Navigating Interdisciplinary Care for Tumor-Infiltrating Lymphocyte Therapy in Melanoma

Tumor-infiltrating lymphocyte (TIL) immunotherapy is a cellular treatment that utilizes a patient’s immune cells to fight and kill cancer cells. Approved by the FDA in 2024, lifileucel (Amtagvi; Iovance Biotherapeutics, Inc) is the first autologous cellular therapy approved for a cancerous solid tumor, specifically in adult patients with unresectable or metastatic melanoma.

The approval filled a space that was previously unmet for metastatic melanoma patients after progression through immunotherapy.¹ However, the path to approval was challenging due to the treatment’s initially short-lived responses. Researchers explored TIL therapy for 3 decades, combining lymphodepletion (LD) prior to TIL administration with simplified culturing methods, before finally receiving approval.^2,3

What Is a TIL?

The body has 2 types of lymphocytes: T cells and B cells, which constantly patrol the body to identify and eliminate cells that should not be there. As cancer grows, certain T lymphocytes known as TILs recognize and directly penetrate abnormal tumor cells. Once in the tumor, TILs begin working to kill the cell from the inside out. Unfortunately, the body’s immune system does not produce enough TILs to eliminate tumors completely because of a hostile microenvironment that suppresses, exhausts, and destroys TILs. The idea behind TIL therapy is to actively collect TILs that already recognize malignant targets, multiply them ex vivo, and reinfuse them to amplify the immune response, with a focus on cancerous cells.^4-6

Coordination of Care

One major difficulty with TIL therapy is the extensive interdisciplinary coordination required for patients throughout treatment. Not only does medical oncology need to be involved, but also transplanters, surgeons, advanced practice practitioners, cellular therapy coordinators, melanoma coordinators, nurses, pharmacists, and social workers in both the inpatient and outpatient arenas. To date, there are approximately 80 authorized treatment centers (ATCs) in just 35 states, meaning many oncologists will have to refer patients to an ATC for treatment. Depending on the patient’s location, this could add additional coordination considerations, such as travel, room, and board, that patients may not be able to afford.⁷ Coordination challenges extend beyond locating and reaching an ATC—they span the entire patient journey from identification through cell infusion. There are 3 major steps a patient must complete once accepted by an ATC for possible TIL therapy, as follows:

1. Patient qualification
2. Metastasectomy
3. TIL administration process (lymphodepletion, TIL therapy, IL-2)

Patient Qualification

To be considered for treatment, a patient must have unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody and, if they are BRAF V600 positive, a BRAF inhibitor with or without a MEK inhibitor.¹ After establishing a patient's treatment history, other factors to consider include the patient’s ability to handle potential adverse effects (AEs) such as cytopenias, hemodynamic fluctuations, and fluid shifts, in addition to social considerations of time off from work, being away from family, and the potential need and cost of travel. Disease-specific factors include disease progression pace (manufacturing can take up to 60 days)⁶ and the tumor location. Currently, it is recommended that patients with untreated brain metastasis not be initially considered for TIL therapy due to the risk of intracranial bleeding.¹

Once treated and off systemic steroids without neurological symptoms and disease stability, patients can then be considered for TIL therapy. Additional qualifying parameters to consider include renal, cardiac, and pulmonary function. When determining medical and social eligibility, if the patient is considered a candidate, it is the responsibility of the medical oncologist and their support staff to coordinate a treatment-free 4-week interval before surgical resection, as the clinical efficacy of metastasectomy during active treatment is currently unknown.^6,8-10

