Lifileucel and tumour-infiltrating lymphocyte therapy
Amtagvi; LN-144; tumour-infiltrating lymphocyte therapy; adoptive cell transfer; TIL therapy
Lifileucel is the first FDA-approved (February 2024) autologous tumour-infiltrating lymphocyte (TIL) cell therapy for advanced melanoma — a substantial milestone in immuno-oncology. The therapy involves surgical resection of a metastasis, isolation and ex-vivo expansion of patient-specific tumour-infiltrating T cells over 22 days at a centralised manufacturing facility, then lymphodepleting chemotherapy followed by reinfusion of the expanded TIL product alongside high-dose IL-2 support. The C-144-01 pivotal study (Chesney et al., JCO 2022) reported objective response rates of 31–35% in patients with melanoma refractory to anti-PD-1 ± anti-CTLA-4 therapy, with durable responses including some complete responses lasting > 3 years. UK access is currently limited to specialist centres and clinical trials; NICE evaluation is anticipated.
Mechanism and manufacture
- Resection of a melanoma metastasis (1.5 cm³ minimum tumour tissue) — typically lymph node, subcutaneous nodule, or visceral metastasis.
- Tumour fragmented and TILs isolated; expanded ex vivo over 22 days with IL-2 and feeder cells; generates ~ 10¹⁰ polyclonal T cells.
- Patient receives 5–7 days of lymphodepleting chemotherapy (cyclophosphamide + fludarabine) — depletes regulatory T cells and creates immunological "space".
- Single infusion of the autologous expanded TIL product followed by 6 doses of high-dose IL-2 (every 8–12 hours) to support TIL survival.
- The therapy is patient-specific; each product is a one-off custom-manufactured cellular medicine.
Evidence
- C-144-01 (phase 2) — Chesney et al., J Clin Oncol 2022. 153 patients with advanced melanoma after progression on anti-PD-1 ± anti-CTLA-4 ± BRAF / MEK targeted therapy.
- Objective response rate 31–35%.
- Median duration of response not reached (some > 3 years).
- Complete response 5–8%.
- FDA accelerated approval February 2024.
- European Medicines Agency under evaluation; UK NICE expected to follow.
- Ongoing trials — TILVANCE-301 tests lifileucel plus pembrolizumab versus pembrolizumab monotherapy in untreated unresectable / metastatic melanoma; other combinations with PD-1 inhibitors are under study.
Patient selection
- Advanced melanoma with progression on prior anti-PD-1 (with or without anti-CTLA-4); BRAF-mutant patients also requiring prior BRAF / MEK exposure.
- Resectable metastasis suitable for TIL harvest (minimum 1.5 cm³ tumour required).
- Adequate organ function for lymphodepleting chemotherapy and high-dose IL-2 (cardiac, pulmonary, renal).
- ECOG performance status 0–1.
- Life expectancy ≥ 3 months — manufacturing takes ~ 4 weeks, then administration ~ 3 weeks of hospitalisation.
- Brain metastases — controlled disease only; active CNS disease excluded in pivotal trial.
Toxicities
- Toxicity profile is dominated by lymphodepletion and IL-2 support, not the TILs themselves.
- Lymphodepleting chemotherapy — pancytopenia, infection risk, gastrointestinal toxicity.
- High-dose IL-2 — capillary leak syndrome, hypotension, hypoxia, acute kidney injury, cytokine release, neurological toxicity.
- TIL-related — fever, fatigue, transient cytopenia.
- Treatment delivered in specialist cell-therapy centres with intensive-care backup.
- Mortality ~ 1–3% in pivotal trials — comparable to allogeneic stem-cell transplantation.
UK access
- Not yet routinely commissioned by NICE; specialist trial and compassionate-use access only.
- UK centres with TIL therapy infrastructure — small number of cell-therapy units linked to advanced melanoma services.
- Patient referral pathway — discuss with regional melanoma MDT for eligibility.
- Cost — substantial (US list price ~ $515,000 per course); future UK access depends on NICE health-economic assessment.
References
- Chesney J et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitor and targeted therapies — C-144-01. J Clin Oncol; 2022.
- Rohaan MW et al. Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma (M14TIL). N Engl J Med; 2022.
- FDA approval of lifileucel (Amtagvi) for advanced melanoma; February 2024.
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