What is TIL (tumor-infiltrating lymphocyte) therapy?
Tumor-infiltrating lymphocyte, or TIL, therapy uses a patient’s own immune system T cells to fight cancer. The therapy involves removing T cells from a piece of the patient’s tumor – where the T cells have congregated after being alerted to the cancer – growing them outside the body, then re-infusing them by the billions to attack the disease.
In early 2024, TIL therapy achieved an important milestone when the Food and Drug Administration approved it, for the first time, as a cancer treatment. The approval is specifically for the treatment of advanced melanoma that doesn’t respond to certain immunotherapy drugs or targeted agents. Researchers are currently conducting clinical trials to learn if TIL therapy can also be effective against other solid tumors such as advanced lung cancer and cervical cancer.
What is special about TILs?
T lymphocytes, or T cells, are an important part of the immune system’s defense against infections and cancer. However, many T cells don’t make their way out of the bloodstream and into the tumor, where they can attack cancer cells.
When specimens of patients’ tumors are examined under a microscope, they often show an accumulation, or infiltration, of T cells actively fighting the cancer. They are like battle-hardened soldiers that have recognized the tumor cells, made 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 better outcomes. Therefore, researchers have sought to harness infiltrating T cells as therapy.
Infiltrating 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 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 treatment for the patient,” he says.
How does TIL therapy work?
The process begins with the removal of a small section of tumor tissue and extraction of TILs. The cells are then grown outside the patient to create an army of T cells 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 interleukin-2 (IL-2). Over a period of weeks, the TILs proliferate and the tumor cells die off, producing billions of TILs that are familiar with 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 cells that suppress the immune system. The patient is then infused with the TILs and is given IL-2, which stimulates the growth of TILs within the body. Ideally, the TILs will then 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.
What’s the latest in TILs research?
Researchers at Dana-Farber are currently conducting clinical trials of TILs for a range of cancer types. They include:
- A trial of a TIL therapy that uses TILs that have not been genetically modified. In this respect, it is like the TIL therapy approved by the FDA but involves a different process for preparing the TILs. The trial is open to patients with advanced melanoma, lung cancer, or head and neck cancer.
- A trial, expected to open for Dana-Farber patients when it reaches the next stage, of genetically modified TILs. These TILs are modified to produce interleukin-15, which spurs an immune response to cancer. The therapy represents an alternative to treating patients with IL-2, which can cause a range of side effects. In its current stage, the trial is for patients with advanced melanoma or lung cancer, but it may be expanded to other cancers in its next stage.
- A trial of a TIL therapy called LN-145 followed by IL-2 for patients with recurrent, metastatic, or persistent cervical cancer. Enrollment in this trial has closed.
Elizabeth Buchbinder, MD, a specialist in the Center for Melanoma Oncology at Dana-Farber, notes that some recent studies have reported response rates of 30-40% with TIL therapy in melanoma patients who had received several previous treatments.
“These are pretty impressive responses and encouraging for the hope that this will be an extra option for patients with advanced disease,” she says.
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.”