Metastasectomy

Once a patient has been vetted through a multidisciplinary discussion and is considered eligible for TIL therapy, the surgical harvest of a malignant tumor, usually from a site of metastasis, is done. Ideally, tumor tissue procurement should be planned within 2 weeks of patient identification and a 4-week therapy break. TIL infusion products have been successfully manufactured using diverse metastasis sites, including skin, lymph nodes, subcutaneous tissue, lung, liver, spleen, peritoneum, musculoskeletal tissue, and breast. To date, no definitive evidence shows a specific metastatic site yielding higher response rates. A tumor sufficient to harvest must be at least 1.5 cm in its largest diameter, or it can be an aggregate of smaller lesions, with care taken to remove necrotic and fatty tissue. The goal is to procure sufficient tumor tissue in the least invasive manner, with minimal impact on healthy tissue. Outpatient procedures are the ideal scenario for tumor collection. Once harvested, TIL cells undergo activation and expansion, a process that can take 3 to 6 weeks. In some settings, due to the time required for activation and expansion and the patient’s disease pace, bridging therapy to control disease may be necessary with immunotherapy, chemotherapy, targeted therapy, or radiation.^6,8-10

Lymphodepletion

Once the tumor tissue is harvested, the cellular therapy team takes over to manage the TIL therapy infusion. Nonmyeloablative lymphodepleting chemotherapy is needed prior to the TIL infusion to prepare the patient’s tumor microenvironment. The goal of LD chemotherapy is to reduce T-cell competition and eliminate immunosuppressive cells. The LD chemotherapy regimen includes 2 doses of cyclophosphamide 60 mg/kg followed by 5 doses of fludarabine 25 mg/m² adjusted for renal function and body mass. Intravenous (IV) hydration, mesna (for uroprotection), and antiemetic prophylaxis should be administered pre- and post chemotherapy to help prevent treatment-related AEs.^6,8,9

Cytopenias are expected during and immediately following lymphodepletion, with lymphocyte recovery expected in the first 4 to 6 days after administration, and platelet and neutrophil counts approximately 1 week later. No IV contrast should be administered without physician approval, starting on the day of lymphodepletion, due to the high doses of chemotherapy that can affect renal function and IV contrast elimination. Patients should avoid IV contrast while receiving IL-2 due to an increased risk of allergic-like reactions. There is no clearly defined duration of how long post–IL-2 IV contrast sensitization persists. However, many centers follow a 4-week or day +30 post–TIL IV contrast-free period. In addition to IV contrast, patients are also advised to avoid systemic steroids immediately after TIL infusion, as these may mitigate immune responses. Unfortunately, some patients will experience persistent cytopenias for which transfusion support is required until count recovery is seen.

Granulocyte colony-stimulating factor is recommended at 5 mcg/kg/day the day after TIL therapy infusion and should be continued until the absolute neutrophil count (ANC) is at least 500/mm³. Antibiotic prophylaxis is also recommended at the onset of neutropenia and continued until the ANC is greater than 500/mm³. Pneumocystis prevention and antiviral prophylaxis are recommended at the start of lymphodepletion. Prophylactic prevention strategies may vary by treating institution; however, most continue antipneumocystis prophylaxis for at least 3 to 6 months and/or until CD4 counts exceed 200 cells/mm³, and antifungal and antibacterial prophylaxis until ANC exceeds 1000/mm³ or for at least 7 days after TIL therapy infusion.^6,8,9

TIL Infusion

TIL infusion should be performed 24 to 96 hours after the final LD chemotherapy dose. A minimum of 24 hours after the last dose allows for renal excretion of fludarabine, whereas a maximum of 96 hours ensures cell administration before the beginning of marrow recovery. TIL infusion should occur in the inpatient setting for appropriate critical care support if needed. Prophylactic premedication to reduce AEs consists of acetaminophen, diphenhydramine, and gentle hydration. Vital sign monitoring should be performed every 30 minutes during infusion, then hourly for 4 hours, and routinely thereafter for approximately 24 hours post TIL infusion. The goal is to avoid significant changes in volume status and keep patients euvolemic prior to IL-2 infusion to prevent capillary leak syndrome. Being more cautious about fluid overload and aggressive with diuresis is recommended.^6,8,9

