Sept. 23, 2025
Outside of clinical trials, there are limited treatment options for metastatic melanoma that has progressed after treatment with immune checkpoint inhibitors or targeted therapies if a BRAF mutation is present. Approximately 50% of patients with melanoma respond to approved first line therapies, and the response rate decreases with each additional therapy. But thanks to groundbreaking advances in precision medicine, Mayo Clinic offers patients with advanced melanoma another treatment option: tumor-infiltrating lymphocyte (TIL) therapy.
TIL therapy is a cellular immunotherapy that involves growing and activating a patient's own T cells to fight cancer. Lifileucel is the first and only TIL therapy approved for a solid tumor, specifically melanoma. Mayo Clinic has been administering lifileucel since its FDA approval in early 2024.
The approval was based in part on the results of a phase 2 multicenter study published in the Journal of Clinical Oncology. Participants had a mean of 3.3 prior therapies, and lifileucel demonstrated an overall response rate of 36% with durable responses.
"When compared to other second line immunotherapies for advanced melanoma, TIL therapy shows increased overall response rate, complete response rate, progression-free survival and overall survival," says James W. Jakub, M.D., a surgical oncologist at Mayo Clinic in Jacksonville, Florida. "But you need the capabilities to choose suitable candidates, harvest the appropriate cells and carry out every step of the treatment process safely. It requires an integrated multidisciplinary strategy, and there are a lot of nuances in the decision-making involved in TIL therapy."
How TIL therapy works to treat advanced melanoma
TIL therapy is like CAR-T cell therapy in that both use a patient's own immune cells. However, with TILs, there is no need to genetically modify the cells; they have already recognized and are fighting the tumor. They just need to grow in number.
"Lymphocytes — immune cells that are often found intermixed with cancer — are isolated in a lab, enriched to make billions of them and given back to the patient to fight the cancer," says Dr. Jakub. The process takes about three weeks.
The FDA requires production of a minimum volume of 7.5 billion TILs before administering the therapy to the patient. Reaching that volume depends on several factors, including the size of the tumor being surgically removed, the number of TILs in the specimen, how active the TILs are and the ability to keep the cells alive.
To support the infused cells and help them fight cancer, patients undergo neoadjuvant and adjuvant treatments:
- High-dose lymphodepleting chemotherapy, known as nonmyeloablative lymphodepletion, is administered before TIL therapy depletes immunosuppressive T-cells that might inhibit infused TILs.
- Interleukin-2 (IL-2) stimulates the growth and activity of the newly infused TILs.
The toxicity of these therapies is high. However, they play a critical role in the durable responses — both partial and complete — achieved with TIL therapy.
"It's been suggested that if TIL therapy is given earlier or there is a lower tumor burden, the efficacy may potentially be higher," says Dr. Jakub. "This is being investigated in trials."
Managing complications associated with TIL therapy
A phase 3 trial published in The New England Journal of Medicine reported grade 3 or higher treatment-related adverse events in 96.3% of patients receiving TIL. Of the 80 trial participants who received TIL therapy, 15% had serious adverse events and 10% required intensive care.
Complications associated with TIL therapy are caused by the lymphodepleting chemotherapy and IL-2. Chemotherapy intentionally wipes out white blood cells; almost all patients experience the effects of low cell count. The number of patients who experience toxicities from IL-2 is much lower.
"The good news is that essentially all of the toxicity occurs during the hospital stay, and it should reverse once treatment ends," says Dr. Jakub. "We have an expert ICU team that knows how to care for patients receiving toxic therapies. And knowing that these therapies are tough factors into the patient selection process for this treatment. Patients need to be able to endure two weeks of having their white cells depleted and tolerate IL-2."
Because TIL therapy involves surgery, patients should also be medically fit and pose a low risk of surgical complications.
"The surgery to remove a portion of the tumor does not improve the cancer outcome in any way," says Dr. Jakub. "If patients have complications related to surgery that ultimately prevent them from getting the TIL cell infusion, it is of zero benefit to them. We are selective because we want to make sure each patient gets the maximum benefit."
TIL therapy is intensive, but it is a one-time treatment — unlike chemotherapy or immunotherapy, which are often delivered for months and years.
Overcoming challenges and looking to the future with TIL therapy
While there are many positives associated with TIL therapy, there are still challenges to overcome, including:
- Availability limited to specialized centers.
- Durable response rate of 36% could be improved.
- Expense.
- High toxicity.
- Labor-intensive.
- Limited number of patients meet the criteria.
- Inconsistent T-cell production.
According to Dr. Jakub, the goals for TIL therapy are to include more patients, lessen toxicity and achieve a higher success rate. Ways to potentially accomplish these goals might include:
- Combining TIL therapy with other immunotherapies, such as CAR-T cell therapy.
- Modifying T cells to make them more robust and effective.
- Identifying alternatives to IL-2 to stimulate white blood cells without the significant cardiopulmonary fluid shifts that cause patients to stop therapy.
- Offering TIL therapy as a first line treatment.
"We have healthcare professionals at Mayo Clinic aggressively working on future developments that will potentially make TIL therapy less toxic and more effective," says Dr. Jakub. "Beyond that, the future will also hopefully involve expanding this therapy to other tumors."
For more information
Sarnaik AA, et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. Journal of Clinical Oncology. 2021;39:2656.
Rohaan MW, et al. Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma. The New England Journal of Medicine. 2022;387:2113.
Refer a patient to Mayo Clinic.