A Closer Look at the Multidisciplinary Process of TILs for Melanoma

Tumor-infiltrating lymphocyte (TIL) therapy has been pursued as a treatment approach for decades, culminating in the 2024 approval of lifileucel (Amtagvi) for patients with previously treated metastatic melanoma. By harvesting immune cells that are able to recognize and target cancer from within the tumor, then expanding and reintroducing them to the body, TIL therapy has shown successful outcomes in patients with few other effective options available.

The process of TIL therapy is complex and requires the coordination of multiple specialties at authorized treatment centers, as well as the manufacturer, to be administered successfully. This means it can be limited by logistical limitations, but treatment centers have worked to perfect the process over several years and overcome these barriers to ensure patients can receive these crucial treatments.

“It truly is a multidisciplinary treatment that requires complex coordination and integration of care, but it offers a lifeline to patients where you can provide people hope even when everything else has failed,” said Andrew Poklepovic, MD, professor of internal medicine at Virginia Commonwealth University (VCU) and associate director for clinical research at VCU Massey Comprehensive Cancer Center in Richmond, Virginia.

Targeted Oncology spoke to Poklepovic and other physicians at Massey who manage the process of harvesting and infusing TILs to learn how TILs moved from clinical trials into practice and what each specialty contributes to delivering this therapy successfully.

The Long Journey of TILs

First developed in the 1980s by Steven Rosenberg, MD, and his colleagues at the National Cancer Institute’s Surgery Branch, TIL therapy took many years to be successfully optimized and refined for use in melanoma and other cancers.¹

“By surgically removing a tumor and removing the immune cells that are inside that tumor, you can take away all of the signaling that happens in the body that makes T cells ineffective at fighting cancer naturally inside the body,” said Benjamin Schmidt, MD, assistant professor at VCU and a surgical oncologist specializing in cutaneous malignancies. “With support in the laboratory, you can regrow those T cells so that you can then give them back to the patient as an effective therapy for cancer.”

The C-144-01 trial (NCT02360579) confirmed the efficacy of Iovance Biotherapeutics’ lifileucel,² leading to its FDA approval in February 2024 for patients with unresectable or metastatic melanoma previously treated with an immune checkpoint inhibitor and appropriate targeted therapies depending on their BRAF mutation status.³

Determining the correct parameters and preparation for the use of TILs in conjunction with IL-2 was crucial to getting TIL therapy to clinics, Poklepovic explained. By achieving this, the researchers “have been able to set the paradigm that this is not just an effective treatment, but one that can be borne out across a nation, not just in a single location.” The logistical obstacles that needed to be overcome speak to the complexity of the process, Poklepovic said.

Examining TIL Logistics

Patients with advanced melanoma are typically referred for TIL therapy by a medical oncologist who considers them a candidate. At Massey, the only authorized center in the state, patients are referred from oncologists throughout the region in addition to its own physicians. Requirements for candidacy include good cardiopulmonary function and performance status, as well as an accessible surgical site from which cells can be harvested from the tumor.

Poklepovic described patients with refractory metastatic melanoma as facing a "race against time," making it vital to coordinate this process to avoid any unnecessary delays. Sneha Purvey, MD, oncologist and solid tumor attending physician at Massey’s Cellular Immunotherapies and Transplant Program, said the time factor is a key issue, and patients will often require bridging therapy. Because insurance authorization can be difficult due to the expense of lifileucel, Massey has coordinators dedicated to obtaining authorizations so the process can move forward smoothly.

At a tumor board attended by cutaneous medical oncologists, surgical oncologists, and cellular therapy specialists, the cases are reviewed, and parallel assessments with a surgeon and the cellular therapy team are set up. At the same time that the surgeon is meeting with the patient to determine the harvest site, various tests that need to be done preinfusion are performed, and insurance logistics are being resolved. The surgery to harvest cells must also align with the availability of a slot for the expansion of cells into the usable cellular therapy product by the manufacturer, which also has a hands-on role.

Once the tumor cells are harvested by a surgeon like Schmidt, it takes up to 31 days to produce the expanded TIL product off-site at the company’s facility, according to Purvey. During this time, she works with a cardio-oncologist for pretesting that includes echocardiograms and pulmonary function tests to ensure patients can tolerate lymphodepleting chemotherapy and IL-2 infusions.

Patients receive 7 days of lymphodepleting chemotherapy and up to 6 doses of IL-2 over the course of 3 to 5 days, along with the infusion of lifileucel, and are then discharged to the medical oncologist for follow-up monitoring.⁴ The majority of adverse events are associated with the lymphodepletion and IL-2 rather than the TIL infusion itself.

Surgery’s Unique Role

The need for surgical harvesting of tumors adds an additional complication for TIL therapy compared with T-cell therapies, where donor cells are drawn from the blood. Schmidt said that he looks at a PET scan or other imaging to determine the target lesion, and choosing the optimal lesion can be the key to success.

“Surgery is generally a critical but small part of the process, and given everything else that the patient goes through, making surgery as safe and quick and easy to recover from is very important,” he said. The ideal target lesion is between 1 cm and 4 cm and is preferably not in the muscle or in deep places like the inside of the chest or abdomen. Schmidt has successfully procured tissue from liver and lung lesions, sometimes with the help of other surgeons, but skin and lymph node targets are preferable.

Typically, the surgery is uneventful and recovery is rapid, but the risks involved can jeopardize the rest of the process. A highly necrotic tumor may not yield viable lymphocytes, and a failed TIL expansion will cause treatment delays that the patient can’t afford. Bacterial infection can occur, particularly in open wounds or with surgical sites near the gastrointestinal tract, and surgery at a lung site could result in a reduced lung reserve that could make IL-2 administration dangerous.

