A form of immune cell therapy for cancer known as tumor infiltrating lymphocyte, or TIL, therapy, involves removing immune T cells from a piece of the patient’s tumor — where the T cells have succeeded in recognizing the cancer — expanding them outside the body, and re-infusing them by the billions to fight the disease.
TILs have shown promise in early clinical trials against advanced melanoma, lung cancer, and cervical cancer – solid tumors that aren’t yet effectively treated by another form of immune cell therapy, CAR T cells. TILs haven’t yet been approved for routine clinical use, but approval for at least one application, in melanoma, may not be far off.
What is special about TILs?
T lymphocytes, or T cells, are an important arm of the immune system defense against infections and cancer. However, many T cells that the immune system directs to attack the tumor don’t make their way out of the bloodstream and successfully penetrate the tumor’s defenses to attack the cancer cells.
It’s been long known that when specimens of some patients’ tumors are examined by pathologists, they show an accumulation, or infiltration, of T cells that are actively fighting the cancer. They are like battle-hardened soldiers that have recognized the tumor cells, fought their way through the stroma (connective tissue and blood vessels) surrounding the tumor, and unleashed their killing power against the cancer.
Patients with T-cell-rich infiltrates in their tumors often have a better outcome. Therefore, in the past 20 years research has been aimed at harnessing these T cells — the infiltrating lymphocytes — as therapy.
These T cells “are a population that has recognized the cancer, so the idea is that if we can remove them and prime them outside the body to engage them against the cancer, when they are reinfused into the patient, hopefully we will see an antitumor response,” says Mark Awad, MD, PhD, clinical director of the Lowe Center for Thoracic Oncology at Dana-Farber.
“There is a lot of interest, but it is a challenging regimen for the patient,” he says.
How does TIL therapy work?
The process involves taking a biopsy sample and removing the TILs from the tumor and growing them outside the patient to create an army of T cells already primed to recognize and attack the cancer when given back to the patient.
In a laboratory, the tumor sample is broken up into fragments, which are placed in a growth medium containing a cytokine, interleukin-2 (IL-2). Over a period of weeks, the TILs proliferate, and the tumor cells die off, producing billions of TILs that already recognize the patient’s cancer because they were harvested from it.
Once the TILs are ready to be deployed against the cancer, the patient undergoes a short course of chemotherapy to deplete the body of immunosuppressive immune cells. The patient is then infused with the TILs and is given IL-2, which stimulates the growth of TILs within the body. The TILs then ideally attack and kill the cancer cells.
One advantage of TIL therapy is that it is usually carried out only once, but there is the possibility of additional treatment if a patient has benefited but later needs to undergo treatment again.
TILs therapy “takes a big effort,” says Ursula Matulonis, MD, chief of the Division of Gynecologic Oncology at Dana-Farber. “You need a surgical team and a patient whose tumor is stable so they can wait a period of time — several weeks — to get the TILs product back and give it to them.”
What’s the latest in TILs research?
Promising preliminary data with TILs in lung cancer has been reported, and plans are to open a TILs trial in lung cancer at Dana-Farber in the near future, starting with a small number of patients.
Two clinical trials of TILs in cervical cancer have also opened at Dana-Farber. Matulonis says that advanced cervical cancer hasn’t responded very well to the more established form of immunotherapy, checkpoint inhibitors, which remove the molecular brakes that allow cancer cells to escape the immune T cell response. Response rates with these drugs have been in the range of 14 to 15%. She says. But some early studies using TILs to treat cervical cancer have had “response rates higher than you’d expect — in the 40% range. But what is the duration of that response? Is it curative? At this point we don’t know.”
Elizabeth Buchbinder, MD, a specialist in the Center for Melanoma Oncology at Dana-Farber, notes that some recent studies have reported response rates of 40 percent with TIL therapy in melanoma patients who had received several previous treatments.
“These are pretty impressive responses and encouraging for the hope that this may be an extra option” for patients with advanced disease, she says.
Use of TIL therapy for melanoma might start within three to six months at Dana-Farber, she says, as there is an application for approval of one TIL therapy pending before the U.S. Food and Drug Administration.
A renewed effort
Scientists have spent decades trying to harness TILs to fight cancer, but their use has been limited, in part because of the lengthy and expensive process required to manufacture them. However, there is new energy in the field as biotech companies have gotten into the game, providing the laboratory infrastructures for creating therapeutic TILs.
TIL therapy was pioneered at the National Institutes of Health, where it achieved some impressive responses in patients with melanoma, but because of side effects and the cumbersome process of manufacturing TILs, widespread application slowed.
“I think some people say, we tried this long ago, and what’s the difference now?” says Awad. “In part, the immunotherapy revolution brought about by checkpoint inhibitors has renewed immunologic approaches in treating cancer. And the hope is with improved understanding of immune cell phenotypes, and better supportive care to get patients through the conditioning regimen, these kinds of approaches will be safer and better tolerated.”