IL-2 Administration

Administering IL-2 further supports the expansion and activity of TIL cells after infusion by stimulating T cells. As a result, the patient receives their first dose of IL-2 within 3 to 24 hours of cells, at 600,000 IU/kg, every 8 to 12 hours IV, for a maximum of 6 doses. Antihypertensives should be discontinued 24 hours prior to IL-2 administration to mitigate the risk of hypotension that is seen in 30% to 65% of patients. In addition to discontinuing antihypertensives, it is recommended to schedule proton pump inhibitors/H2 blockers for stress ulcer prophylaxis and a nonsteroidal anti-inflammatory drug (if the patient is a candidate) for inflammatory responses manifesting as arthralgias, myalgias, or body aches in conjunction with IL-2. Opioids can be prescribed as needed for rigors, and antiemetics can be prescribed for nausea or vomiting. Depending on the patient’s response, IL-2 can be held or discontinued at the treating clinician’s discretion at any time.^6,9

Currently, there is no clear correlation between the total number of IL-2 doses given and TIL cell therapy response. IL-2 post TIL infusion is intended to be T-cell supportive rather than directly therapeutic, serving as the primary growth factor for T-cell expansion and survival; however, patient tolerability is the rate-limiting step. If 24 hours elapse without significant recovery from adverse effects, IL-2 should be discontinued. Most patients receive 2 to 4 doses. Obtain vitals and monitor pulse oximetry every 4 hours after IL-2 administration, with the ability to shorten or extend the interval as needed. Weights and laboratory tests (complete blood count, complete metabolic panel) are performed at least daily, along with neurologic assessments, strict intake and output, and telemetry monitoring from the time of the lifileucel infusion to at least 24 hours after the last IL-2 dose.

Most AEs associated with TIL therapy and IL-2 administration are acute and transient, resolving before discharge, with peak effects occurring 4 hours after administration. Monitor for delayed toxicities, including elevated transaminases, elevated bilirubin, oliguria, and fatigue. Most toxicities observed will occur during the first 14 days of therapy when the patient is expected to be in an acute care setting. Once IL-2 is discontinued, it is recommended to stop IL-2 supportive medications (eg, pain, antinausea, and antipyretic scheduled doses) and related IL-2 monitoring. Antihypertensives can be resumed after IL-2 when clinically indicated, based on blood pressure readings, cardiovascular risk factors, and organ protection needs.^6,9

Discharge

Three milestones should be met prior to considering a TIL patient for discharge. Once a patient’s ANC is greater than 500/mm³ or trending that way for the next 24 hours, the patient has remained afebrile for 24 hours after stopping antibacterial and antifungal prophylaxis, and their platelets are greater than 20, then the patient is eligible for discharge. It is recommended that patients remain near the treatment center, within 30 to 50 miles (less than 1 hour away), for 30 days after TIL therapy. At that point, many patients will return to their local oncologist for routine follow-up and monitoring of disease progression.^8,9

Clinical Relevance

The pivotal, multicenter phase 2 C-144-01 clinical trial (NCT02360579) supported lifileucel’s FDA approval, which was over 30 years in the making. Five-year follow-up data were published in June 2025 in the Journal of Clinical Oncology.¹¹ The overall response rate was 31.4% at 5 years, with 5.9% of participants having a complete response and 25.5% a partial response. Overall survival (OS) at 5 years was 19.7%, with 41.7% of responders maintaining a response for 18 or more months. These numbers may not sound encouraging, but for patients with advanced melanoma who have progressed after immunotherapy, the expected median OS rate is generally poor, ranging from 6 to 16 months, with 2-year survival rates below 30%.^11,12

Future Directions

Iovance Biotherapeutics has started enrolling patients in trials for additional disease states, including advanced lung, ovarian, and head-and-neck cancers, as well as a combination trial for advanced melanoma using a PD-L1 inhibitor plus lifileucel. Not only are additional trials with lifileucel, the first-generation TIL, underway, but research is also underway to develop more potent TIL-based products for a broader range of solid tumors.² With the number of resources needed to get a patient from start to finish, any method of shortening inpatient stays or making TIL more accessible is also being evaluated, such as shortening the number of LD days and administering LD chemotherapy in an outpatient setting. Reducing toxicities is another focus, specifically examining IL-2 administration and its overall utility. Lastly, the manufacturing process is also being evaluated to streamline processes, reduce costs, and shorten turnaround time.^10,13