Because the lymphodepletion weakens the immune system for 7 days, any open wound would get in the way of starting the infusion process, Purvey stressed. The surgery must also not interfere with the bridging therapy that enables patients to receive the TIL. “We cannot start the process if the excision site or wound [in the] tumor harvest site is not healed,” she said.

Adapting to Real-World Experience

The Massey team has worked with TILs for several years, participating in some of the pivotal clinical trials that led to lifileucel’s FDA approval. They have used TILs not only in refractory melanoma but also in trials of frontline melanoma and lung cancer. Poklepovic said their program’s past experiences, such as separate use of IL-2, using autologous TILs without expansion, and harvesting TILs before disease progression, have given them familiarity with the challenges and logistics of employing TILs in different ways.

In clinical trials, Poklepovic explained, there are more minutiae that need to be observed to maintain data consistency, such as less flexibility in the timing of administration vs real-world use, but generally, the clinical approach is the same. Schmidt reflected that wider use of PET scans during site selection has contributed greatly to his confidence in finding the best possible tumor site to ensure the TILs can be expanded.

Patients with symptomatic or uncontrolled central nervous system (CNS) metastases, who were excluded from trials, are a case where more data need to be collected post approval. “The moment something is FDA approved, you run into scenarios that may not have been eligible for clinical trials,” Poklepovic said. One of the major concerns was that high-dose IL-2 could lead to cerebral edema and bleeding in patients with CNS metastases. However, Purvey said they have given lifileucel to 2 patients with CNS metastases that were controlled with stereotactic radiosurgery and low-dose steroids, and treatment was successful with no swelling or bleeding.

Geographic Barriers to Access

With the multiple steps to receiving TILs and only a limited number of authorized treatment centers, some patients face barriers to access for lifileucel. Those referred to a site like Massey from longer distances may not be able to travel multiple times for tumor harvesting, pretesting, infusion, and other important visits, or be able to remain at the treatment center for postinfusion care and monitoring after treatment. Patients are encouraged to remain near the treatment center for a period of time, which can vary depending on institutional guidelines and the patient's fitness. Most adverse events were reported in the first 14 days of therapy.^2,5

Purvey said that Massey’s social workers can arrange for temporary accommodations during pretesting and surgical procurement from The Doorways, a philanthropic service in Richmond that provides temporary lodging and support for patients and their families. Some insurance providers may also cover nearby patient accommodations at the site, within a 30-minute driving distance.

“We recognize that we're the only center in Virginia, and patients are driving potentially very long distances to come for this procurement that is otherwise...just a 30- or 45-minute procedure,” Schmidt said. “Having places like Doorways where patients can stay the night before and stay the night after surgery so that they're nearby…in the rare event that anything happened and we can do more checks, [has] been a really wonderful part of our program.”

Making use of satellite sites outside of Richmond has also reduced the burden on patients. Purvey said that several other VCU locations, between 1 and 2 hours’ drive, let local patients see an oncologist and have pretesting and laboratory work done remotely, which is more convenient for them. Schmidt said that initial surgery consultations can often be conducted closer to patients, as well as from VCU outreach locations, thereby avoiding unnecessary travel.

Potential Growth of TILs

Lifileucel is being investigated beyond the relapsed melanoma setting, such as in a phase 3 study (IOV-MEL-301; NCT05727904) comparing lifileucel plus pembrolizumab (Keytruda) vs pembrolizumab alone in the first line. Early-phase trials are being done in melanoma in the adjuvant and neoadjuvant settings and in those with brain metastases. Outside of skin cancers, it has shown promise in metastatic non–small cell lung cancer, where it yielded a 21.4% overall response rate in 28 patients with heavily pretreated disease.⁶

Considering the complexity of the procedure, Poklepovic said it is likely that lifileucel will remain available only at tertiary referral centers with multiple specialties that can coordinate together. Nevertheless, it fills a crucial role in patients who have already exhausted the best available frontline therapies. “At the beginning of my career, [these patients] had a [median] survival of 6 months, and…what we're able to do with another form of therapy beyond checkpoint inhibitors and targeted therapy is providing that much more hope and opportunity for patients to survive this disease,” he said. “It's remarkable to see what we've been able to accomplish when we all work together.”

REFERENCES

1. Phillips C. First cancer TIL therapy gets FDA approval for advanced melanoma. National Cancer Institute. March 5, 2024. Accessed November 14, 2025. https://tinyurl.com/5a6fvets

2. Chesney J, Lewis KD, Kluger H, et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer. 2022;10(12):e005755. doi:10.1136/jitc-2022-005755

3. FDA grants accelerated approval to lifileucel for unresectable or metastatic melanoma. FDA. February 16, 2024. Accessed November 14, 2025. https://tinyurl.com/3nsdw54h

4. Amtagvi. Prescribing information. Iovance Biotherapeutics; 2024. Accessed November 14, 2025. https://www.fda.gov/media/176417/download

5. Betof Warner A, Hamid O, Komanduri K, et al. Expert consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. J Immunother Cancer. 2024;12(2):e008735. doi:10.1136/jitc-2023-008735

6. Schoenfeld AJ, Lee SM, Doger de Spéville B, et al. Lifileucel, an autologous tumor-infiltrating lymphocyte monotherapy, in patients with advanced non-small cell lung cancer resistant to immune checkpoint inhibitors. Cancer Discov. 2024;14(8):1389-1402. doi:10.1158/2159-8290.CD-23-1334