s this kind of cell therapy that’s the most exciting area of modern oncologic treatment.
Dr. Steven Rosenberg
The treatment doesn’t just hold promise for melanoma patients.
“I think that it’s this kind of cell therapy that’s the most exciting area of modern oncologic treatment,” Rosenberg said. He likened TIL therapy’s potential to that of another type of cancer treatment that revolutionized how certain blood cancers are treated.
That treatment is CAR-T therapy. Similar to TIL therapy, it involves harvesting immune cells and later reinfusing them back into the body to fight cancer. Unlike TILs, the cells used in CAR-T therapy must be genetically modified in the lab before going back into the patient.
The hope is that TIL therapy will also be used for other solid cancers, not just melanoma, Rosenberg said. Solid cancers — any type of cancer that forms a mass in the body, such as lung, breast or colon cancer — account for 90% of all cancer deaths, he said.
Using TIL therapy for other cancers besides metastatic melanoma requires additional work. With melanoma, any TILs extracted from the tumor will work to fight the cancer. For other cancers, however, the approach doesn’t work unless cells are selected that recognize the cancer, he said.
Dr. George Coukos, an oncologist at the Lausanne University Hospital and the Ludwig Institute for Cancer Research in Switzerland, said in an email that there’s early evidence that TIL therapy may also work against other tumors, including lung cancer, as well as cancers caused by HPV (human papillomavirus), which include cervical cancer and anal cancer.
Iovance Biotherapeutics is also investigating TIL therapy for these cancers, according to Saunders. Other researchers and companies are also working on TIL therapy products, she said.
In Hwu's lab at the Moffitt Cancer Center, researchers continue to study TIL.
"I think we could potentially, in the long run, grow TIL out of almost any tumor type, he said. "And the reason we're studying it so hard in my lab is that TIL therapy will be a game-changer for many kinds of cancers."
Hawley, from Florida, said he would be dead if not for TIL therapy. He had the treatment in December 2018. His melanoma tumors shrank for about two years, he said. In 2021, he noticed another growth — one that his surgeon was able to cut out completely.
“They said, as far as we could see, we got it, we got it all,” he said.
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