TIL therapy has been a step in the right direction for those with metastatic melanoma, offering a treatment option where there had been none. Despite its excitement, there are many logistical concerns, including the involvement of multiple disciplines in getting a patient from start to finish, patient social deterrents, and limited treatment facilities. In addition to logistics, overall tolerability for therapy-experienced patients is a worry, weighing the risks vs benefits of undergoing such procedures. Further research and time with the product will not only help with logistics, but also patient candidacy, affordability, and tolerability. The wave of the future is here for both solid and nonsolid cancers, with a new precision focus toward harnessing the immune system to self-attack cancerous tumors.

REFERENCES

1. Amtagvi. Prescribing information. Iovance Biotherapeutics, Inc; 2025. Accessed November 1, 2025. https://www.iovance.com/AMTAGVI_USPI/

2. Phillips C. First cancer TIL therapy gets FDA approval for advanced melanoma. National Cancer Institute. March 5, 2024. Accessed November 1, 2025. https://www.cancer.gov/news-events/cancer-currents-blog/2024/fda-amtagvi-til-therapy-melanoma

3. Pancholi NJ. TIL therapy: a new melanoma treatment 30 years in the making. American Association for Cancer Research. May 29, 2024. Accessed November 1, 2025. https://www.aacr.org/blog/2024/05/29/til-therapy-a-new-melanoma-treatment-30-years-in-the-making/

4. Zhao Y, Deng J, Rao S, et al. Tumor infiltrating lymphocyte (TIL) therapy for solid tumor treatment: progressions and challenges. Cancers (Basel). 2022;14(17):4160. doi:10.3390/cancers14174160

5. Matsueda S, Chen L, Li H, Yao H, Yu F. Recent clinical researches and technological development in TIL therapy. Cancer Immunol Immunother. 2024;73(11):232. doi:10.1007/s00262-024-03793-4

6. Turcotte S, Donia M, Gastman B, et al. Art of TIL immunotherapy: SITC’s perspective on demystifying a complex treatment. J Immunother Cancer. 2025;13(1):e010207. doi:10.1136/jitc-2024-010207

7. Find an AMTAGVI authorized treatment center. Amtagvi. Accessed November 1, 2025. https://www.amtagvi.com/support-and-resources/authorized-treatment-center

8. Ferguson KM, Telfort F, Gochett CG. Tumor-infiltrating lymphocyte therapy for melanoma: nursing considerations. Clin J Oncol Nurs. 2025;29(2):125-129. doi:10.1188/25.CJON.125-129

9. 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

10. Kirane A, Lee D, Ariyan C. Surgical considerations in tumor-infiltrating lymphocyte therapy: challenges and opportunities. Transplant Cell Ther. 2025;31(suppl 3):S591-S598. doi:10.1016/j.jtct.2024.11.015

11. Medina T, Chesney JA, Kluger HM, et al; C-144-01 Investigators. Long-term efficacy and safety of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in patients with advanced melanoma: a 5-year analysis of the C-144-01 study. J Clin Oncol. 2025;43(33):3565-3572. doi:10.1200/JCO-25-00765

12. Hu L, Fan C, Bross P, et al. FDA approval summary: lifileucel for unresectable or metastatic melanoma previously treated with an anti-PD-1-based immunotherapy. Clin Cancer Res. 2025;31(19):4004-4009. doi:10.1158/1078-0432.CCR-25-0880

13. Krishnamurthy A. Looking ahead with TIl therapy in melanoma and beyond. Targeted Oncology. May 24, 2025. Accessed November 1, 2025. https://www.targetedonc.com/view/looking-ahead-with-til-therapy-in-melanoma-and-beyond